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    Journal of Molecular Neuroscience

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    ClC-2-like Chloride Current Alterations in a Cell Model of Spinal and Bulbar Muscular Atrophy, a Polyglutamine Disease

    Abstract

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by expansions of a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. SBMA is associated with the progressive loss of lower motor neurons, together with muscle weakness and atrophy. PolyQ-AR is converted to a toxic species upon binding to its natural ligands, testosterone, and dihydrotestosterone (DHT). Our previous patch-clamp studies on a motor neuron-derived cell model of SBMA showed alterations in voltage-gated ion currents. Here, we identified and characterized chloride currents most likely belonging to the chloride channel-2 (ClC-2) subfamily, which showed significantly increased amplitudes in the SBMA cells. The treatment with the pituitary adenylyl cyclase-activating polypeptide (PACAP), a neuropeptide with a proven protective effect in a mouse model of SBMA, recovered chloride channel current alterations in SBMA cells. These observations suggest that the CIC-2 currents are affected in SBMA, an alteration that may contribute and potentially determine the pathophysiology of the disease.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Identification of Key Genes and Pathways in Mouse Spinal Cord Involved in ddC-Induced Neuropathic Pain by Transcriptome Sequencing

    Abstract

    Highly active antiretroviral therapy (HAART) works effectively in inhibiting HIV replication in patients. However, the use of nucleoside reverse transcriptase inhibitors (NRTIs) often causes side effects of neuropathic pain, and its mechanism remains to be elucidated. Therefore, we aim to explore the mechanism of NRTIs-induced neuropathic pain at the transcriptome level. C57BL/6 J mice were given intraperitoneal injection of zalcitabine (ddC) or saline (control) for 2 weeks, during which the mechanical pain threshold of the mice was detected by von Frey test. Then the L3~L5 spinal segments of the mice were isolated and subsequently used for RNA sequencing (RNA-seq) on the last day of treatment. The mechanical pain threshold of mice given ddC decreased significantly. Compared with the control group, ddC caused significant changes in the expression of 135 genes, of which 66 upregulated and 69 downregulated. Enrichment analysis showed that the functions of these genes are mainly enriched in regulation of transcription, multicellular organism development, and cell differentiation, and the pathway is mainly enriched in the cGMP-PKG signaling pathway and AMPK signaling pathway. Furthermore, key genes such as Gabrd, Kcnd3, Npcd, Insr, Lypd6, Scd2, and Mef2d were also identified. These may serve as drug targets for the prevention or treatment of NRTI-induced neuropathic pain.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    The Effect of Optogenetic Inhibition of the Anterior Cingulate Cortex in Neuropathic Pain Following Sciatic Nerve Injury

    Abstract

    Cortical disinhibition is the underlying pathological alteration contributing to neuropathic pain associated with peripheral nerve injury. Nerve injury resulting in disinhibition of the anterior cingulate cortex has been reported. However, the effect of optogenetic inhibition of the anterior cingulate cortex (ACC) on the sensory component of nerve injury–induced neuropathic pain has not been well studied. To investigate the feasibility of optogenetic ACC modulation, we injected an optogenetic virus or a null virus into the ACC of a nerve injury–induced neuropathic pain model. The unilateral ACC was modulated, and the optogenetic effect was measured by mechanical and thermal sensitivity tests. The assessment was performed in “pre—light off,” “stimulation—yellow light on,” and “post—light off” states. Optogenetic inhibition of the ACC in injury models revealed improved mechanical and thermal latencies with profound pain-relieving effects against nerve injury–induced neuropathic pain. The sensory thalamic discharge in electrophysiological in vivo recordings was also altered during laser stimulation. This finding indicates that hyperactivity of the ACC in nerve injury increases output to the spinothalamic tract through direct or indirect pathways. The direct photoinhibition of ACC neurons could play a vital role in restoring equilibrium and provide novel insight into techniques that can assuage peripheral nerve injury–induced neuropathic pain.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Cadaverine and Spermine Elicit Ca 2+ Uptake in Human CP Cells via a Trace Amine-Associated Receptor 1 Dependent Pathway

    Abstract

    The choroid plexus (CP) constitutes a barrier between the blood and the cerebrospinal fluid (CSF) which regulates the exchange of substances between these two fluids through mechanisms that are not completely understood. Polyamines as spermine, spermidine and putrescine are produced by all cells and are present in the CSF. Interestingly, their levels are altered in some neuronal disorders as Alzheimer’s and Parkinson’s diseases, thus increasing the interest in their signalling in the central nervous system (CNS). Cadaverine, on the other hand, is synthetized by the intestinal microbiome, suggesting that the presence of this bacterial metabolite in the CSF requires that it is up taken to the CNS across brain barriers. We knew that polyamines are detected by the olfactory signalling cascade operating at the CP, but the receptor involved had not been identified. The zebrafish TAAR13c was the only receptor known to bind a polyamine-cadaverine. Thus, we searched for a human receptor with homology to TAAR13c and found that some human TAARs including TAAR1 showed great homology. Then, we confirmed the expression of TAAR1 mRNA and protein in a human cell line of the CP, and in human CP samples. Calcium imaging assays after TAAR1 knockdown in these cells with a specific siRNA against TAAR1 showed a consistent reduction in the responses of these cells to cadaverine and spermidine, but not to spermine, suggesting that TAAR1 is activated by cadaverine and spermidine, but not spermine.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Different Activation of IL-10 in the Hippocampus and Prefrontal Cortex During Neurodegeneration Caused by Trimethyltin Chloride

    Abstract

    Anti-inflammatory cytokine interleukin-10 (IL-10) plays a crucial role in controlling the resolution of inflammation. In this study, we aimed to assess gene expression and the level of IL-10 in the hippocampus and prefrontal cortex of rats, after a single injection of neurotoxicant trimethyltin chloride (TMT). It was shown that 4 weeks after the treatment with TMT, the level of IL-10 in the prefrontal cortex, but not in the hippocampus of TMT-treated rats, was increased. However, expression level of IL-10 mRNA was upregulated both in the hippocampus and in the prefrontal cortex 3 weeks after the injection. Concomitantly, within the same post-treatment period, the expression level of the cyclooxygenase-2 was upregulated in both brain structures, indicating the induction of neuroinflammation. Considering that TMT leads to the death of neurons mainly in the hippocampus, we assume that in contrast to the prefrontal cortex, the level of anti-inflammatory cytokine IL-10 in the hippocampus is not sufficiently increased to prevent the damaging effect of the neurotoxicant. Therefore, an exogenous increase in the level of IL-10 may be useful for the survival of neurons in conditions of neurotoxic damage to the hippocampus.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    A Novel CREBBP in-Frame Deletion Variant in a Chinese Girl with Atypical Rubinstein–Taybi Syndrome Phenotypes

    Abstract

    Loss-of-function variants in CREBBP or EP300 result in Rubinstein–Taybi syndrome (RSTS). The previously reported cluster of variants in the last part of exon 30 and the beginning of exon 31 of CREBBP, overlapping with the ZNF2 (zinc finger, ZZ-type; residues 1701 to 1744) and ZNF3 (zinc finger, TAZ-type; residues 1764 to 1853) domains, is associated with atypical RSTS. The main features include developmental delay, short stature, microcephaly, distinctive facial features, autistic behavior, feeding difficulties, recurrent upper airway infections, and hearing impairment. Here, we report a 2-year-7-month-old Chinese girl presenting mild cognitive impairments, developmental delay, short stature, recurrent upper airway infections, and facial dysmorphism that resembled the phenotypes of previously reported atypical RSTS patients. The characteristic facial and limb dysmorphism for RSTS was absent in our patient. In addition, our patient exhibited novel phenotypes including attention deficit hyperactivity disorder (ADHD), sleep problem, and abnormal walking posture. Whole-exome sequencing (WES) identified a novel de novo in-frame deletion variant in the beginning of exon 30 of CREBBP (NM_004380:c.4897_4899delTTC, p.Phe1633del) in the HAT domain where no pathogenic variants have been previously reported to be responsible for atypical RSTS. Our case allows us to more accurately define the borders of the CREBBP coding sequence resulting in atypical RSTS, which are extended to the beginning of exon 30 (residue 1633) at the 5′ end of CREBBP in the HAT domain, and reveals novel phenotypes observed in our atypical Chinese RSTS patient.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    KLF4 Exerts Sedative Effects in Pentobarbital-Treated Mice

    Abstract

    KLF4 is a zinc-finger transcription factor that plays an essential role in many biological processes, including neuroinflammation, neuron regeneration, cell proliferation, and apoptosis. Through effects on these processes, KLF4 has likely roles in Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. However, little is known about the role of KLF4 in more immediate behavioral processes that similarly depend upon broad changes in brain excitability, such as the sleep process. Here, behavioral approaches, western blot, and immunohistochemical experiments were used to explore the role of KLF4 on sedation and the potential mechanisms of those effects. The results showed that overexpression of KLF4 prolonged loss of righting reflex (LORR) duration in pentobarbital-treated mice and increased c-Fos expression in the lateral hypothalamus (LH) and the ventrolateral preoptic nucleus (VLPO), while it decreased c-Fos expression in the tuberomammillary nucleus (TMN). Moreover, overexpression of KLF4 reduced the expression of p53 in the hypothalamus and increased the expression of STAT3 in the hypothalamus. Therefore, these results suggest that KLF4 exerts sedative effects through the regulation of p53 and STAT3 expression, and it indicates a role of KLF4 ligands in the treatment of sleep disorders.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Microtubule Stabilization Promotes Microcirculation Reconstruction After Spinal Cord Injury

    Abstract

    Spinal cord microcirculation plays an important role in maintaining the function of spinal cord neurons and other cells. Previous studies have largely focused on the ability of microtubule stabilization to inhibit the fibroblast migration and promote axon regeneration after spinal cord injury (SCI). However, the effect of microtubule stabilization treatment on microcirculation reconstruction after SCI remains unclear. By using immunofluorescence, we found that microtubule stabilization treatment improved microcirculation reconstruction via increasing the number of microvessels, pericytes, and the perfused microvessels after SCI. To clarify the underlying mechanisms, rat brain microvascular endothelial cells and pericytes were subjected to glucose oxygen deprivation. By using flow cytometry and western blotting, we found that microtubule stabilization treatment inhibited apoptosis and migration of endothelial cells and pericytes but promoted proliferation and survival of endothelial cells and pericytes through upregulated expression of vascular endothelial growth factor A (VEGFA), VEGF receptor 2, platelet-derived growth factor-B (PDGFB), PDGF receptor β, and angiopoietin-1 after SCI. Taken together, this study provides evidence for the mechanisms underlying the promotion of microcirculation reconstruction after SCI by microtubule stabilization treatment. Importantly, this study suggests the potential of microtubule stabilization as a therapeutic target to reduce microcirculation dysfunction after SCI in the clinic.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Robust Dopaminergic Differentiation and Enhanced LPS-Induced Neuroinflammatory Response in Serum-Deprived Human SH-SY5Y Cells: Implication for Parkinson’s Disease

    Abstract

    Parkinson’s disease (PD) is a chronic neurodegenerative condition characterized by motor symptoms such as bradykinesia, resting tremor, and rigidity. PD diagnosis is based on medical history, review of signs, symptoms, neurological and physical examinations. Unfortunately, by the time the disease is diagnosed, dopamine (DA) neuronal loss is often extended, thereby resulting in ineffective therapies. Recent evidence suggests that neuroinflammation may be pivotal during PD onset and progression. However, suitable cellular models and biomarkers to detect early signs of neuroinflammation are still missing. In this study, we developed a well-differentiated DAergic neuronal cell line where we triggered a neuroinflammatory response to assess the temporal expression of the tissue- and urokinase plasminogen activators (tPA and uPA) and their endogenous inhibitor (PAI-1) along with that of pro-inflammatory mediators and the neuronal marker nNOS. Human neuroblastoma cells SH-SY5Y were differentiated into DAergic neuronal-like cells using a combination of 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum depletion. Terminally-differentiated neurons were then exposed to lipopolysaccharide (LPS) for short (up to 24 h) or long term (up to 10 days) to mimic acute or chronic inflammation. Results demonstrated that uPA protein expression was stably upregulated during chronic inflammation, whereas the expression of nNOS protein better reflected the cellular response to acute inflammation. Additional studies revealed that the temporal induction of uPA was associated with increased AKT phosphorylation, but did not seem to involve cAMP-responsive element-binding protein (CREB) activation, nor the mitogen-activated protein kinase (MAPK) pathway. In conclusion, our in vitro data suggests that nNOS and uPA may serve as viable candidate biomarkers of acute and chronic neuroinflammation.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    The Role of EZH2 Inhibitor, GSK-126, in Seizure Susceptibility

    Abstract

    GSK-126 is recognized as an inhibitor of enhancer of zeste homolog-2 (EZH2) activity. Because of its inhibition of EZH2 activation, GSK-126 is considered a potential anti-tumor drug. EZH2 is a histone methyltransferase that catalyzes histone 3 tri-methylation at lysine 27 (H3K27me3), resulting in gene silencing. A previous report showed that decreased H3K27me3 levels in the hippocampus may promote seizure susceptibility, possibly restricting the clinical application of GSK-126. The role of GSK-126 in seizure susceptibility was investigated in this study. We first determined a critical concentration of pentamethazol (PTZ) under which mice exhibit no seizures. We then found that mice pretreated with GSK-126 and injected with the same concentration of PTZ experienced marked convulsions. Peripheral injections of GSK-126 decreased H3K27me3 levels in the hippocampus of mice, while some seizure-related genes (Oasl1, Sox7, armcx5, Ncx3, etc.) were found to be differentially expressed in the hippocampus of those mice . These differences in the expression levels might reflect the crucial role of these genes and related pathways in the promotion of seizure susceptibility. Our results suggest that GSK-126 promotes seizure susceptibility due to its role as an EZH2 inhibitor. These findings may provide evidence to support the development of GSK-126 as a clinical drug.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    The Proteomics Study of Compounded HFE/TF/TfR2/HJV Genetic Variations in a Thai Family with Iron Overload, Chronic Anemia, and Motor Neuron Disorder

    Abstract

    The mutation of the homeostatic iron regulatory genes (HFE) impaired the hepatic hepcidin transcription leading to the chronic excess of the iron pool, with the adverse consequences of free radical oxidative damages. We herein reported the findings of Thai family members who had the compound of uncommon HFE rs2794719, together with transferrin (TF) rs1867504, transferrin receptor 2 (TfR2) rs7385804, and hemojuvelin (HJV) rs16827043 genetic variants involved in the hepcidin transcriptional pathway. These compounded genetic variants could produce the spectrum of clinical phenotypes that spanned from mild to moderate symptoms of chronic anemia to an established motor neuron disorder. The feasible pathophysiologies were the impairment of the transferrin receptor functions, which affected the endocytic uptake of halo-transferrin into the erythroblast precursors. Such a defect left the erythropoiesis depleted of their iron supply. These alterations also promoted the TfR-independent uptake of iron into other target tissues and left the TrF2/BMP-dependent-hepcidin activation pathway unattended. We used the predicted molecular interactive proteomes to support our speculated dysregulated iron metabolism. During the early stage of an elevated ferritin level, there was no inhibition of ferroportin activities from hepcidin. These pathophysiological processes went on to the point of an iron overload threshold. After that, the hepcidin transcription started to kick in with the resulting decreased serum iron levels and deterioration of clinical symptoms.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response

    Abstract

    Mechanisms and progression of ischemic injuries in the retina are still incompletely clarified. Therefore, the time course of microglia activation as well as resulting cytokine expression and downstream signaling were investigated. Ischemia was induced in one eye by transiently elevated intraocular pressure (60 min) followed by reperfusion; the other eye served as a control. Eyes were processed for RT-qPCR and immunohistochemistry analyses at 2, 6, 12, and 24 h as well as at 3 and 7 days. Already 2 h after ischemia, more microglia/macrophages were in an active state in the ischemia group. This was accompanied by an upregulation of pro-inflammatory cytokines, like IL-1β, IL-6, TNFα, and TGFβ. Activation of TLR3, TLR2, and the adaptor molecule Myd88 was also observed after 2 h. NFκB revealed a wave-like activation pattern. In addition, an extrinsic caspase pathway activation was noted at early time points, while enhanced numbers of cleaved caspase 3+ cells could be observed in ischemic retinae throughout the study. Retinal ischemia induced an early and strong microglia/macrophage response as well as cytokine and apoptotic activation processes. Moreover, in early and late ischemic damaging processes, TLR expression and downstream signaling were involved, suggesting an involvement in neuronal death in ischemic retinae.

    Graphical Abstract

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Preoperative Chronic and Acute Pain Affects Postoperative Cognitive Function Mediated by Neurotransmitters

    Abstract

    The effective prevention of postoperative cognitive dysfunction (POCD) needs to be explored, and the effect of preoperative pain on POCD remains unclear. We established a chronic pain model induced by chronic constriction injury (CCI) and models of acute pain and anxiety without pain in mice that were subsequently subjected to partial hepatectomy surgery. Morris water maze (MWM) tests were performed to evaluate the learning and memory abilities of the mice. ELISA was used to measure IL-1β, IL-6, and TNF-α in serum, and HPLC-MS was used to detect neurotransmitters in the prefrontal cortices and hippocampi of the mice. The results indicated that chronic pain induced by CCI might have significantly impaired the learning and memory abilities of mice, while acute pain and anxiety without pain only affected the memory abilities of mice. Perioperative acute pain increased the level of IL-1β in serum, and CCI might have increased the level of IL-6. CCI and acute pain increased dopamine (DA) levels in the cortex, similar to anxiety. Like anxiety, CCI increased 5-hydroxytryptamine (5-HT) levels in the prefrontal cortex and hippocampus. Acute pain led to a decrease in the acetylcholine (ACH) level in the hippocampus. Our results suggest that acute pain and CCI-induced chronic pain might aggravate postoperative cognitive dysfunction via neurotransmitters and by changing the levels of inflammatory factors such as IL-1β and IL-6.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Oxidative/Nitroxidative Stress and Multiple Sclerosis

    Abstract

    Multiple sclerosis (MS) is a multifactorial, central nervous system, immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration. Evidence suggests a steady rise in MS prevalence over the past five decades in the United States and around the world. Even with increased understanding of immunology, the specific etiological trigger of MS remains unknown. Evidence suggests that oxidative/nitroxidative stress is an important contributor to MS etiology, progression, and clinical symptoms. A multifaceted treatment approach aimed at counteracting oxidative/nitroxidative stress including MS disease–modifying medications, Mediterranean style diet, stress-relieving activities, smoking and alcohol cessation, exercise, and peer support programs is the best way to treat the disease.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Interactions of Antibodies to the Gram-Negative Gastric Bacterium Helicobacter pylori with the Synaptic Calcium Sensor Synaptotagmin 5, Correlate to Impaired Vesicle Recycling in SiMa Human Neuroblastoma Cells

    Abstract

    Due to molecular mimicry, maternal antibacterial antibodies are suspected to promote neurodevelopmental changes in the offspring that finally can cause disorders like autism and schizophrenia. Using a human first trimester prenatal brain multiprotein array (MPA), we demonstrate here that antibodies to the digestive tract bacteria Helicobacter pylori (α-HPy) and Campylobacter jejuni (α-CJe) interact with different synaptic proteins, including the calcium sensor synaptotagmin 5 (Syt5). Interactions of both antisera with Syt5 were confirmed by Western blot with a HEK293-cells overexpression lysate of this protein. Immunofluorescence and Western blotting revealed SiMa cells to express Syt5, which also co-migrated with a band/spot labeled by either α-HPy or α-CJe. Functionally, a 12-h pretreatment of SiMa cells with 10 μg/ml of either α-HPy or α-CJe resulted in a significant reduction of acetylcholine(ACh)-dependent calcium signals as compared to controls. Also ACh-dependent vesicle recycling was significantly reduced in cells pretreated with either α-HPy or α-CJe. Similar effects were observed upon pretreatment of SiMa cells with Syt5-specific antibodies. In conclusion, the present study supports the view that prenatal maternal antibacterial immune responses towards HPy and by this to Syt5 are able to cause functional changes, which in the end might contribute also to neurodevelopmental disorders.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Integrative Analysis of Gene Expression and Regulatory Network Interaction Data Reveals the Protein Kinase C Family of Serine/Threonine Receptors as a Significant Druggable Target for Parkinson’s Disease

    Abstract

    Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the ventral midbrain dopaminergic neurons, resulting in motor defects mainly tremor, rigidity, and bradykinesia along with a wide array of non-motor symptoms. The current study is focused on determining the potential druggable targets of PD by consolidating gene expression profiling and network methodology. Initially, the differentially expressed genes were established from which the central network was constructed by assimilating the interacting partners. Investigating the topological parameters of the network, the genes SYT1, CXCR4, CDC42, KIT, RET, DRD2, NTN1, PRKACB, KDR, NR4A2, SLC18A2, CCK, TH, KCNJ6, and TAC1 were identified as the hub genes and can be explored as potential candidate genes for PD therapeutics. Gene ontology and cluster analysis of the hub genes has provided further insights about the pathophysiology of the disease. Among the hub genes, PRKACB is observed in relatively all the enriched pathways which are modulated by G protein-coupled receptors through protein kinases. Further, we noticed SYT1 as a novel biomarker for PD. Moreover, the regulatory network was constructed with the hub genes as seed nodes with associated transcription factors (TFs) and microRNA (miRNAs). In this analysis, we identified MYC as the major TF and the miRNAs miR-21, miR-155, miR-7, and miR26A1 have a significant role in modulating the hub genes. Briefly, these significant hub genes and their enriched pathways, TFs, and miRNAs have aided in the better understanding of molecular mechanisms underlying PD and its potential core target genes.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Study and Characterization of Long Non-coding RUNX1-IT1 among Large Artery Atherosclerosis Stroke Patients Based on the ceRNA Hypothesis

    Abstract

    Recent studies have shed light on the involvement of long non-coding RNAs (lncRNAs) in the initiation and development of stroke. However, the regulatory function of many lncRNAs in large artery atherosclerosis (LAA) has not been fully elucidated. Based on the competing endogenous RNA (ceRNA) hypothesis recently proposed by Pandolfi, the present study was conducted using experimental techniques and bioinformatics to investigate the expression and regulatory function of a lncRNA involved in the development of LAA. The lncRNAs differentially expressed in stroke were obtained using meta-analysis, and one lncRNA was selected for experimental studies on patients with LAA (n = 100) and healthy controls (n = 100) using quantitative real-time polymerase chain reaction (qRT-PCR). The patients were also evaluated through meta-analysis to identify the function of the selected lncRNA, miRNAs, and mRNAs with altered expression in stroke. Finally, the experimental results and meta-analysis findings were integrated, and different functional groups were assigned. The results indicated that the level of lncRNA-RUNX1-IT1 was significantly lower in the patients with LAA compared to the healthy control subjects (p > 0.05). Logistic regression analyses revealed that the expression of lncRNA-RUNX1-IT1 was inversely correlated with LAA (P = 009, OR = 0.871, 95% CI: 0.786–0.965). In addition, a network of differentially expressed genes (DE genes) was created for miRNAs and mRNAs based on their association with lncRNA-RUNX1-IT1. Functional analysis showed that the DE genes in the network are involved in the apoptosis and alternative splicing of RNAs. The findings of the present study suggest that the downregulation of lncRNA-RUNX1-IT1 is associated with LAA development by interrupting the regulatory network of cells. The results of network analysis demonstrated that the lncRNA-RUNX1-IT1 could influence the expression of mRNAs and miRNAs involved in the apoptosis and alternative splicing of RNAs.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Short-Term Effect of MgSO 4 on the Expression of NRG-ErbB, Dopamine, GABA, and Glutamate Systems in the Fetal Rat Brain

    Abstract

    MgSO4 has been used for the past two decades as neuroprotective treatment in a variety of preterm conditions. Despite the putative advantages of MgSO4 as a neuroprotective agent in the preterm brain, the short- and long-term molecular function of MgSO4 as a neuroprotective agent has not been fully elucidated. Neuregulin (NRG1)-ErbB4 signaling plays a critical role in embryonic brain development, in the biology of dopaminergic, GABAergic, and glutamatergic systems. We hypothesize that this pathway may be associated with the neuroprotective role of MgSO4. The current study aims to investigate the ability of MgSO4 to modulate the normal developing expression pattern of selected genes related to the NRG1-ErbB, dopaminergic, GABAergic, and glutamatergic systems. We demonstrate that overall short-term treatment of dam rats with MgSO4 affects the expression of fetal brain NRG1, NRG3, ErbB4, GAD67, tyrosine hydroxylase (TH), dopamine D2 and D1 receptors, GluN1, and GluN2B. More specifically, the administration of MgSO4 alters the expression of NRG-ErbB, GAD67, TH, and D2R at early gestation day 16 (GD16) regardless of the activation of the maternal immune system by lipopolysaccharide (LPS). Our data suggest that MgSO4 treatment may affect the expression of major neuronal systems and pathways mostly at an early gestation day. These changes might be an initial clue (foundation stone) in the molecular mechanism that underlies the beneficial effect of MgSO4 as a neuroprotective agent for the developmental brain.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory Mechanisms

    Abstract

    Psychosocial stress has been widely reported to contribute to psychiatric disturbances. Perturbations in the enzymes of GABAergic and cholinergic systems have been implicated as precursors in different stress-related neuropsychiatric diseases. Targeting glutamic acid decarboxylase-67 kDa (GAD67) and acetylcholinesterase (AChE) via oxidative, nitrergic, and neuroinflammatory mechanisms have been recognized as prospective strategies for the prevention of psychosocial stress-induced behavioral impairments. Naringin, a neuro-active flavonoid compound isolated from citrus fruits, has been shown to produce memory-enhancing, antiepileptic, antidepressant, and anti-inflammatory activities similarly to ginseng, a very potent adaptogen. In this communication, we assessed the effect of naringin on social-defeat stress (SDS)-induced behavioral, GABAergic, cholinergic, oxidative, nitrergic, and neuroinflammatory changes in mice using the resident–intruder paradigm. The intruder male mice were culled into six groups. Groups 1 and 2 (normal- and SDS-controls) received sterile saline, groups 3–5 were given naringin (25-100 mg/kg, i.p.) whereas group 6 had ginseng (50 mg/kg, i.p.) daily for 14 days, but followed by 10 min SDS (physical and psychological) exposure to groups 2–6 with aggressor–resident mice. Behavioral effects using Y-maze, elevated-plus maze, sociability, and tail-suspension tests were assessed on day 14. GAD67, AChE enzymes, and biomarkers of oxidative, nitrergic, and neuroinflammatory changes were assayed in the striatum, prefrontal cortex, and hippocampus. Naringin and ginseng reversed all SDS-induced behavioral impairments. Naringin increased the levels of GAD67 and decreased AChE activities in the striatum, prefrontal cortex, and hippocampus. Furthermore, naringin reduced pro-inflammatory cytokines (TNF-α, IL-6), malondialdehyde, nitrite concentrations, and increased glutathione levels in a region-dependent manner. Our study suggests that naringin attenuated SDS-induced behavioral endophenotypes of neuropsychiatric disease through increased GAD67 synthesis, inhibition of AChE activity, oxidative, nitrergic stress, and neuroinflammatory processes in stress-sensitive brain regions.

    in Journal of Molecular Neuroscience on March 01, 2021 12:00 AM.

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    Modelling SARS-CoV-2 coevolution with genetic algorithms. (arXiv:2102.12365v1 [cs.NE])

    At the end of 2020, policy responses to the SARS-CoV-2 outbreak have been shaken by the emergence of virus variants, impacting public health and policy measures worldwide. The emergence of these strains suspected to be more contagious, more severe, or even resistant to antibodies and vaccines, seem to have taken by surprise health services and policymakers, struggling to adapt to the new variants constraints. Anticipating the emergence of these mutations to plan ahead adequate policies, and understanding how human behaviors may affect the evolution of viruses by coevolution, are key challenges. In this article, we propose coevolution with genetic algorithms (GAs) as a credible approach to model this relationship, highlighting its implications, potential and challenges. Because of their qualities of exploration of large spaces of possible solutions, capacity to generate novelty, and natural genetic focus, GAs are relevant for this issue. We present a dual GA model in which both viruses aiming for survival and policy measures aiming at minimising infection rates in the population, competitively evolve. This artificial coevolution system may offer us a laboratory to "debug" our current policy measures, identify the weaknesses of our current strategies, and anticipate the evolution of the virus to plan ahead relevant policies. It also constitutes a decisive opportunity to develop new genetic algorithms capable of simulating much more complex objects. We highlight some structural innovations for GAs for that virus evolution context that may carry promising developments in evolutionary computation, artificial life and AI.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    Functional neural network for decision processing, a racing network of programmable neurons with fuzzy logic where the target operating model relies on the network itself. (arXiv:2102.12339v1 [cs.NE])

    In this paper, we are introducing a novel model of artificial intelligence, the functional neural network for modeling of human decision-making processes. This neural network is composed of multiple artificial neurons racing in the network. Each of these neurons has a similar structure programmed independently by the users and composed of an intention wheel, a motor core and a sensory core representing the user itself and racing at a specific velocity. The mathematics of the neuron's formulation and the racing mechanism of multiple nodes in the network will be discussed, and the group decision process with fuzzy logic and the transformation of these conceptual methods into practical methods of simulation and in operations will be developed. Eventually, we will describe some possible future research directions in the fields of finance, education and medicine including the opportunity to design an intelligent learning agent with application in business operations supervision. We believe that this functional neural network has a promising potential to transform the way we can compute decision-making and lead to a new generation of neuromorphic chips for seamless human-machine interactions.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    Optimal Control Policies to Address the Pandemic Health-Economy Dilemma. (arXiv:2102.12279v1 [cs.NE])

    Non-pharmaceutical interventions (NPIs) are effective measures to contain a pandemic. Yet, such control measures commonly have a negative effect on the economy. Here, we propose a macro-level approach to support resolving this Health-Economy Dilemma (HED). First, an extension to the well-known SEIR model is suggested which includes an economy model. Second, a bi-objective optimization problem is defined to study optimal control policies in view of the HED problem. Next, several multi-objective evolutionary algorithms are applied to perform a study on the health-economy performance trade-offs that are inherent to the obtained optimal policies. Finally, the results from the applied algorithms are compared to select a preferred algorithm for future studies. As expected, for the proposed models and strategies, a clear conflict between the health and economy performances is found. Furthermore, the results suggest that the guided usage of NPIs is preferable as compared to refraining from employing such strategies at all. This study contributes to pandemic modeling and simulation by providing a novel concept that elaborates on integrating economic aspects while exploring the optimal moment to enable NPIs.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    Abelian Neural Networks. (arXiv:2102.12232v1 [cs.LG])

    We study the problem of modeling a binary operation that satisfies some algebraic requirements. We first construct a neural network architecture for Abelian group operations and derive a universal approximation property. Then, we extend it to Abelian semigroup operations using the characterization of associative symmetric polynomials. Both models take advantage of the analytic invertibility of invertible neural networks. For each case, by repeating the binary operations, we can represent a function for multiset input thanks to the algebraic structure. Naturally, our multiset architecture has size-generalization ability, which has not been obtained in existing methods. Further, we present modeling the Abelian group operation itself is useful in a word analogy task. We train our models over fixed word embeddings and demonstrate improved performance over the original word2vec and another naive learning method.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    An Online Prediction Approach Based on Incremental Support Vector Machine for Dynamic Multiobjective Optimization. (arXiv:2102.12133v1 [cs.NE])

    Real-world multiobjective optimization problems usually involve conflicting objectives that change over time, which requires the optimization algorithms to quickly track the Pareto optimal front (POF) when the environment changes. In recent years, evolutionary algorithms based on prediction models have been considered promising. However, most existing approaches only make predictions based on the linear correlation between a finite number of optimal solutions in two or three previous environments. These incomplete information extraction strategies may lead to low prediction accuracy in some instances. In this paper, a novel prediction algorithm based on incremental support vector machine (ISVM) is proposed, called ISVM-DMOEA. We treat the solving of dynamic multiobjective optimization problems (DMOPs) as an online learning process, using the continuously obtained optimal solution to update an incremental support vector machine without discarding the solution information at earlier time. ISVM is then used to filter random solutions and generate an initial population for the next moment. To overcome the obstacle of insufficient training samples, a synthetic minority oversampling strategy is implemented before the training of ISVM. The advantage of this approach is that the nonlinear correlation between solutions can be explored online by ISVM, and the information contained in all historical optimal solutions can be exploited to a greater extent. The experimental results and comparison with chosen state-of-the-art algorithms demonstrate that the proposed algorithm can effectively tackle dynamic multiobjective optimization problems.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    Perspective: Purposeful Failure in Artificial Life and Artificial Intelligence. (arXiv:2102.12076v1 [cs.AI])

    Complex systems fail. I argue that failures can be a blueprint characterizing living organisms and biological intelligence, a control mechanism to increase complexity in evolutionary simulations, and an alternative to classical fitness optimization. Imitating biological successes in Artificial Life and Artificial Intelligence can be misleading; imitating failures offers a path towards understanding and emulating life it in artificial systems.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    A Genetic Algorithm with Tree-structured Mutation for Hyperparameter Optimisation of Graph Neural Networks. (arXiv:2102.11995v1 [cs.LG])

    In recent years, graph neural networks (GNNs) have gained increasing attention, as they possess excellent capability of processing graph-related problems. In practice, hyperparameter optimisation (HPO) is critical for GNNs to achieve satisfactory results, but this process is costly because the evaluations of different hyperparameter settings require excessively training many GNNs. Many approaches have been proposed for HPO which aims to identify promising hyperparameters efficiently. In particular, genetic algorithm (GA) for HPO has been explored, which treats GNNs as a black-box model, of which only the outputs can be observed given a set of hyperparameters. However, because GNN models are extremely sophisticated and the evaluations of hyperparameters on GNNs are expensive, GA requires advanced techniques to balance the exploration and exploitation of the search and make the optimisation more effective given limited computational resources. Therefore, we proposed a tree-structured mutation strategy for GA to alleviate this issue. Meanwhile, we reviewed the recent HPO works which gives the room to the idea of tree-structure to develop, and we hope our approach can further improve these HPO methods in the future.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    A Robotic Model of Hippocampal Reverse Replay for Reinforcement Learning. (arXiv:2102.11914v1 [q-bio.NC])

    Hippocampal reverse replay is thought to contribute to learning, and particularly reinforcement learning, in animals. We present a computational model of learning in the hippocampus that builds on a previous model of the hippocampal-striatal network viewed as implementing a three-factor reinforcement learning rule. To augment this model with hippocampal reverse replay, a novel policy gradient learning rule is derived that associates place cell activity with responses in cells representing actions. This new model is evaluated using a simulated robot spatial navigation task inspired by the Morris water maze. Results show that reverse replay can accelerate learning from reinforcement, whilst improving stability and robustness over multiple trials. As implied by the neurobiological data, our study implies that reverse replay can make a significant positive contribution to reinforcement learning, although learning that is less efficient and less stable is possible in its absence. We conclude that reverse replay may enhance reinforcement learning in the mammalian hippocampal-striatal system rather than provide its core mechanism.

    in arXiv: Quantitative Biology: Neurons and Cognition on February 25, 2021 01:30 AM.

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    Analysis of Evolutionary Algorithms on Fitness Function with Time-linkage Property. (arXiv:2004.12304v4 [cs.NE] UPDATED)

    In real-world applications, many optimization problems have the time-linkage property, that is, the objective function value relies on the current solution as well as the historical solutions. Although the rigorous theoretical analysis on evolutionary algorithms has rapidly developed in recent two decades, it remains an open problem to theoretically understand the behaviors of evolutionary algorithms on time-linkage problems. This paper takes the first step to rigorously analyze evolutionary algorithms for time-linkage functions. Based on the basic OneMax function, we propose a time-linkage function where the first bit value of the last time step is integrated but has a different preference from the current first bit. We prove that with probability $1-o(1)$, randomized local search and $(1+1)$ EA cannot find the optimum, and with probability $1-o(1)$, $(\mu+1)$ EA is able to reach the optimum.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 25, 2021 01:30 AM.

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    Forward thinking on backward tracing

    Nature Physics, Published online: 25 February 2021; doi:10.1038/s41567-021-01188-1

    SARS, MERS and now SARS-CoV-2 are unlikely to be the last emerging infections we face during our lifetimes. Tracing contacts both forward and backward through our heterogeneous populations will prove essential to future response strategies.

    in Nature Physics on February 25, 2021 12:00 AM.

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    The effectiveness of backward contact tracing in networks

    Nature Physics, Published online: 25 February 2021; doi:10.1038/s41567-021-01187-2

    Contact tracing is key to epidemic control, but network analysis now suggests that whom you infect may not be as pertinent a question as who infected you. Biases due to contact heterogeneity reveal the efficacy of backward over forward tracing.

    in Nature Physics on February 25, 2021 12:00 AM.

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    Lentivirus-mediated gene therapy for Fabry disease

    Nature Communications, Published online: 25 February 2021; doi:10.1038/s41467-021-21371-5

    Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.

    in Nature Communications on February 25, 2021 12:00 AM.

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    How Europe's €100 billion science fund will shape 7 years of research

    Nature, Published online: 25 February 2021; doi:10.1038/d41586-021-00496-z

    As Horizon Europe issues its first call for grants, Nature reviews some big changes — from open science to goal-oriented 'missions'.

    in Nature on February 25, 2021 12:00 AM.

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    Journal of Neurology

    in Journal of Neurology on February 25, 2021 12:00 AM.

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    Experimental Brain Research

    in Experimental Brain Research on February 25, 2021 12:00 AM.

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    The Cerebellum

    in The Cerebellum on February 25, 2021 12:00 AM.

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    Cerebellar tDCS Alters the Perception of Optic Flow

    Abstract

    Studies have shown that the cerebellar vermis is involved in the perception of motion. However, it is unclear how the cerebellum influences motion perception. tDCS is a non-invasive brain stimulation technique that can reduce (through cathodal stimulation) or increase neuronal excitability (through anodal stimulation). To explore the nature of the cerebellar involvement on large-field global motion perception (i.e., optic flow-like motion), we applied tDCS on the cerebellar midline while participants performed an optic flow motion discrimination task. Our results show that anodal tDCS improves discrimination threshold for optic flow perception, but only for left-right motion in contrast to up-down motion discrimination. This result was evident within the first 10 min of stimulation and was also found post-stimulation. Cathodal stimulation did not have any significant effects on performance in any direction. The results show that discrimination of optic flow can be improved with tDCS of the cerebellar midline and provide further support for the role of the human midline cerebellum in the perception of optic flow.

    in The Cerebellum on February 25, 2021 12:00 AM.

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    Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose–response meta-analysis

    Abstract

    Background

    A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close to 1:1).

    Objective

    To provide a global SR estimate and investigate its relation with respect to population age.

    Methods

    A systematic review and meta-analysis was conducted including only population-based studies with a high-quality methodology in European ancestral origin population. Male-to-female SR was estimated by three different measures: SR number, SR crude incidence and SR standardized incidence. Standard and dose–response meta-analyses were performed to assess the pooled SR measures (irrespective of population age) and the evolution of the SR measures with respect to population age, respectively. Potential sources of heterogeneity were investigated via meta-regression.

    Results

    Overall, 3254 articles were retrieved in the literature search. Thirty-nine studies stratified by time periods were included. The overall pooled male-to-female ratio was 1.28 (95% CI 1.23–1.32) for SR number, 1.33 (95% CI 1.29–1.38) for SR crude incidence and 1.35 (95% CI 1.31–1.40) for SR standardized incidence. The SR number with respect to population age reveals a progressive reduction of SR at increasing age, while the SR crude incidence in relation to age displays a U-shaped curve.

    Conclusions

    The number and the incidence of ALS cases were consistently higher in males than females. Dose–response meta-analysis showed that SR measures change with respect to population age. Further original research is needed to clarify if our findings are reproducible in other populations.

    in Journal of Neurology on February 25, 2021 12:00 AM.

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    Contribution of neuropsychiatric symptoms in Parkinson’s disease to different domains of caregiver burden

    Abstract

    Introduction

    Caregiver burden is high among caregivers of PD patients (CPD). Neuropsychiatric symptoms are leading contributors to CPD burden, but whether different symptoms differentially impact domains of caregiver burden is not known. Our objective was to examine which neuropsychiatric symptoms and demographic factors contribute to different domains of caregiver burden in PD.

    Methods

    This was a cross-sectional online survey study. Participants were recruited from the Fox Insight (FI) study and were eligible if they identified themselves as a CPD. The primary outcome was the Caregiver Burden Inventory (CBI) total score and its 5 sub-domain scores. The Neuropsychiatric Inventory Questionnaire (NPI-Q) assessed caregiver-reported neuropsychiatric symptoms in the care recipient. Multivariable linear regression models were used to characterize the associations between NPI-Q symptom severity scores and CBI scores. Covariates were caregiver age, sex, education, and caregiving duration.

    Results

    The sample consisted of 450 CPD, mean age 65.87 (SD 10.39) years, 74% females. After adjusting for covariates, CBI total score was predicted by NPI-Q total score (β = 1.96, p < 0.001); model adjusted R2 = 39.2%. Anxiety severity had the largest effect size [standardized β (sβ) = 0.224] on the time-dependency domain, which was also associated with female sex (sβ = − 0.133) and age (sβ = 0.088). Severity of disinhibition (sβ = 0.218), agitation (sβ = 0.199), and female sex (sβ = 0.104) were associated with greater emotional burden.

    Conclusion

    Our findings indicate that demographic characteristics and specific neuropsychiatric symptoms contribute differentially to domains of caregiver burden. Tailored interventions to support CPD are needed.

    in Journal of Neurology on February 25, 2021 12:00 AM.

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    Assessing the relative contribution of vision to odometry via manipulations of gait in an over-ground homing task

    Abstract

    The visual, vestibular, and haptic perceptual systems are each able to detect self-motion. Such information can be integrated during locomotion to perceive traversed distances. The process of distance integration is referred to as odometry. Visual odometry relies on information in optic flow patterns. For haptic odometry, such information is associated with leg movement patterns. Recently, it has been shown that haptic odometry is differently calibrated for different types of gaits. Here, we use this fact to examine the relative contributions of the perceptual systems to odometry. We studied a simple homing task in which participants travelled set distances away from an initial starting location (outbound phase), before turning and attempting to walk back to that location (inbound phase). We manipulated whether outbound gait was a walk or a gallop-walk. We also manipulated the outbound availability of optic flow. Inbound reports were performed via walking with eyes closed. Consistent with previous studies of haptic odometry, inbound reports were shorter when the outbound gait was a gallop-walk. We showed that the availability of optic flow decreased this effect. In contrast, the availability of optic flow did not have an observable effect when the outbound gait was walking. We interpreted this to suggest that visual odometry and haptic odometry via walking are similarly calibrated. By measuring the decrease in shortening in the gallop-walk condition, and scaling it relative to the walk condition, we estimated a relative contribution of optic flow to odometry of 41%. Our results present a proof of concept for a new, potentially more generalizable, method for examining the contributions of different perceptual systems to odometry, and by extension, path integration. We discuss implications for understanding human wayfinding.

    in Experimental Brain Research on February 25, 2021 12:00 AM.

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    Progress in Brain Computer Interface: Challenges and Opportunities

    Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming, and neuroscience. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and non-linear brain dynamics and related feature extraction and classification challenges. Time-variant psycho-neurophysiological fluctuations and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes state-of-the-art progress in the BCI field over the last decades and highlights critical challenges.

    in Frontiers in Systems Neuroscience on February 25, 2021 12:00 AM.

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    Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons

    Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4–L6 spinal dorsal horn in Vglut2-cre+/– mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/– mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.

    in Frontiers in Molecular Neuroscience on February 25, 2021 12:00 AM.

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    The F-Box Protein CG5003 Regulates Axon Pruning and the Integrity of the Drosophila Mushroom Body

    Protein homeostasis serves as an important step in regulating diverse cellular processes underlying the function and development of the nervous system. In particular, the ubiquitination proteasome system (UPS), a universal pathway mediating protein degradation, contributes to the development of numerous synaptic structures, including the Drosophila olfactory-associative learning center mushroom body (MB), thereby affecting associated function. Here, we describe the function of a newly characterized Drosophila F-box protein CG5003, an adaptor for the RING-domain type E3 ligase (SCF complex), in MB development. Lacking CG5003 ubiquitously causes MB γ axon pruning defects and selective CG5003 expression in pan-neurons leads to both γ axon and α/β lobe abnormalities. Interestingly, change in CG5003 expression in MB neurons does not cause any abnormalities in axons, suggesting that CG5003 functions in cells extrinsic to MB to regulate its development. Mass spectrum analysis indicates that silencing CG5003 expression in all neurons affects expression levels of proteins in the cell and structural morphogenesis, transcription regulator activity, and catalytic activity. Our findings reinforce the importance of UPS and identify a new factor in regulating neuronal development as exemplified by the synaptic structure MB.

    in Frontiers in Molecular Neuroscience on February 25, 2021 12:00 AM.

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    Identification of Natural Antisense Transcripts in Mouse Brain and Their Association With Autism Spectrum Disorder Risk Genes

    Genome-wide sequencing technologies have greatly contributed to our understanding of the genetic basis of neurodevelopmental disorders such as autism spectrum disorder (ASD). Interestingly, a number of ASD-related genes express natural antisense transcripts (NATs). In some cases, these NATs have been shown to play a regulatory role in sense strand gene expression and thus contribute to brain function. However, a detailed study examining the transcriptional relationship between ASD-related genes and their NAT partners is lacking. We performed strand-specific, deep RNA sequencing to profile expression of sense and antisense reads with a focus on 100 ASD-related genes in medial prefrontal cortex (mPFC) and striatum across mouse post-natal development (P7, P14, and P56). Using de novo transcriptome assembly, we generated a comprehensive long non-coding RNA (lncRNA) transcriptome. We conducted BLAST analyses to compare the resultant transcripts with the human genome and identified transcripts with high sequence similarity and coverage. We assembled 32861 de novo antisense transcripts mapped to 12182 genes, of which 1018 are annotated by Ensembl as lncRNA. We validated the expression of a subset of selected ASD-related transcripts by PCR, including Syngap1 and Cntnap2. Our analyses revealed that more than 70% (72/100) of the examined ASD-related genes have one or more expressed antisense transcripts, suggesting more ASD-related genes than previously thought could be subject to NAT-mediated regulation in mice. We found that expression levels of antisense contigs were mostly positively correlated with their cognate coding sense strand RNA transcripts across developmental age. A small fraction of the examined transcripts showed brain region specific enrichment, indicating possible circuit-specific roles. Our BLAST analyses identified 110 of 271 ASD-related de novo transcripts with >90% identity to the human genome at >90% coverage. These findings, which include an assembled de novo antisense transcriptome, contribute to the understanding of NAT regulation of ASD-related genes in mice and can guide NAT-mediated gene regulation strategies in preclinical investigations toward the ultimate goal of developing novel therapeutic targets for ASD.

    in Frontiers in Molecular Neuroscience on February 25, 2021 12:00 AM.

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    The Mechanical Basis of Memory – the MeshCODE Theory

    One of the major unsolved mysteries of biological science concerns the question of where and in what form information is stored in the brain. I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix (ECM) adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.

    in Frontiers in Molecular Neuroscience on February 25, 2021 12:00 AM.

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    Brain Structural Network Compensation Is Associated With Cognitive Impairment and Alzheimer’s Disease Pathology

    Background

    Structural network alterations in Alzheimer’s disease (AD) are related to worse cognitive impairment. The aim of this study was to quantify the alterations in gray matter associated with impaired cognition and their pathological biomarkers in AD-spectrum patients.

    Methods

    We extracted gray matter networks from 3D-T1 magnetic resonance imaging scans, and a graph theory analysis was used to explore alterations in the network metrics in 34 healthy controls, 70 mild cognitive impairment (MCI) patients, and 40 AD patients. Spearman correlation analysis was computed to investigate the relationships among network properties, neuropsychological performance, and cerebrospinal fluid pathological biomarkers (i.e., Aβ, t-tau, and p-tau) in these subjects.

    Results

    AD-spectrum individuals demonstrated higher nodal properties and edge properties associated with impaired memory function, and lower amyloid-β or higher tau levels than the controls. Furthermore, these compensations at the brain regional level in AD-spectrum patients were mainly in the medial temporal lobe; however, the compensation at the whole-brain network level gradually extended from the frontal lobe to become widely distributed throughout the cortex with the progression of AD.

    Conclusion

    The findings provide insight into the alterations in the gray matter network related to impaired cognition and pathological biomarkers in the progression of AD. The possibility of compensation was detected in the structural networks in AD-spectrum patients; the compensatory patterns at regional and whole-brain levels were different and the clinical significance was highlighted.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 25, 2021 12:00 AM.

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    Wnt/β-Catenin Signaling Promotes Differentiation of Ischemia-Activated Adult Neural Stem/Progenitor Cells to Neuronal Precursors

    Modulating endogenous regenerative processes may represent a suitable treatment for central nervous system (CNS) injuries, such as stroke or trauma. Neural stem/progenitor cells (NS/PCs), which naturally reside in the subventricular zone (SVZ) of the adult brain, proliferate and differentiate to other cell types, and therefore may compensate the negative consequences of ischemic injury. The fate of NS/PCs in the developing brain is largely influenced by Wingless/Integrated (Wnt) signaling; however, its role in the differentiation of adult NS/PCs under ischemic conditions is still enigmatic. In our previous study, we identified the Wnt/β-catenin signaling pathway as a factor promoting neurogenesis at the expense of gliogenesis in neonatal mice. In this study, we used adult transgenic mice in order to assess the impact of the canonical Wnt pathway modulation (inhibition or hyper-activation) on NS/PCs derived from the SVZ, and combined it with the middle cerebral artery occlusion (MCAO) to disclose the effect of focal cerebral ischemia (FCI). Based on the electrophysiological properties of cultured cells, we first identified three cell types that represented in vitro differentiated NS/PCs – astrocytes, neuron-like cells, and precursor cells. Following FCI, we detected fewer neuron-like cells after Wnt signaling inhibition. Furthermore, the immunohistochemical analysis revealed an overall higher expression of cell-type-specific proteins after FCI, indicating increased proliferation and differentiation rates of NS/PCs in the SVZ. Remarkably, Wnt signaling hyper-activation increased the abundance of proliferating and neuron-like cells, while Wnt pathway inhibition had the opposite effect. Finally, the expression profiling at the single cell level revealed an increased proportion of neural stem cells and neuroblasts after FCI. These observations indicate that Wnt signaling enhances NS/PCs-based regeneration in the adult mouse brain following FCI, and supports neuronal differentiation in the SVZ.

    in Frontiers in Neuroscience: Neurogenesis on February 25, 2021 12:00 AM.

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    Local Differences in Cortical Excitability – A Systematic Mapping Study of the TMS-Evoked N100 Component

    Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography applied to the primary motor cortex provides two parameters for cortical excitability: motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). This study aimed to evaluate the effects of systematic coil shifts on both the TEP N100 component and MEPs in addition to the relationship between both parameters. In 12 healthy adults, the center of a standardized grid was fixed above the hot spot of the target muscle of the left primary motor cortex. Twelve additional positions were arranged in a quadratic grid with positions between 5 and 10 mm from the hot spot. At each of the 13 positions, TMS single pulses were applied. The topographical maximum of the resulting N100 was located ipsilateral and slightly posterior to the stimulation site. A source analysis revealed an equivalent dipole localized more deeply than standard motor cortex coordinates that could not be explained by a single seeded primary motor cortex dipole. The N100 topography might not only reflect primary motor cortex activation, but also sum activation of the surrounding cortex. N100 amplitude and latency decreased significantly during stimulation anterior-medial to the hot spot although MEP amplitudes were smaller at all other stimulation sites. Therefore, N100 amplitudes might be suitable for detecting differences in local cortical excitability. The N100 topography, with its maximum located posterior to the stimulation site, possibly depends on both anatomical characteristics of the stimulated cortex and differences in local excitability of surrounding cortical areas. The less excitable anterior cortex might contribute to a more posterior maximum. There was no correlation between N100 and MEP amplitudes, but a single-trial analysis revealed a trend toward larger N100 amplitudes in trials with larger MEPs. Thus, functionally efficient cortical excitation might increase the probability of higher N100 amplitudes, but TEPs are also generated in the absence of MEPs.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 25, 2021 12:00 AM.

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    Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

    There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.

    in Frontiers in Neuroscience: Neurodegeneration on February 25, 2021 12:00 AM.

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    Optimized Inner-Volume 3D TSE for High-Resolution Vessel Wall Imaging of Intracranial Perforating Arteries at 7T

    The impairment of microvessels can lead to neurologic diseases such as stroke and vascular dementia. The imaging of lumen and vessel wall of perforating arteries requires an extremely high resolution due to their small caliber size. Current imaging techniques have the difficulty in observing the wall of perforating arteries. In this study, we developed a 3D inner-volume (IV) TSE (SPACE) sequence with optimized 2D spatially selective excitation (SSE) RF pulses. The optimized SSE RF pulses were designed through a series of optimization including iterative RF pulse design, trajectory optimization, and phase convention of Carr-Purcell-Meiboom-Gill (CPMG) condition to meet the perforating arteries imaging demands. High resolution of isotropic 0.30 mm within 10 min was achieved for the black- blood images of lenticulostriate artery (LSA). The LSA lumen and vessel wall were imaged by the IV-SPACE sequence simultaneously. Images obtained by the optimized RF pulse has fewer aliasing artifacts from outside of ROI than the traditional pulse. The IV-SPACE images showed clearer delineation of vessel wall and lumen of LSA than conventional SPACE images. IV-SPACE might be a promising method for detecting microvasculopathies of cerebral vascular diseases.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 25, 2021 12:00 AM.

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    Dysregulation of Phosphoinositide 5-Phosphatases and Phosphoinositides in Alzheimer's Disease

    in Frontiers in Neuroscience: Neurodegeneration on February 25, 2021 12:00 AM.

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    Parkinson’s Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?

    The reason why dopamine neurons die in Parkinson’s disease remains largely unknown. Emerging evidence points to a role for brain inflammation in neurodegeneration. Essential questions are whether brain inflammation happens sufficiently early so that interfering with this process can be expected to slow down neuronal death and whether the contribution from inflammation is large enough so that anti-inflammatory agents can be expected to work. Here I discuss data from human PD studies indicating that brain inflammation is an early event in PD. I also discuss the role of T-lymphocytes and peripheral inflammation for neurodegeneration. I critically discuss the failure of clinical trials targeting inflammation in PD.

    in Frontiers in Neuroscience: Neurodegeneration on February 25, 2021 12:00 AM.

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    How Can We Prove the Causality of Interbrain Synchronization?

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Case Report: Multimodal Functional and Structural Evaluation Combining Pre-operative nTMS Mapping and Neuroimaging With Intraoperative CT-Scan and Brain Shift Correction for Brain Tumor Surgical Resection

    Background: Maximum safe resection of infiltrative brain tumors in eloquent area is the primary objective in surgical neuro-oncology. This goal can be achieved with direct electrical stimulation (DES) to perform a functional mapping of the brain in patients awake intraoperatively. When awake surgery is not possible, we propose a pipeline procedure that combines advanced techniques aiming at performing a dissection that respects the anatomo-functional connectivity of the peritumoral region. This procedure can benefit from intraoperative monitoring with computerized tomography scan (iCT-scan) and brain shift correction. Associated with this intraoperative monitoring, the additional value of preoperative investigation combining brain mapping by navigated transcranial magnetic stimulation (nTMS) with various neuroimaging modalities (tractography and resting state functional MRI) has not yet been reported.

    Case Report: A 42-year-old left-handed man had increased intracranial pressure (IICP), left hand muscle deficit, and dysarthria, related to an infiltrative tumor of the right frontal lobe with large mass effect and circumscribed contrast enhancement in motor and premotor cortical areas. Spectroscopy profile and intratumoral calcifications on CT-scan suggested an WHO grade III glioma, later confirmed by histology. The aforementioned surgical procedure was considered, since standard awake surgery was not appropriate for this patient. In preoperative time, nTMS mapping of motor function (deltoid, first interosseous, and tibialis anterior muscles) was performed, combined with magnetic resonance imaging (MRI)-based tractography reconstruction of 6 neural tracts (arcuate, corticospinal, inferior fronto-occipital, uncinate and superior and inferior longitudinal fasciculi) and resting-state functional MRI connectivity (rs-fMRI) of sensorimotor and language networks. In intraoperative time, DES mapping was performed with motor evoked response recording and tumor resection was optimized using non-rigid image transformation of the preoperative data (nTMS, tractography, and rs-fMRI) to iCT data. Image guidance was updated with correction for brain shift and tissue deformation using biomechanical modeling taking into account brain elastic properties. This correction was done at crucial surgical steps, i.e., when tumor bulged through the craniotomy after dura mater opening and when approaching the presumed eloquent brain regions. This procedure allowed a total resection of the tumor region with contrast enhancement as well as a complete regression of IICP and dysarthria. Hand paresis remained stable with no additional deficit. Postoperative nTMS mapping confirmed the good functional outcome.

    Conclusion: This case report and technical note highlights the value of preoperative functional evaluation by nTMS updated intraoperatively with correction of brain deformation by iCT. This multimodal approach may become the optimized technique of reference for patients with brain tumors in eloquent areas that are unsuitable for awake brain surgery.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Multimodal Assessment of Precentral Anodal TDCS: Individual Rise in Supplementary Motor Activity Scales With Increase in Corticospinal Excitability

    Background

    Transcranial direct current stimulation (TDCS) targeting the primary motor hand area (M1-HAND) may induce lasting shifts in corticospinal excitability, but after-effects show substantial inter-individual variability. Functional magnetic resonance imaging (fMRI) can probe after-effects of TDCS on regional neural activity on a whole-brain level.

    Objective

    Using a double-blinded cross-over design, we investigated whether the individual change in corticospinal excitability after TDCS of M1-HAND is associated with changes in task-related regional activity in cortical motor areas.

    Methods

    Seventeen healthy volunteers (10 women) received 20 min of real (0.75 mA) or sham TDCS on separate days in randomized order. Real and sham TDCS used the classic bipolar set-up with the anode placed over right M1-HAND. Before and after each TDCS session, we recorded motor evoked potentials (MEP) from the relaxed left first dorsal interosseus muscle after single-pulse transcranial magnetic stimulation(TMS) of left M1-HAND and performed whole-brain fMRI at 3 Tesla while participants completed a visuomotor tracking task with their left hand. We also assessed the difference in MEP latency when applying anterior-posterior and latero-medial TMS pulses to the precentral hand knob (AP-LM MEP latency).

    Results

    Real TDCS had no consistent aftereffects on mean MEP amplitude, task-related activity or motor performance. Individual changes in MEP amplitude, measured directly after real TDCS showed a positive linear relationship with individual changes in task-related activity in the supplementary motor area and AP-LM MEP latency.

    Conclusion

    Functional aftereffects of classical bipolar anodal TDCS of M1-HAND on the motor system vary substantially across individuals. Physiological features upstream from the primary motor cortex may determine how anodal TDCS changes corticospinal excitability.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Modulatory Effects of Prediction Accuracy on Electroencephalographic Brain Activity During Prediction

    Prediction is essential for the efficiency of many cognitive processes; however, this process is not always perfect. Predictive coding theory suggests that the brain generates and updates a prediction to respond to an upcoming event. Although an electrophysiological index of prediction, the stimulus preceding negativity (SPN), has been reported, it remains unknown whether the SPN reflects the prediction accuracy, or whether it is associated with the prediction error, which corresponds to a mismatch between a prediction and an actual input. Thus, the present study aimed to investigate this question using electroencephalography (EEG). Participants were asked to predict the original pictures from pictures that had undergone different levels of pixelation. The SPN amplitude was affected by the level of pixelation and correlated with the subjective evaluation of the prediction accuracy. Furthermore, late positive components (LPC) were negatively correlated with SPN. These results suggest that the amplitude of SPN reflects the prediction accuracy; more accurate prediction increases the SPN and reduces the prediction error, resulting in reduced LPC amplitudes.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Examining Different Motor Learning Paradigms for Improving Balance Recovery Abilities Among Older Adults, Random vs. Block Training—Study Protocol of a Randomized Non-inferiority Controlled Trial

    Introduction: Falls are the leading cause of fatal and nonfatal injuries among older adults. Studies showed that older adults can reduce the risk of falls after participation in an unexpected perturbation-based balance training (PBBT), a relatively novel approach that challenged reactive balance control. This study aims to investigate the effect of the practice schedule (i.e., contextual interference) on reactive balance function and its transfer to proactive balance function (i.e., voluntary step execution test and Berg balance test). Our primary hypothesis is that improvements in reactive balance control following block PBBT will be not inferior to the improvements following random PBBT.

    Methods and Analysis: This is a double-blind randomized controlled trial. Fifty community-dwelling older adults (over 70 years) will be recruited and randomly allocated to a random PBBT group (n = 25) or a block PBBT group (n = 25). The random PBBT group will receive eight training sessions over 4 weeks that include unexpected machine-induced perturbations of balance during hands-free treadmill walking. The block PBBT group will be trained by the same perturbation treadmill system, but only one direction will be trained in each training session, and the direction of the external perturbations will be announced. Both PBBT groups (random PBBT and block PBBT) will receive a similar perturbation intensity during training (which will be customized to participant’s abilities), the same training period, and the same concurrent cognitive tasks during training. The generalization and transfer of learning effects will be measured by assessing the reactive and proactive balance control during standing and walking before and after 1 month of PBBT, for example, step and multiple steps and fall thresholds, Berg balance test, and fear of falls. The dependent variable will be rank transformed prior to conducting the analysis of covariance (ANCOVA) to allow for nonparametric analysis.

    Discussion: This research will explore which of the balance retraining paradigms is more effective to improve reactive balance and proactive balance control in older adults (random PBBT vs. block PBBT) over 1 month. The research will address key issues concerning balance retraining: older adults’ neuromotor capacities to optimize training responses and their applicability to real-life challenges.

    Clinical Trial Registration: Helsinki research ethics approval has been received (Soroka Medical Center approval #0396-16-SOR; MOH_2018-07-22_003536; www.ClinicalTrials.gov, NCT04455607).

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Event-Related Potential Correlates of Valence, Arousal, and Subjective Significance in Processing of an Emotional Stroop Task

    The present study is the first to measure event-related potentials associated with the processing of the emotional Stroop task (EST) with the use of an orthogonal factorial manipulation for emotional valence, arousal, and subjective significance (the importance of the current experience for goals and plans for the future). The current study aimed to investigate concurrently the role of the three dimensions describing the emotion-laden words for interference control measured in the classical version of the EST paradigm. The results showed that reaction times were affected by the emotional valence of presented words and the interactive effect of valence and arousal. The expected emotional arousal effect was only found in behavioral results for neutrally valenced words. Electrophysiological results showed valence and subjective significance correlated with the amplitude differences in the P2 component. Moreover, the amplitude of the N450 component varied with the level of subjective significance. This study also demonstrated that exploratory event-related potential analysis provides additional information beyond the classical component-based analysis. The obtained results show that cognitive control effects in the EST may be altered by manipulation in the subjective significance dimension.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Structural and Functional Changes Are Related to Cognitive Status in Wilson’s Disease

    Patients with Wilson’s disease (WD) suffer from prospective memory (PM) impairment, and some of patients develop cognitive impairment. However, very little is known about how brain structure and function changes effect PM in WD. Here, we employed multimodal neuroimaging data acquired from 22 WD patients and 26 healthy controls (HC) who underwent three-dimensional T1-weighted, diffusion tensor imaging (DTI), and resting state functional magnetic resonance imaging (RS-fMRI). We investigated gray matter (GM) volumes with voxel-based morphometry, DTI metrics using the fiber tractography method, and RS-fMRI using the seed-based functional connectivity method. Compared with HC, WD patients showed GM volume reductions in the basal ganglia (BG) and occipital fusiform gyrus, as well as volume increase in the visual association cortex. Moreover, whiter matter (WM) tracks of WD were widely impaired in association and limbic fibers. WM tracks in association fibers are significant related to PM in WD patients. Relative to HC, WD patients showed that the visual association cortex functionally connects to the thalamus and hippocampus, which is associated with global cognitive function in patients with WD. Together, these findings suggested that PM impairment in WD may be modulated by aberrant WM in association fibers, and that GM volume changes in the association cortex has no direct effect on cognitive status, but indirectly affect global cognitive function by its aberrant functional connectivity (FC) in patients with WD. Our findings may provide a new window to further study how WD develops into cognitive impairment, and deepen our understanding of the cognitive status and neuropathology of WD.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    The Role of the Cerebellum in Social and Non-Social Action Sequences: A Preliminary LF-rTMS Study

    An increasing number of studies demonstrated the involvement of the cerebellum in (social) sequence processing. The current preliminary study is the first to investigate the causal involvement of the cerebellum in sequence generation, using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). By targeting the posterior cerebellum, we hypothesized that the induced neuro-excitability modulation would lead to altered performance on a Picture and Story sequencing task, which involve the generation of the correct chronological order of various social and non-social stories depicted in cartoons or sentences. Our results indicate that participants receiving LF-rTMS over the cerebellum, as compared to sham participants, showed a stronger learning effect from pre to post stimulation for both tasks and for all types of sequences (i.e. mechanical, social scripts, false belief, true belief). No differences between sequence types were observed. Our results suggest a positive effect of LF-rTMS on sequence generation. We conclude that the cerebellum is causally involved in the generation of sequences of social and nonsocial events. Our discussion focuses on recommendations for future studies.

    in Frontiers in Human Neuroscience on February 25, 2021 12:00 AM.

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    Monosynaptic Retrograde Tracing From Prelimbic Neuron Subpopulations Projecting to Either Nucleus Accumbens Core or Rostromedial Tegmental Nucleus

    The prelimbic (PL) region of the medial prefrontal cortex (mPFC) has been implicated in both driving and suppressing motivated behaviors, including cocaine-seeking in rats. These seemingly opposing functions may be mediated by different efferent targets of PL projections, such as the nucleus accumbens (NAc) core and rostromedial tegmental nucleus (RMTg), which have contrasting roles in reward-seeking behaviors. We sought to characterize the anatomical connectivity differences between PL neurons projecting to NAc core and RMTg. We used conventional retrograde tracers to reveal distinct subpopulations of PL neurons projecting to NAc core vs. RMTg in rats, with very little overlap. To examine potential differences in input specificity for these two PL subpopulations, we then used Cre-dependent rabies virus (EnvA-RV-EGFP) as a monosynaptic retrograde tracer and targeted specific PL neurons via injections of retrograde CAV2-Cre in either NAc core or RMTg. We observed a similar catalog of cortical, thalamic, and limbic afferents for both NAc- and RMTg-projecting populations, with the primary source of afferent information arising from neighboring prefrontal neurons in ipsilateral PL and infralimbic cortex (IL). However, when the two subpopulations were directly compared, we found that RMTg-projecting PL neurons received a greater proportion of input from ipsilateral PL and IL, whereas NAc-projecting PL neurons received a greater proportion of input from most other cortical areas, mediodorsal thalamic nucleus, and several other subcortical areas. NAc-projecting PL neurons also received a greater proportion of contralateral cortical input. Our findings reveal that PL subpopulations differ not only in their efferent target but also in the input specificity from afferent structures. These differences in connectivity are likely to be critical to functional differences of PL subpopulations.

    in Frontiers in Neural Circuits on February 25, 2021 12:00 AM.

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    Genetic Background Effects on the Expression of an Odorant Receptor Gene

    There are more than 1000 odorant receptor (OR) genes in the mouse genome. Each olfactory sensory neuron expresses only one of these genes, in a monoallelic fashion. The transcript abundance of homologous OR genes vary between distinct mouse strains. Here we analyzed the expression of the OR gene Olfr17 (also named P2) in different genomic contexts. Olfr17 is expressed at higher levels in the olfactory epithelium from 129 mice than from C57BL/6 (B6) mice. However, we found that in P2-IRES-tauGFP knock-in mice, the transcript levels of the 129 Olfr17 allele are highly reduced when compared to the B6 Olfr17 allele. To address the mechanisms involved in this variation we compared the 5′ region sequence and DNA methylation patterns of the B6 and 129 Olfr17 alleles. Our results show that genetic variations in cis regulatory regions can lead to differential DNA methylation frequencies in these OR gene alleles. They also show that expression of the Olfr17 alleles is largely affected by the genetic background, and suggest that in knock-in mice, expression can be affected by epigenetic modifications in the region of the targeted locus.

    in Frontiers in Cellular Neuroscience on February 25, 2021 12:00 AM.

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    Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

    Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain – the locus coeruleus – and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators – including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.

    in Frontiers in Cellular Neuroscience on February 25, 2021 12:00 AM.

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    Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer’s Disease

    As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer’s disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, “dampening inflammation” through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.

    in Frontiers in Cellular Neuroscience on February 25, 2021 12:00 AM.

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    Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

    Strokes are the most common types of cerebrovascular disease and remain a major cause of death and disability worldwide. Cerebral ischemic stroke is caused by a reduction in blood flow to the brain. In this disease, two major zones of injury are identified: the lesion core, in which cells rapidly progress toward death, and the ischemic penumbra (surrounding the lesion core), which is defined as hypoperfusion tissue where cells may remain viable and can be repaired. Two methods that are approved by the Food and Drug Administration (FDA) include intravenous thrombolytic therapy and endovascular thrombectomy, however, the narrow therapeutic window poses a limitation, and therefore a low percentage of stroke patients actually receive these treatments. Developments in stem cell therapy have introduced renewed hope to patients with ischemic stroke due to its potential effect for reversing the neurological sequelae. Over the last few decades, animal tests and clinical trials have been used to treat ischemic stroke experimentally with various types of stem cells. However, several technical and ethical challenges must be overcome before stem cells can become a choice for the treatment of stroke. In this review, we summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. We also discuss new developing trends in this field.

    in Frontiers in Cellular Neuroscience on February 25, 2021 12:00 AM.

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    Topographical Organization of M-Current on Dorsal and Median Raphe Serotonergic Neurons

    Dorsal and median raphe nuclei (DR and MR, respectively) are members of the reticular activating system and play important role in the regulation of the sleep-wakefulness cycle, movement, and affective states. M-current is a voltage-gated potassium current under the control of neuromodulatory mechanisms setting neuronal excitability. Our goal was to determine the proportion of DR and MR serotonergic neurons possessing M-current and whether they are organized topographically. Electrophysiological parameters of raphe serotonergic neurons influenced by this current were also investigated. We performed slice electrophysiology on genetically identified serotonergic neurons. Neurons with M-current are located rostrally in the DR and dorsally in the MR. M-current determines firing rate, afterhyperpolarization amplitude, and adaptation index (AI) of these neurons, but does not affect input resistance, action potential width, and high threshold oscillations.These findings indicate that M-current has a strong impact on firing properties of certain serotonergic neuronal subpopulations and it might serve as an effective contributor to cholinergic and local serotonergic neuromodulatory actions.

    in Frontiers in Cellular Neuroscience on February 25, 2021 12:00 AM.

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    Thalamic Structural Connectivity Abnormalities in Minimal Hepatic Encephalopathy

    Background and Aims: Numerous studies have demonstrated thalamus-related structural, functional, and metabolic abnormalities in minimal hepatic encephalopathy (MHE). We conducted the first study to investigate thalamic structural connectivity alterations in MHE.

    Methods

    Diffusion tensor imaging (DTI)-based probabilistic tractography was employed to determine the structural linkage between the thalamus and cortical/subcortical regions in 52 cirrhotic patients [22 with MHE; 30 without MHE (NHE)] and 30 controls. We measured these thalamic connections, which included connectivity strength (CS), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), and then compared these among the three groups. Neurocognitive assessment was also performed. Correlation analysis was conducted to investigate the relationship between neurocognitive performance and the above measurements. Classification analysis was performed to determine whether thalamic connection measurements can distinguish MHE from NHE.

    Results

    The probabilistic tractography revealed thalamic structural connections, which were disrupted in cirrhotic patients (as reflected by a decrease in CS/FA and an increase in MD/AD/RD). Abnormal thalamic connections primarily involved the prefrontal cortex, sensorimotor cortex, parietal cortex, medial temporal cortex and hippocampus, and striatum. Thalamic connectivity abnormalities deteriorated from NHE to MHE, and they were correlated with patients’ neurocognitive performance. The moderate classification accuracy was obtained using CS and MD as discriminating indexes.

    Conclusion

    Our results demonstrated the altered thalamic structural connectivity involving both cortical and subcortical regions in MHE, which could be regarded as representative of MHE-related widespread impairments in white matter pathways. The disturbed thalamic connectivity may underlie the mechanism of cognitive deficits in MHE and may potentially be utilized as a biomarker for diagnosing MHE and in monitoring disease progression. In addition to thalamic–cortical/subcortical connections, further studies are recommended to explore the structural alterations in other white matter pathways in MHE.

    in Frontiers in Neuroanatomy on February 25, 2021 12:00 AM.

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    Cellular Senescence in Brain Aging

    Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

    Neurofibrillary tangles (NFTs) are a major pathologic hallmark of Alzheimer’s disease (AD). Several studies have shown that amyloid β oligomers (Aβo) and tau oligomers mediate their toxicity, in part, via binding to cellular prion protein (PrPC) and that some anti-PrP antibodies can block this interaction. We have generated a novel monoclonal anti-PrP antibody (TW1) and assessed the efficacy of passive immunization with it in a mouse model of AD with extensive tau pathology: hTau/PS1 transgenic (Tg) mice. These mice were injected intraperitoneally once a week with TW1 starting at 5 months of age. Behavior was assessed at 8 months of age and brain tissue was subsequently harvested for analysis of treatment efficacy at 9 months. Mice treated with TW1 did not show any significant difference in sensorimotor testing including traverse beam, rotarod, and locomotor activity compared to controls. Significant cognitive benefits were observed with the novel object recognition test (ORT) in the immunized mice (two-tailed, t-test p = 0.0019). Immunized mice also showed cognitive benefits on the closed field symmetrical maze (day 1 two-tailed t-test p = 0.0001; day 2 two-tailed t-test p = 0.0015; day 3 two-tailed t-test p = 0.0002). Reduction of tau pathology was observed with PHF-1 immunohistochemistry in the piriform cortex by 60% (two-tailed t-test p = 0.01) and in the dentate gyrus by 50% (two-tailed t-test p = 0.02) in animals treated with TW1 compared to controls. There were no significant differences in astrogliosis or microgliosis observed between treated and control mice. As assessed by Western blots using PHF-1, the TW1 therapy reduced phosphorylated tau pathology (two-tailed t-test p = 0.03) and improved the ratio of pathological soluble tau to tubulin (PHF1/tubulin; two-tailed t-test p = 0.0006). Reduction of tau pathology also was observed using the CP13 antibody (two-tailed t-test p = 0.0007). These results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology as assessed by immunohistochemical and biochemical methods, resulting in improved cognitive function in a tau transgenic mouse model of AD.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease

    Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the TNFRSF1B gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia. Further, a replication study was performed in 48 patients with MCI with positive AD biomarkers who were treated at a memory clinic. Cerebrospinal fluid (CSF) sTNFR2 levels along with two related TNFRSF1B gene single nucleotide polymorphisms (SNPs) rs976881 and rs1061622 were assessed. General linear models were used to evaluate the effect of CSF sTNFR2 levels and each SNP in relationship to CSF t-tau and p-tau, cognitive domains, MRI brain measures, and longitudinal cognitive changes after adjustments were made for covariates such as APOE ε4 status. In the ADNI cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF t-tau and p-tau levels; hippocampal and whole brain volumes; and Digit Span Forwards subtest scores. In the replication cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF p-tau. A significant interaction between rs976881 and CSF sTNFR2 also impacts Clinical Dementia Rating Sum of Boxes scores over 12 months in the ADNI cohort. The interaction between TNFRSF1B variant rs976881 and CSF sTNFR2 levels was noted to modulate multiple AD-associated severity markers and cognitive domains. This interaction impacts resilience-related clinical outcomes in AD and lends support to sTNFR2 as a promising candidate for therapeutic targeting to improve clinical outcomes of interest.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    Reduced Superficial Capillary Density in Cerebral Infarction Is Inversely Correlated With the NIHSS Score

    Purpose: The retina and the brain share similar neuronal and microvascular features, therein we aimed to assess the structural and microvascular changes in the macula and choriocapillaris (CC) in patients with cerebral infarction when compared with healthy controls using optical coherence tomography angiography (OCTA).

    Methods: OCTA was used to image and measure the capillary density in the radial peripapillary capillaries (RPC), superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), and mean area of the foveal avascular zone (FAZ) in all participants. Twenty-two cerebral infarction patients based on their magnetic resonance imaging (MRI) and 25 healthy controls were included in our study.

    Results: Density of the RPC (P < 0.001), SCP (P = 0.001), DCP (P < 0.001) and CC (P < 0.001) were significantly reduced in cerebral infarction patients when compared with healthy controls, respectively. Retinal thickness measurements (P < 0.05) were significantly reduced in cerebral infarction patients when compared with healthy controls. The mean FAZ area was significantly larger (P = 0.012) in cerebral infarction patients when compared with healthy controls. National Institute of HealthStroke Scale (NIHSS) inversely correlated with SCP density in cerebral infarction patients (Rho = −0.409, P = 0.001). Receiver operating characteristics curve analysis showed that the blood flow of the choriocapillaris had the highest index [area under the receiver operatingcharacteristic (AUROC) = 0.964] to discriminate cerebral infarction patients from the healthy controls.

    Conclusions: Our study suggests that cerebral microcirculation dysfunction which occurs in cerebral infarction is mirrored in the macula and choroidal microcirculation. OCTA has the potential to non-invasively characterize the macula and choroidal changes in cerebral infarction in vivo.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    Serum Uric Acid and the Risk of Dementia: A Systematic Review and Meta-Analysis

    Background: This meta-analysis aimed to evaluate the relationship between serum uric acid (UA) and the risk of dementia and its subtypes.

    Methods: Embase, PubMed, and Web of Science were searched from inception to July 2020. Random-effect models were employed to analyze the standard mean difference (SMD) with the corresponding 95% confidence intervals (CI).

    Results: Twenty-three eligible studies involving 5,575 participants were identified. The overall results showed lower levels of UA in dementia relative to non-dementia controls [SMD = −0.32 (−0.64; −0.01) p = 0.04]. The subgroup analysis of the type of dementia demonstrated a significant association of UA with Alzheimer's disease (AD) [SMD = −0.58 (−1.02; −0.15) p = 0.009] and Parkinson's disease with dementia (PDD) [SMD = −0.33 (−0.52; −0.14) p = 0.001] but not with vascular dementia (VaD). The stratification analysis of the concentrations of UA revealed that the UA quartile 1–2 was negatively correlated with dementia and neurodegenerative subtypes (p < 0.05), whereas a positive correlation of UA quartile 4 with dementia was noted (p = 0.028). Additionally, the meta-regression analysis on confounders showed that not age, body mass index, diabetes mellitus, hypertension, or smoking but education (p = 0.003) exerted an influence of the UA in the risk estimate of dementia.

    Conclusions: Low concentrations of UA (< 292 μmol/L or 4.91 mg/dL) is a potential risk factor for AD and PDD but not for VaD. The mechanism of different concentrations of the UA in dementia needs to be confirmed through further investigation.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    The Listening Network and Cochlear Implant Benefits in Hearing-Impaired Adults

    Older adults with mild or no hearing loss make more errors and expend more effort listening to speech. Cochlear implants (CI) restore hearing to deaf patients but with limited fidelity. We hypothesized that patient-reported hearing and health-related quality of life in CI patients may similarly vary according to age. Speech Spatial Qualities (SSQ) of hearing scale and Health Utilities Index Mark III (HUI) questionnaires were administered to 543 unilaterally implanted adults across Europe, South Africa, and South America. Data were acquired before surgery and at 1, 2, and 3 years post-surgery. Data were analyzed using linear mixed models with visit, age group (18–34, 35–44, 45–54, 55–64, and 65+), and side of implant as main factors and adjusted for other covariates. Tinnitus and dizziness prevalence did not vary with age, but older groups had more preoperative hearing. Preoperatively and postoperatively, SSQ scores were significantly higher (Δ0.75–0.82) for those aged <45 compared with those 55+. However, gains in SSQ scores were equivalent across age groups, although postoperative SSQ scores were higher in right-ear implanted subjects. All age groups benefited equally in terms of HUI gain (0.18), with no decrease in scores with age. Overall, younger adults appeared to cope better with a degraded hearing before and after CI, leading to better subjective hearing performance.

    in Frontiers in Ageing Neuroscience on February 25, 2021 12:00 AM.

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    A Non-stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging

    A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus<strong>.</strong> Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.

    in eLife on February 25, 2021 12:00 AM.

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    The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

    The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8A (SWELL1) is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-eNOS signaling under basal, stretch and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of Type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.

    in eLife on February 25, 2021 12:00 AM.

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    An Adeno-Associated Viral vector encoding Neurotrophin 3 injected into affected forelimb muscles modestly improves sensorimotor function after contusive mid-cervical spinal cord injury.

    Traumatic spinal cord injury (SCI) in humans occurs most frequently in the cervical spine where it can cause substantial sensorimotor impairments to upper limb function. The altered input to spinal circuits below the lesion leads to maladaptive reorganisation which often leads to hyperreflexia in proprioceptive circuits. Neurotrophin 3 (NT3) is growth factor essential for the development of proprioceptive neurons. We have previously shown that following bilateral corticospinal tract axotomy, intramuscular delivery of an Adeno-Associated Viral vector encoding NT3 (AAV-NT3) induces proprioceptive circuit reorganisation linked to functional recovery. To assess its therapeutic effects following a clinically relevant bilateral C5-C6 contusion in rats, AAV-NT3 was injected intramuscularly into the dominant limb 24 hours after injury and forelimb function was assessed over 13 weeks. The injury generated hyperreflexia of a distal forelimb proprioceptive circuit. There was also loss of fine motor skills during reach-and-grasp and walking on a horizontal ladder. Ex vivo magnetic resonance imaging (MRI) revealed atrophy of the spinal cord and white matter disruption throughout the lesion site together with extensive loss of grey matter. Unexpectedly, animals treated with AAV-NT3 had a slightly smaller lesion in the regions close to the epicentre compared to PBS treated animals. Rats treated with AAV-NT3 showed subtly better performance on the horizontal ladder and transient benefits on reach-and-grasp. AAV-NT3 did not normalise hyperreflexia in a treated muscle. The treatment increased the amount of NT3 in treated muscles but, unexpectedly, serum levels were only elevated in a small subset of animals. These results show that this dose and delivery of AAV-NT3 may generate subtle improvements in locomotion but additional treatments will be required to overcome the widespread sensorimotor deficits caused by contusion injury.

    in bioRxiv: Neuroscience on February 25, 2021 12:00 AM.

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    A synaptic novelty signal in the dentate gyrus supports switching hippocampal attractor networks from generalization to discrimination

    Episodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice navigating in familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarization of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favoring the switch from generalization to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

    in bioRxiv: Neuroscience on February 25, 2021 12:00 AM.

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    More comprehensive proprioceptive stimulation of the hand amplifies its cortical processing

    Corticokinematic coherence (CKC) quantifies the phase coupling between limb kinematics and cortical neurophysiological signals reflecting proprioceptive feedback to the primary sensorimotor (SM1) cortex. We studied CKC to proprioceptive stimulation (i.e. movement-actuator-evoked movements) of right-hand digits (index, middle, ring and little) performed simultaneously or separately. CKC was computed between magnetoencephalography (MEG) and finger acceleration signals. The strongest CKC was obtained by stimulating the fingers simultaneously at fixed 3-Hz frequency, and can, therefore, be recommended as design for fast functional localization of the hand area in the primary sensorimotor (SM1) cortex using MEG. The peaks of CKC sources were concentrated in the hand region of the SM1 cortex, but did not follow consistent somatotopic order. This result suggests that spatial specificity of MEG is not sufficient to separate proprioceptive finger representations of the same hand adequately or that their representations are overlapping.

    in bioRxiv: Neuroscience on February 25, 2021 12:00 AM.

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    Power spectra reveal distinct BOLD resting-state time courses in white matter

    Accurate characterization of the time courses of BOLD signal changes is crucial for the analysis and interpretation of functional MRI data. While several studies have shown that white matter (WM) exhibits distinct BOLD responses evoked by tasks, there have been no comprehensive investigations into the time courses of spontaneous signal fluctuations in WM. We measured the power spectra of the resting-state time courses in a set of regions within WM identified as showing synchronous signals using independent components analysis. In each component, a clear separation between voxels into two categories was evident, based on their power spectra: one group exhibited a single peak, the other had an additional peak at a higher frequency. Their groupings are location-specific, and their distributions reflect unique neurovascular and anatomical configurations. Importantly, the two categories of voxels differed in their engagement in functional integration, revealed by differences in the number of inter-regional connections based on the two categories separately. Moreover, the power spectral measurements in voxels with two peaks in specific components predict specific human behaviors. Taken together, these findings suggest WM signals are heterogeneous in nature and depend on local structural-vascular-functional associations.

    in bioRxiv: Neuroscience on February 25, 2021 12:00 AM.

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    Core Concept: Integrated assessment climate policy models have proven useful, with caveats [Earth, Atmospheric, and Planetary Sciences]

    The headlines are bleak: Regions of our planet becoming uninhabitably hot (1), crippling droughts, wildfires, and floods, collapsing ecosystems. Extreme climate change, models suggest, is likely if nations continue to increase emissions at close to their current rate, with global average temperature rises of at least 1.1 to 3.1 °C...

    in PNAS on February 24, 2021 07:07 PM.

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    Profile of Nora J. Besansky [Profiles]

    Biologist Nora J. Besansky has dedicated much of her life’s work to winning the battle against malaria. Besansky, the Gillen Professor of Biological Sciences at the University of Notre Dame, says about the mosquito-borne disease, “When you take a look at what a disease like malaria does to people—especially in...

    in PNAS on February 24, 2021 07:07 PM.

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    Monitoring epidemics: Lessons from measuring population prevalence of the coronavirus [Statistics]

    For the United States, data available from the Centers for Disease Control and Prevention (CDC) on 22 January 2021 (1–3) describe at least 442,000 additional deaths beyond what was expected in 2020 (Fig. 1). The bulk—roughly 336,000—can be attributed directly to COVID-19, and many of the remainder are related to...

    in PNAS on February 24, 2021 07:07 PM.

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    Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown [Immunology and Inflammation]

    New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM+...

    in PNAS on February 24, 2021 07:07 PM.

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    Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches [Immunology and Inflammation]

    Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly...

    in PNAS on February 24, 2021 07:07 PM.

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    Molecular bases of an alternative dual-enzyme system for light color acclimation of marine Synechococcus cyanobacteria [Microbiology]

    Marine Synechococcus cyanobacteria owe their ubiquity in part to the wide pigment diversity of their light-harvesting complexes. In open ocean waters, cells predominantly possess sophisticated antennae with rods composed of phycocyanin and two types of phycoerythrins (PEI and PEII). Some strains are specialized for harvesting either green or blue light,...

    in PNAS on February 24, 2021 07:07 PM.

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    T cells selectively filter oscillatory signals on the minutes timescale [Engineering]

    T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with...

    in PNAS on February 24, 2021 07:07 PM.

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    The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65 [Neuroscience]

    Long-term potentiation (LTP) has long been considered as an important cellular mechanism for learning and memory. LTP expression involves NMDA receptor-dependent synaptic insertion of AMPA receptors (AMPARs). However, how AMPARs are recruited and anchored at the postsynaptic membrane during LTP remains largely unknown. In this study, using CRISPR/Cas9 to delete...

    in PNAS on February 24, 2021 07:07 PM.

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    Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model [Genetics]

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in...

    in PNAS on February 24, 2021 07:07 PM.

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    Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy [Neuroscience]

    Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we...

    in PNAS on February 24, 2021 07:07 PM.

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    Neural stem cells secreting bispecific T cell engager to induce selective antiglioma activity [Immunology and Inflammation]

    Glioblastoma (GBM) is the most lethal primary brain tumor in adults. No treatment provides durable relief for the vast majority of GBM patients. In this study, we've tested a bispecific antibody comprised of single-chain variable fragments (scFvs) against T cell CD3ε and GBM cell interleukin 13 receptor alpha 2 (IL13Rα2)....

    in PNAS on February 24, 2021 07:07 PM.

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    Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain [Biophysics and Computational Biology]

    Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular...

    in PNAS on February 24, 2021 07:07 PM.

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    Cross Knowledge-based Generative Zero-Shot Learning approach with Taxonomy Regularization

    Publication date: Available online 24 February 2021

    Source: Neural Networks

    Author(s): Cheng Xie, Hongxin Xiang, Ting Zeng, Yun Yang, Beibei Yu, Qing Liu

    in Neural Networks on February 24, 2021 02:00 PM.

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    Visual question answering based on local-scene-aware referring expression generation

    Publication date: Available online 24 February 2021

    Source: Neural Networks

    Author(s): Jung-Jun Kim, Dong-Gyu Lee, Jialin Wu, Hong-Gyu Jung, Seong-Whan Lee

    in Neural Networks on February 24, 2021 02:00 PM.

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    Synchronization criteria of delayed inertial neural networks with generally Markovian jumping

    Publication date: Available online 24 February 2021

    Source: Neural Networks

    Author(s): Junyi Wang, Zhanshan Wang, Xiangyong Chen, Jianlong Qiu

    in Neural Networks on February 24, 2021 02:00 PM.

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    Correction: Biophysically grounded mean-field models of neural populations under electrical stimulation

    by Caglar Cakan, Klaus Obermayer

    in PLoS Computational Biology on February 24, 2021 02:00 PM.

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    On the evolution and development of morphological complexity: A view from gene regulatory networks

    by Pascal F. Hagolani, Roland Zimm, Renske Vroomans, Isaac Salazar-Ciudad

    How does morphological complexity evolve? This study suggests that the likelihood of mutations increasing phenotypic complexity becomes smaller when the phenotype itself is complex. In addition, the complexity of the genotype-phenotype map (GPM) also increases with the phenotypic complexity. We show that complex GPMs and the above mutational asymmetry are inevitable consequences of how genes need to be wired in order to build complex and robust phenotypes during development. We randomly wired genes and cell behaviors into networks in EmbryoMaker. EmbryoMaker is a mathematical model of development that can simulate any gene network, all animal cell behaviors (division, adhesion, apoptosis, etc.), cell signaling, cell and tissues biophysics, and the regulation of those behaviors by gene products. Through EmbryoMaker we simulated how each random network regulates development and the resulting morphology (i.e. a specific distribution of cells and gene expression in 3D). This way we obtained a zoo of possible 3D morphologies. Real gene networks are not random, but a random search allows a relatively unbiased exploration of what is needed to develop complex robust morphologies. Compared to the networks leading to simple morphologies, the networks leading to complex morphologies have the following in common: 1) They are rarer; 2) They need to be finely tuned; 3) Mutations in them tend to decrease morphological complexity; 4) They are less robust to noise; and 5) They have more complex GPMs. These results imply that, when complexity evolves, it does so at a progressively decreasing rate over generations. This is because as morphological complexity increases, the likelihood of mutations increasing complexity decreases, morphologies become less robust to noise, and the GPM becomes more complex. We find some properties in common, but also some important differences, with non-developmental GPM models (e.g. RNA, protein and gene networks in single cells).

    in PLoS Computational Biology on February 24, 2021 02:00 PM.

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    Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis

    by Mengmeng Niu, Yajun He, Jing Xu, Liangping Ding, Tao He, Yong Yi, Mengyuan Fu, Rongtian Guo, Fengtian Li, Hu Chen, Ye-Guang Chen, Zhi-Xiong Jim Xiao

    Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-β receptor I (TβRI), FBXO3, and p63 protein expression and that high expression of TβRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-β signaling in promoting tumor metastasis and that the TβRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.

    in PLoS Biology on February 24, 2021 02:00 PM.

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    Training early career researchers to use meta-research to improve science: A participant-guided “learn by doing” approach

    by Tracey L. Weissgerber

    Meta-research, or the science of science, is a powerful technique that scientists can use to improve science, however most scientists are unaware that meta-research exists and courses are rare. This initiative demonstrates the feasibility of a participant-guided “learn by doing” approach, in which a multidisciplinary, global team of early career researchers learned meta-research skills by working together to design, conduct and publish a meta-research study. This Community Page article describes a participant-guided "learn by doing" initiative, in which a multidisciplinary, global team of early career researchers learned meta-research skills by working together to design, conduct and publish a meta-research (science of science) study. Participants can now apply these skills to solve problems in their own fields.

    in PLoS Biology on February 24, 2021 02:00 PM.

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    Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

    Objective Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late‐onset Alzheimer's disease, with the ε4 allele increasing risk in a dose‐dependent fashion. In addition to ApoE4 playing a crucial role in amyloid‐β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau‐mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau‐mediated neurodegeneration. Methods Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. Results Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO‐treated mice. Interpretation We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021

    in Annals of Neurology on February 24, 2021 01:19 PM.

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    Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis

    Objective The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS. Methods We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria. Results The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7–94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69–93.2%) and rEEC (88.6, 95% CI = 84.8–91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity. Interpretation The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021

    in Annals of Neurology on February 24, 2021 10:14 AM.

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    Inflammatory Cytokine Patterns Associated with Neurological Diseases in Coronavirus Disease 2019

    Patients with coronavirus disease 2019 (COVID‐19) can present with distinct neurological manifestations. This study shows that inflammatory neurological diseases were associated with increased levels of interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, IL‐12, chemokine (C‐X‐C motif) ligand 8 (CXCL8), and CXCL10 in the cerebrospinal fluid. Conversely, encephalopathy was associated with high serum levels of IL‐6, CXCL8, and active tumor growth factor β1. Inflammatory syndromes of the central nervous system in COVID‐19 can appear early, as a parainfectious process without significant systemic involvement, or without direct evidence of severe acute respiratory syndrome coronavirus 2 neuroinvasion. At the same time, encephalopathy is mainly influenced by peripheral events, including inflammatory cytokines. ANN NEUROL 2021

    in Annals of Neurology on February 24, 2021 10:02 AM.

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    Effects of isolated nonspecific binders upon the search for specific targets: Absolute rates versus competition between the targets

    Author(s): Boris P. Belotserkovskii

    Many biological processes involve macromolecules searching for their specific targets that are surrounded by other objects, and binding to these objects affects the target search. Acceleration of the target search by nonspecific binders was observed experimentally and analyzed theoretically, for exa...


    [Phys. Rev. E 103, 022413] Published Wed Feb 24, 2021

    in Physical Review E: Biological physics on February 24, 2021 10:00 AM.

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    Organization of radial glia reveals growth pattern in the telencephalon of a percomorph fish Astatotilapia burtoni

    The orientation of radial glia in the dorsal telencephalon of teleost fish follows a morphogenetic process called eversion. We studied the radial glia in the cichlid fish Astatotilapia burtoni and found that glial processes get increasingly displaced by central pallial areas during growth. New cells are added to the growing brain subventricularly consistent with a stacking growth pattern (Cell Addition I). In addition, our data suggest that radial glial cells give rise to migrating astroglial cells providing new neurons and glia to deeper pallial regions (Cell Addition II). Abstract In the brain of teleost fish, radial glial cells are the main astroglial cell type. To understand how radial glia structures are adapting to continuous growth of the brain, we studied the astroglial cells in the telencephalon of the cichlid fish Astatotilapia burtoni in small fry to large specimens. These animals grow to a standard length of 10–12 cm in this fish species, corresponding to a more than 100‐fold increase in brain volume. Focusing on the telencephalon where glial cells are arranged radially in the everted (dorsal) pallium, immunocytochemistry for glial markers revealed an aberrant pattern of radial glial fibers in the central division of the dorsal pallium (DC, i.e., DC4 and DC5). The main glial processes curved around these nuclei, especially in the posterior part of the telencephalon. This was verified in tissue‐cleared brains stained for glial markers. We further analyzed the growth of radial glia by immunocytochemically applied stem cell (proliferating cell nuclear antigen [PCNA], Sox2) and differentiation marker (doublecortin) and found that these markers were expressed at the ventricular surface consistent with a stacking growth pattern. In addition, we detected doublecortin and Sox2 positive cells in deeper nuclei of DC areas. Our data suggest that radial glial cells give rise to migrating cells providing new neurons and glia to deeper pallial regions. This results in expansion of the central pallial areas and displacement of existing radial glial. In summary, we show that radial glial cells can adapt to morphological growth processes in the adult fish brain and contribute to this growth.

    in Journal of Comparative Neurology on February 24, 2021 04:54 AM.

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    Mesoscale microscopy for micromammals: image analysis tools for understanding the rodent brain. (arXiv:2102.11812v1 [q-bio.NC])

    Over the last ten years, developments in whole-brain microscopy now allow for high-resolution imaging of intact brains of small rodents such as mice. These complex images contain a wealth of information, but many neuroscience laboratories do not have all of the computational knowledge and tools needed to process these data. We review recent open source tools for registration of images to atlases, and the segmentation, visualisation and analysis of brain regions and labelled structures such as neurons. Since the field lacks fully integrated analysis pipelines for all types of whole-brain microscopy analysis, we propose a pathway for tool developers to work together to meet this challenge.

    in arXiv: Quantitative Biology: Neurons and Cognition on February 24, 2021 01:30 AM.

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    Multi-Space Evolutionary Search for Large-Scale Optimization. (arXiv:2102.11693v2 [cs.NE] UPDATED)

    In recent years, to improve the evolutionary algorithms used to solve optimization problems involving a large number of decision variables, many attempts have been made to simplify the problem solution space of a given problem for the evolutionary search. In the literature, the existing approaches can generally be categorized as decomposition-based methods and dimension-reduction-based methods. The former decomposes a large-scale problem into several smaller subproblems, while the latter transforms the original high-dimensional solution space into a low-dimensional space. However, it is worth noting that a given large-scale optimization problem may not always be decomposable, and it is also difficult to guarantee that the global optimum of the original problem is preserved in the reduced low-dimensional problem space. This paper thus proposes a new search paradigm, namely the multi-space evolutionary search, to enhance the existing evolutionary search methods for solving large-scale optimization problems. In contrast to existing approaches that perform an evolutionary search in a single search space, the proposed paradigm is designed to conduct a search in multiple solution spaces that are derived from the given problem, each possessing a unique landscape. The proposed paradigm makes no assumptions about the large-scale optimization problem of interest, such as that the problem is decomposable or that a certain relationship exists among the decision variables. To verify the efficacy of the proposed paradigm, comprehensive empirical studies in comparison to four state-of-the-art algorithms were conducted using the CEC2013 large-scale benchmark problems.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    On Sexual Selection. (arXiv:2102.11667v1 [q-bio.PE])

    Sexual selection is a fundamental aspect of evolution for all eukaryotic organisms with mating types. This paper suggests intersexual selection is best viewed as a mechanism to compensate for the unavoidable dynamics of coevolution between sexes that emerge with isogamy. Using the NK model of fitness landscapes, the conditions under which allosomes emerge are first explored. This extends previous work on the evolution of sex where the fitness landscape smoothing of a rudimentary form of the Baldwin effect is suggested as the underlying cause. The NKCS model of coevolution is then used to show how varying fitness landscape size, ruggedness, and connectedness can vary the conditions under which a very simple sexual selection mechanism proves beneficial. This is found to be the case whether one or both sexes exploit sexual selection.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Comparative evaluation of CNN architectures for Image Caption Generation. (arXiv:2102.11506v1 [cs.CV])

    Aided by recent advances in Deep Learning, Image Caption Generation has seen tremendous progress over the last few years. Most methods use transfer learning to extract visual information, in the form of image features, with the help of pre-trained Convolutional Neural Network models followed by transformation of the visual information using a Caption Generator module to generate the output sentences. Different methods have used different Convolutional Neural Network Architectures and, to the best of our knowledge, there is no systematic study which compares the relative efficacy of different Convolutional Neural Network architectures for extracting the visual information. In this work, we have evaluated 17 different Convolutional Neural Networks on two popular Image Caption Generation frameworks: the first based on Neural Image Caption (NIC) generation model and the second based on Soft-Attention framework. We observe that model complexity of Convolutional Neural Network, as measured by number of parameters, and the accuracy of the model on Object Recognition task does not necessarily co-relate with its efficacy on feature extraction for Image Caption Generation task.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Data Driven Testing of Cyber Physical Systems. (arXiv:2102.11491v1 [cs.CR])

    Consumer grade cyber-physical systems are becoming an integral part of our life, automatizing and simplifying everyday tasks; they are almost always capable of connection to the network allowing remote monitoring and programming. They rely on powerful programming languages, cloud infrastructures, and ultimately on complex software stacks. Indeed, due to complex interactions between hardware, networking and software, developing and testing such systems is known to be a challenging task. Ensuring properties such as dependability, security or data confidentiality is far from obvious. Various quality assurance and testing strategies have been proposed.

    The most common approach for pre-deployment testing is to model the system and run simulations with models or software in the loop. In practice, most often, tests are run for a small number of simulations, which are selected based on the engineers' domain knowledge and experience.

    We have implemented our approach in Python, using standard frameworks and used it to generate scenarios violating temperature constraints for a smart thermostat implemented as a part of our IoT testbed. Data collected from an application managing a smart building have been used to learn models of the environment under ever changing conditions. The suggested approach allowed us to identify several pit-fails, scenarios (i.e. environment conditions), where the system behaves not as expected.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Analysis of Evolutionary Diversity Optimisation for Permutation Problems. (arXiv:2102.11469v1 [cs.NE])

    Generating diverse populations of high quality solutions has gained interest as a promising extension to the traditional optimization tasks. We contribute to this line of research by studying evolutionary diversity optimization for two of the most prominent permutation problems, namely the Traveling Salesperson Problem (TSP) and Quadratic Assignment Problem (QAP). We explore the worst-case performance of a simple mutation-only evolutionary algorithm with different mutation operators, using an established diversity measure. Theoretical results show most mutation operators for both problems ensure production of maximally diverse populations of sufficiently small size within cubic expected run-time. We perform experiments on QAPLIB instances in unconstrained and constrained settings, and reveal much more optimistic practical performances. Our results should serve as a baseline for future studies.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Blending Dynamic Programming with Monte Carlo Simulation for Bounding the Running Time of Evolutionary Algorithms. (arXiv:2102.11461v1 [cs.NE])

    With the goal to provide absolute lower bounds for the best possible running times that can be achieved by $(1+\lambda)$-type search heuristics on common benchmark problems, we recently suggested a dynamic programming approach that computes optimal expected running times and the regret values inferred when deviating from the optimal parameter choice.

    Our previous work is restricted to problems for which transition probabilities between different states can be expressed by relatively simple mathematical expressions. With the goal to cover broader sets of problems, we suggest in this work an extension of the dynamic programming approach to settings in which the transition probabilities cannot necessarily be computed exactly, but in which they can be approximated numerically, up to arbitrary precision, by Monte Carlo sampling.

    We apply our hybrid Monte Carlo dynamic programming approach to a concatenated jump function and demonstrate how the obtained bounds can be used to gain a deeper understanding into parameter control schemes.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Neuroscience-Inspired Algorithms for the Predictive Maintenance of Manufacturing Systems. (arXiv:2102.11450v1 [cs.NE])

    If machine failures can be detected preemptively, then maintenance and repairs can be performed more efficiently, reducing production costs. Many machine learning techniques for performing early failure detection using vibration data have been proposed; however, these methods are often power and data-hungry, susceptible to noise, and require large amounts of data preprocessing. Also, training is usually only performed once before inference, so they do not learn and adapt as the machine ages. Thus, we propose a method of performing online, real-time anomaly detection for predictive maintenance using Hierarchical Temporal Memory (HTM). Inspired by the human neocortex, HTMs learn and adapt continuously and are robust to noise. Using the Numenta Anomaly Benchmark, we empirically demonstrate that our approach outperforms state-of-the-art algorithms at preemptively detecting real-world cases of bearing failures and simulated 3D printer failures. Our approach achieves an average score of 64.71, surpassing state-of-the-art deep-learning (49.38) and statistical (61.06) methods.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Nerve theorems for fixed points of neural networks. (arXiv:2102.11437v1 [q-bio.NC])

    Nonlinear network dynamics are notoriously difficult to understand. Here we study a class of recurrent neural networks called combinatorial threshold-linear networks (CTLNs) whose dynamics are determined by the structure of a directed graph. They are a special case of TLNs, a popular framework for modeling neural activity in computational neuroscience. In prior work, CTLNs were found to be surprisingly tractable mathematically. For small networks, the fixed points of the network dynamics can often be completely determined via a series of {\it graph rules} that can be applied directly to the underlying graph. For larger networks, it remains a challenge to understand how the global structure of the network interacts with local properties. In this work, we propose a method of covering graphs of CTLNs with a set of smaller {\it directional graphs} that reflect the local flow of activity. While directional graphs may or may not have a feedforward architecture, their fixed point structure is indicative of feedforward dynamics. The combinatorial structure of the graph cover is captured by the {\it nerve} of the cover. The nerve is a smaller, simpler graph that is more amenable to graphical analysis. We present three nerve theorems that provide strong constraints on the fixed points of the underlying network from the structure of the nerve. We then illustrate the power of these theorems with some examples. Remarkably, we find that the nerve not only constrains the fixed points of CTLNs, but also gives insight into the transient and asymptotic dynamics. This is because the flow of activity in the network tends to follow the edges of the nerve.

    in arXiv: Quantitative Biology: Neurons and Cognition on February 24, 2021 01:30 AM.

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    Optimal Prediction Intervals for Macroeconomic Time Series Using Chaos and NSGA II. (arXiv:2102.11427v1 [cs.NE])

    In a first-of-its-kind study, this paper proposes the formulation of constructing prediction intervals (PIs) in a time series as a bi-objective optimization problem and solves it with the help of Nondominated Sorting Genetic Algorithm (NSGA-II). We also proposed modeling the chaos present in the time series as a preprocessor in order to model the deterministic uncertainty present in the time series. Even though the proposed models are general in purpose, they are used here for quantifying the uncertainty in macroeconomic time series forecasting. Ideal PIs should be as narrow as possible while capturing most of the data points. Based on these two objectives, we formulated a bi-objective optimization problem to generate PIs in 2-stages, wherein reconstructing the phase space using Chaos theory (stage-1) is followed by generating optimal point prediction using NSGA-II and these point predictions are in turn used to obtain PIs (stage-2). We also proposed a 3-stage hybrid, wherein the 3rd stage invokes NSGA-II too in order to solve the problem of constructing PIs from the point prediction obtained in 2nd stage. The proposed models when applied to the macroeconomic time series, yielded better results in terms of both prediction interval coverage probability (PICP) and prediction interval average width (PIAW) compared to the state-of-the-art Lower Upper Bound Estimation Method (LUBE) with Gradient Descent (GD). The 3-stage model yielded better PICP compared to the 2-stage model but showed similar performance in PIAW with added computation cost of running NSGA-II second time.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Learning Associative Inference Using Fast Weight Memory. (arXiv:2011.07831v2 [cs.LG] UPDATED)

    Humans can quickly associate stimuli to solve problems in novel contexts. Our novel neural network model learns state representations of facts that can be composed to perform such associative inference. To this end, we augment the LSTM model with an associative memory, dubbed Fast Weight Memory (FWM). Through differentiable operations at every step of a given input sequence, the LSTM updates and maintains compositional associations stored in the rapidly changing FWM weights. Our model is trained end-to-end by gradient descent and yields excellent performance on compositional language reasoning problems, meta-reinforcement-learning for POMDPs, and small-scale word-level language modelling.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Deep Innovation Protection: Confronting the Credit Assignment Problem in Training Heterogeneous Neural Architectures. (arXiv:2001.01683v2 [cs.NE] UPDATED)

    Deep reinforcement learning approaches have shown impressive results in a variety of different domains, however, more complex heterogeneous architectures such as world models require the different neural components to be trained separately instead of end-to-end. While a simple genetic algorithm recently showed end-to-end training is possible, it failed to solve a more complex 3D task. This paper presents a method called Deep Innovation Protection (DIP) that addresses the credit assignment problem in training complex heterogenous neural network models end-to-end for such environments. The main idea behind the approach is to employ multiobjective optimization to temporally reduce the selection pressure on specific components in multi-component network, allowing other components to adapt. We investigate the emergent representations of these evolved networks, which learn to predict properties important for the survival of the agent, without the need for a specific forward-prediction loss.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 24, 2021 01:30 AM.

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    Investigating the brain structural connectome following working memory training in children born extremely preterm or extremely low birth weight

    In this randomized controlled trial, we found little evidence that the Cogmed working memory training program influenced brain structural connectivity networks compared with a placebo program in children born extremely preterm or extremely low birth weight. There was also little evidence for relationships between structural connectivity and working memory performance. Abstract Children born extremely preterm (EP, <28 weeks’ gestation) or extremely low birth weight (ELBW, <1,000 g) are a vulnerable population at high risk of working memory impairments. We aimed to examine changes in the brain structural connectivity networks thought to underlie working memory performance, after completion of a working memory training program (Cogmed) compared with a placebo program in EP/ELBW children. This was a double‐blind, placebo‐controlled randomized trial (the Improving Memory in a Preterm Randomised Intervention Trial). Children born EP/ELBW received either the Cogmed or placebo program at 7 years of age (n = 91). A subset of children had magnetic resonance imaging of the brain immediately pre‐ and 2 weeks post‐training (Cogmed n = 28; placebo n = 27). T1‐weighted and diffusion‐weighted images were used to perform graph theoretical analysis of structural connectivity networks. Changes from pre‐training to post‐training in structural connectivity metrics were generally similar between randomized groups. There was little evidence that changes in structural connectivity metrics were related to changes in working memory performance from pre‐ to post‐training. Overall, our results provide little evidence that the Cogmed working memory training program has training‐specific effects on structural connectivity networks in EP/ELBW children.

    in Journal of Neuroscience Research on February 24, 2021 01:28 AM.

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    Model organisms on roads less traveled

    Nature Methods, Published online: 24 February 2021; doi:10.1038/s41592-021-01086-7

    Beyond the well-known pantheon of model organisms are others. A shift is underway to level the playing field.

    in Nature Methods on February 24, 2021 12:00 AM.

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    Angular momentum generation in nuclear fission

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03304-w

    γ-ray spectroscopy experiments on the origin of spin in the products of nuclear fission of spin-zero nuclei suggest that the fission fragments acquire their spin after scission, rather than before.

    in Nature on February 24, 2021 12:00 AM.

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    A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03298-5

    A peri-arteriolar niche in the bone marrow for osteogenesis and lymphopoiesis is maintained by mechanical stimulation and is depleted during ageing.

    in Nature on February 24, 2021 12:00 AM.

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    Deterministic multi-qubit entanglement in a quantum network

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03288-7

    High-fidelity deterministic quantum state transfer and multi-qubit entanglement are demonstrated in a quantum network comprising two superconducting quantum nodes one metre apart, with each node including three interconnected qubits.

    in Nature on February 24, 2021 12:00 AM.

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    Efficient perovskite solar cells via improved carrier management

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03285-w

    An improved device design for perovskite-based photovoltaic cells enables a certified power conversion efficiency of 25.2 per cent, translating to 80.5 per cent of the thermodynamic limit for its bandgap, which approaches those achieved by silicon solar cells.

    in Nature on February 24, 2021 12:00 AM.

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    A multi-scale brain map derived from whole-brain volumetric reconstructions

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03284-x

    Two complete volumetric reconstructions of the Caenorhabditis elegans main neuropil (the nerve ring) reveal multi-scale spatial organization that supports both conserved and variable circuitry, and enables the derivation of a modular structure–function model of the neuropil.

    in Nature on February 24, 2021 12:00 AM.

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    The asymmetry of antimatter in the proton

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03282-z

    Quark–antiquark annihilation measurements provide a precise determination of the ratio of down and up antiquarks within protons as a function of momentum, which confirms the asymmetry between the abundance of down and up antiquarks.

    in Nature on February 24, 2021 12:00 AM.

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    Reset of hippocampal–prefrontal circuitry facilitates learning

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03272-1

    Exposure to a novel experience can ‘reset’ connections between the hippocampus and prefrontal cortex in mice, allowing them to overcome an existing learned behaviour and to replace it with a new one.

    in Nature on February 24, 2021 12:00 AM.

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    Sulfur sequestration promotes multicellularity during nutrient limitation

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03270-3

    Depriving unicellular Dictyostelium discoideum of nutrients generates reactive oxygen species that sequester cysteine within glutathione, which maintains this amoeba in a nonproliferating state that promotes aggregation into a multicellular organism.

    in Nature on February 24, 2021 12:00 AM.

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    Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03269-w

    Breaks in mitochondrial DNA cause leakage of mitochondrial RNA into the cytoplasm, enhancing immune surveillance and synergizing with nuclear DNA damage to mount a robust type-I interferon immune response.

    in Nature on February 24, 2021 12:00 AM.

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    An organoid-based organ-repurposing approach to treat short bowel syndrome

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03247-2

    In a rat model of short bowel syndrome, transplantation of small intestinal organoids into the colon partially restores intestinal function and improves survival—a proof of principle that organoid transplantation might have therapeutic benefit.

    in Nature on February 24, 2021 12:00 AM.

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    Multi-kingdom ecological drivers of microbiota assembly in preterm infants

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03241-8

    Absolute microbial abundances delineate longitudinal dynamics of bacteria, fungi and archaea in the infant gut microbiome, uncovering drivers of microbiome development masked by relative abundances and revealing notable parallels to macroscopic ecosystem assemblies.

    in Nature on February 24, 2021 12:00 AM.

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    Lipid signalling enforces functional specialization of Treg cells in tumours

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03235-6

    Identification of a metabolic checkpoint involving lipid signalling that is specific to regulatory T cells (Treg cells) in the tumour microenvironment raises the possibility of targeting this checkpoint for treatment of cancer.

    in Nature on February 24, 2021 12:00 AM.

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    Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03232-9

    Spatial and temporal variations among individual human cell proteomes are comprehensively mapped across the cell cycle using proteomic imaging and transcriptomics.

    in Nature on February 24, 2021 12:00 AM.

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    Strong tough hydrogels via the synergy of freeze-casting and salting out

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03212-z

    A strategy that combines freeze-casting and salting-out treatments produces strong, tough, stretchable and fatigue-resistant poly(vinyl alcohol) hydrogels.

    in Nature on February 24, 2021 12:00 AM.

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    Experimental demonstration of the mechanism of steady-state microbunching

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-021-03203-0

    The mechanism of steady-state electron microbunching is demonstrated, providing a basis that will enable its full implementation in electron storage rings to generate high-repetition, high-power coherent radiation.

    in Nature on February 24, 2021 12:00 AM.

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    Structural and developmental principles of neuropil assembly in C. elegans

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-020-03169-5

    The C. elegans neuropil is shown to be organized into four strata composed of related behavioural circuits, and its design principles are linked to the developmental processes that underpin its assembly.

    in Nature on February 24, 2021 12:00 AM.

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    First return, then explore

    Nature, Published online: 24 February 2021; doi:10.1038/s41586-020-03157-9

    A reinforcement learning algorithm that explicitly remembers promising states and returns to them as a basis for further exploration solves all as-yet-unsolved Atari games and out-performs previous algorithms on Montezuma’s Revenge and Pitfall.

    in Nature on February 24, 2021 12:00 AM.

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    Publisher Correction: Charge radii of exotic potassium isotopes challenge nuclear theory and the magic character of N = 32

    Nature Physics, Published online: 24 February 2021; doi:10.1038/s41567-021-01192-5

    Publisher Correction: Charge radii of exotic potassium isotopes challenge nuclear theory and the magic character of N = 32

    in Nature Physics on February 24, 2021 12:00 AM.

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    Reply to ‘Ideal solar cell efficiencies’

    Nature Photonics, Published online: 24 February 2021; doi:10.1038/s41566-021-00775-1

    Reply to ‘Ideal solar cell efficiencies’

    in Nature Photomics on February 24, 2021 12:00 AM.

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    Ideal solar cell efficiencies

    Nature Photonics, Published online: 24 February 2021; doi:10.1038/s41566-021-00772-4

    Ideal solar cell efficiencies

    in Nature Photomics on February 24, 2021 12:00 AM.

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    The tumor therapy landscape of synthetic lethality

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21544-2

    Various methods have been proposed to identify synthetic lethality interactions, but selective treatment opportunities for various tumors have not yet been explored. Here, the authors develop the Synthetic Lethality Knowledge Graph webserver (SLKG, http://www.slkg.net) to explore the comprehensive tumor therapy landscape and uncover cancer-specific susceptibilities based on the principle of synthetic lethality.

    in Nature Communications on February 24, 2021 12:00 AM.

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    Strand-specific single-cell methylomics reveals distinct modes of DNA demethylation dynamics during early mammalian development

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21532-6

    Erasure of DNA methylation from the parental genomes is critical to reset the methylome of differentiated gametes to pluripotent cells in the blastocyst. Here, the authors present a high-throughput single-cell method that enables strand-specific quantification of DNA methylation and identify distinct modes of DNA demethylation dynamics during early mammalian development.

    in Nature Communications on February 24, 2021 12:00 AM.

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    Flexible thermal interface based on self-assembled boron arsenide for high-performance thermal management

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21531-7

    Well-developed prototype interface materials for electronics thermal management are limited to a low thermal conductivity or high elastic modulus. Here, the authors report flexible thermal interfaces through self-assembled manufacturing of polymetric composites based on the high thermal conductivity of cubic boron arsenide.

    in Nature Communications on February 24, 2021 12:00 AM.

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    The secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21516-6

    The question as to how the soma regulates the germline has been much studied. Here, the authors show in C. elegans that the poly-U specific endoribonuclease ENDU-2 is secreted from the soma and taken-up by the germline, binding mature mRNA, repressing expression of somatic transcripts and maintaining germline immortality.

    in Nature Communications on February 24, 2021 12:00 AM.

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    Ocean fronts and eddies force atmospheric rivers and heavy precipitation in western North America

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21504-w

    Atmospheric rivers are responsible for much of the poleward water vapour transport in the mid-latitudes and can cause extreme precipitation after landfall. Here, the authors show that ocean fronts and eddies can influence atmospheric rivers and increase the associated precipitation along the North American west coast.

    in Nature Communications on February 24, 2021 12:00 AM.

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    Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21396-w

    Resistance to ALK inhibitors such as lorlatinib often arise due to on-target mutations. Here, the authors show the multi-kinase inhibitor gilteritinib is effective against different mutations that arise during lorlatinib in ALK fusion positive lung cancer to cause resistance.

    in Nature Communications on February 24, 2021 12:00 AM.

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    Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21247-8

    Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.

    in Nature Communications on February 24, 2021 12:00 AM.

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    A superconducting switch actuated by injection of high-energy electrons

    Nature Communications, Published online: 24 February 2021; doi:10.1038/s41467-021-21231-2

    A recent finding of tuning critical current in metallic nanowires by application of small gate voltages seems at odds with general understanding. Here, Ritter et al. study similar nanowires and link the origin of the critical current suppression to tunneling of few high-energy electrons between gate and nanowire, ruling out direct tuning by electric fields.

    in Nature Communications on February 24, 2021 12:00 AM.

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    The quark of the matter: what's really inside a proton?

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00509-x

    The surprising structure of protons, and a method for growing small intestines for transplantation.

    in Nature on February 24, 2021 12:00 AM.

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    So your grandmother is a starship now: a quick guide for the bewildered

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00503-3

    It’s a new beginning.

    in Nature on February 24, 2021 12:00 AM.

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    Massive Google-funded COVID database will track variants and immunity

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00490-5

    Open repository will give free access to more than 160 million data points with details about individual infections.

    in Nature on February 24, 2021 12:00 AM.

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    Paul J. Crutzen (1933–2021)

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00479-0

    Ozone Nobel prizewinner who coined the term Anthropocene.

    in Nature on February 24, 2021 12:00 AM.

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    An ancient Alaskan dog’s DNA hints at an epic shared journey

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00477-2

    To scientists’ surprise, a 10,000-year-old bone found in an Alaskan cave belonged to a domestic dog — one of the earliest known from the Americas.

    in Nature on February 24, 2021 12:00 AM.

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    Rich countries should tithe their vaccines

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00470-9

    Game theory suggests that donating doses can help nations of all income levels.

    in Nature on February 24, 2021 12:00 AM.

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    Collaborations with artists go beyond communicating the science

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00469-2

    Scientists and artists are working together as never before, finds a Nature poll. Both sides need to invest time, and embrace surprise and challenge.

    in Nature on February 24, 2021 12:00 AM.

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    Planet Nine, Russian education law and COVID variants

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00459-4

    The latest science news, in brief.

    in Nature on February 24, 2021 12:00 AM.

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    Accelerator-based light sources get a boost

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00431-2

    The structure of matter can be explored using the light emitted by particle accelerators. An experiment demonstrates how the properties of two such light sources — synchrotrons and free-electron lasers — can be combined.

    in Nature on February 24, 2021 12:00 AM.

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    Antimatter in the proton is more down than up

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00430-3

    Protons are found in all atoms, so it might be surprising to learn that they contain antimatter. It now emerges that there is an imbalance in the types of antimatter in the proton — a finding for which there is no agreed theoretical explanation.

    in Nature on February 24, 2021 12:00 AM.

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    Breaks in mitochondrial DNA rig the immune response

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00429-w

    Damage to DNA in a cellular organelle called the mitochondrion triggers an immune response in the nucleus. Mechanistic insights into this process shed light on how organelles communicate.

    in Nature on February 24, 2021 12:00 AM.

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    Cancer aided by greasy traitors

    Nature, Published online: 24 February 2021; doi:10.1038/d41586-021-00421-4

    Cancer can evade destruction by the immune system if aided by immunosuppressive regulatory T cells. These cells depend on a lipid-production pathway in the tumour environment, a vulnerability that might be used to target them.

    in Nature on February 24, 2021 12:00 AM.

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    Trazodone improves obstructive sleep apnea after ischemic stroke: a randomized, double-blind, placebo-controlled, crossover pilot study

    Abstract

    Background

    Low arousal threshold plays a part in the pathogenesis of obstructive sleep apnea (OSA) and may be improved by sedatives. Sedative antidepressants are frequently prescribed for stroke patients due to their high prevalence of insomnia and depression. However, the effect of sedative antidepressants on the severity of OSA in stroke patients has not been studied well.

    Methods

    In a double-blinded randomized crossover pilot study, 22 post-acute ischemic stroke patients (mean age, 61.7 ± 10.6 y) with OSA received 100 mg of trazodone or a placebo just before polysomnography, with approximately 1 week between measures. The study also measured baseline heart rate variability and 24-h ambulatory blood pressure.

    Results

    Administration of trazodone significantly increased the percentage time of slow-wave sleep (31.5 ± 13.2 vs. 18.4 ± 8.7%; P < 0.001) and improved almost all the parameters of OSA severity, including the apnea–hypopnea index (AHI, 25.4 ± 15.4 vs. 39.1 ± 18.4 events/h; P < 0.001), the respiratory arousal index (9.8 (5.8–11.95) vs. 14.1 (11.3–18.7) events/h; P < 0.001), and the minimum oxygen saturation (80.2 ± 9.1 vs. 77.1 ± 9.6%; P = 0.016). Responders to therapy (AHI reduced by > 50%; n = 7/22) had predominant OSA during rapid-eye-movement sleep and decreased sympathetic tone, as reflected in significantly lower mean blood pressure, diastolic blood pressure, and normalized low-frequency power.

    Conclusions

    Obstructive sleep apnea with comorbid ischemic stroke may be a distinctive phenotype which responds quite well to trazodone, decreasing OSA severity without increasing nocturnal hypoxia.

    Trial Registration

    Clinicaltrials.gov: NCT04162743, 2019/11/10.

    in Journal of Neurology on February 24, 2021 12:00 AM.

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    The impact of interrupting enzyme replacement therapy in late-onset Pompe disease

    Abstract

    Background

    Late-onset Pompe disease (LOPD) is a rare autosomal recessive disorder caused by mutations in the GAA gene, leading to progressive weakness of locomotor and respiratory muscles. Enzyme replacement therapy (ERT), administered every second week, has been proven to slow down disease progression and stabilize pulmonary function. Due to the COVID-19 pandemic in Germany, ERT was interrupted at our centre for 29 days. As reports on ERT discontinuation in LOPD are rare, our study aimed to analyse the impact of ERT interruption on the change in clinical outcome.

    Methods

    We performed a prospective cohort study in 12 LOPD patients. Clinical assessments were performed after ERT interruption and after the next three consecutive infusions. We assessed motor function by muscle strength testing, a 6-minute-walk-test, pulmonary function tests, and adverse events. For statistical analysis, an estimated baseline was calculated based on the individual yearly decline.

    Results

    The mean time of ERT interruption was 49.42 days (SD ± 12.54). During ERT interruption, seven patients reported 14 adverse events and two of them were severe. Frequent symptoms were reduced muscle endurance/increased muscle fatigability and shortness of breath/worsening of breathing impairment. After ERT interruption, significant deterioration was found for MIP%pred (p = 0.026) and MRC%pred, as well as a trend to clinical deterioration in FVC%pred and the 6MWT%pred.

    Conclusion

    Interruption of ERT was associated with a deterioration in the core clinical outcome measures. Therefore, an interruption of ERT should be kept as short as possible.

    in Journal of Neurology on February 24, 2021 12:00 AM.

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    Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan

    Abstract

    Background

    We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan.

    Methods

    DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32.

    Results

    We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy.

    Conclusions

    Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

    in Journal of Neurology on February 24, 2021 12:00 AM.

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    (Dys)regulation of Synaptic Activity and Neurotransmitter Release by β-Amyloid: A Look Beyond Alzheimer's Disease Pathogenesis

    Beside its widely studied role in the pathogenesis of Alzheimer's disease (AD), β-amyloid (Aβ) is a normal and soluble product of neuronal metabolism that regulates several key physiological functions, exerting neuromodulatory effects on synaptic plasticity, memory, and neurotransmitter release. Such effects have been observed to occur in a hormetic fashion, with Aβ exhibiting a dual role influenced by its concentration, the different isoforms, or aggregation forms of the peptide. However, to date, our knowledge about the physiological functions of Aβ and, in particular, its modulatory role on synaptic activity and neurotransmission in the normal brain is fragmentary, thus hindering a clear comprehension of the biological mechanisms underlying the derangement from function to dysfunction. In particular, according to the amyloid cascade hypothesis, the switch from physiology to pathology is linked to the abnormal increase in Aβ levels, due to an imbalance in Aβ production and clearance. In this regard, increased Aβ levels have been hypothesized to induce early defects in synaptic function and such alterations have been suggested to account, at least in part, for the onset of neuropsychiatric symptoms (e.g., apathy, anxiety, changes in mood, depression, and agitation/aggression), frequently observed in the prodromal stage of AD. Therefore, understanding the biological mechanisms underlying early synaptic alterations in AD is a key starting point to frame the relevant time windows for AD treatment and to gain insight into AD etiopathogenesis.

    in Frontiers in Molecular Neuroscience on February 24, 2021 12:00 AM.

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    Diffusion Tensor Imaging Detects Acute Pathology-Specific Changes in the P301L Tauopathy Mouse Model Following Traumatic Brain Injury

    Traumatic brain injury (TBI) has been linked with tauopathy. However, imaging methods that can non-invasively detect tau-protein abnormalities following TBI need further investigation. This study aimed to investigate the potential of diffusion tensor imaging (DTI) to detect tauopathy following TBI in P301L mutant-tau-transgenic-pR5-mice. A total of 24 9-month-old pR5 mice were randomly assigned to sham and TBI groups. Controlled cortical injuries/craniotomies were performed for TBI/sham groups followed by DTI data acquisition on days 1 and 7 post-injury. DTI data were analyzed by using voxelwise analysis and track-based spatial statistics for gray matter and white matter. Further, immunohistochemistry was performed for total-tau and phosphorylated-tau, astrocytes, and microglia. To detect the association of DTI with these pathological markers, a correlation analysis was performed between DTI and histology findings. At day 1 post-TBI, DTI revealed a widespread reduction in fractional anisotropy (FA) and axial diffusivity (AxD) in the TBI group compared to shams. On day 7, further reduction in FA, AxD, and mean diffusivity and increased radial diffusivity were observed. FA was significantly increased in the amygdala and cortex. Correlation results showed that in the ipsilateral hemisphere FA reduction was associated with increased phosphorylated-tau and glial-immunoreactivity, whereas in the contralateral regions, the FA increase was associated with increased immunostaining for astrocytes. This study is the first to exploit DTI to investigate the effect of TBI in tau-transgenic mice. We show that alterations in the DTI signal were associated with glial activity following TBI and would most likely reflect changes that co-occur with/without phosphorylated-tau. In addition, FA may be a promising measure to identify discrete pathological processes such as increased astroglia activation, tau-hyperphosphorylation or both in the brain following TBI.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 24, 2021 12:00 AM.

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    The Epidemiological and Mechanistic Understanding of the Neurological Manifestations of COVID-19: A Comprehensive Meta-Analysis and a Network Medicine Observation

    The clinical characteristics and biological effects on the nervous system of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain poorly understood. The aim of this study is to advance epidemiological and mechanistic understanding of the neurological manifestations of coronavirus disease 2019 (COVID-19) using stroke as a case study. In this study, we performed a meta-analysis of clinical studies reporting stroke history, intensive inflammatory response, and procoagulant state C-reactive protein (CRP), Procalcitonin (PCT), and coagulation indicator (D-dimer) in patients with COVID-19. Via network-based analysis of SARS-CoV-2 host genes and stroke-associated genes in the human protein-protein interactome, we inspected the underlying inflammatory mechanisms between COVID-19 and stroke. Finally, we further verified the network-based findings using three RNA-sequencing datasets generated from SARS-CoV-2 infected populations. We found that the overall pooled prevalence of stroke history was 2.98% (95% CI, 1.89–4.68; I2=69.2%) in the COVID-19 population. Notably, the severe group had a higher prevalence of stroke (6.06%; 95% CI 3.80–9.52; I2 = 42.6%) compare to the non-severe group (1.1%, 95% CI 0.72–1.71; I2 = 0.0%). There were increased levels of CRP, PCT, and D-dimer in severe illness, and the pooled mean difference was 40.7 mg/L (95% CI, 24.3–57.1), 0.07 μg/L (95% CI, 0.04–0.10) and 0.63 mg/L (95% CI, 0.28–0.97), respectively. Vascular cell adhesion molecule 1 (VCAM-1), one of the leukocyte adhesion molecules, is suspected to play a vital role of SARS-CoV-2 mediated inflammatory responses. RNA-sequencing data analyses of the SARS-CoV-2 infected patients further revealed the relative importance of inflammatory responses in COVID-19-associated neurological manifestations. In summary, we identified an elevated vulnerability of those with a history of stroke to severe COVID-19 underlying inflammatory responses (i.e., VCAM-1) and procoagulant pathways, suggesting monotonic relationships, thus implicating causality.

    in Frontiers in Neuroscience: Systems Biology on February 24, 2021 12:00 AM.

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    A Deep Learning Approach for the Photoacoustic Tomography Recovery From Undersampled Measurements

    Photoacoustic tomography (PAT) is a propitious imaging modality, which is helpful for biomedical study. However, fast PAT imaging and denoising is an exigent task in medical research. To address the problem, recently, methods based on compressed sensing (CS) have been proposed, which accede the low computational cost and high resolution for implementing PAT. Nevertheless, the imaging results of the sparsity-based methods strictly rely on sparsity and incoherence conditions. Furthermore, it is onerous to ensure that the experimentally acquired photoacoustic data meets CS’s prerequisite conditions. In this work, a deep learning–based PAT (Deep-PAT)method is instigated to overcome these limitations. By using a neural network, Deep-PAT is not only able to reconstruct PAT from a fewer number of measurements without considering the prerequisite conditions of CS, but also can eliminate undersampled artifacts effectively. The experimental results demonstrate that Deep-PAT is proficient at recovering high-quality photoacoustic images using just 5% of the original measurement data. Besides this, compared with the sparsity-based method, it can be seen through statistical analysis that the quality is significantly improved by 30% (approximately), having average SSIM = 0.974 and PSNR = 29.88 dB with standard deviation ±0.007 and ±0.089, respectively, by the proposed Deep-PAT method. Also, a comparsion of multiple neural networks provides insights into choosing the best one for further study and practical implementation.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 24, 2021 12:00 AM.

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    Correcting for Non-stationarity in BOLD-fMRI Connectivity Analyses

    In this work fMRI BOLD datasets are shown to contain slice-dependent non-stationarities. A model containing slice-dependent, non-stationary signal power is proposed to address time-varying signal power during BOLD data acquisition. The impact of non-stationary power on functional MRI connectivity is analytically derived, establishing that pairwise connectivity estimates are scaled by a function of the time-varying signal power, with magnitude upper bound by 1, and that the variance of sample correlation is increased, thereby inducing spurious connectivity. Consequently, we make the observation that time-varying power during acquisition of BOLD timeseries has the propensity to diminish connectivity estimates. To ameliorate the impact of non-stationary signal power, a simple correction for slice-dependent non-stationarity is proposed. Our correction is analytically shown to restore both signal stationarity and, subsequently, the integrity of connectivity estimates. Theoretical results are corroborated with empirical evidence demonstrating the utility of our correction. In addition, slice-dependent non-stationary variance is experimentally determined to be optimally characterized by an inverse Gamma distribution. The resulting distribution of a voxel's signal intensity is analytically derived to be a generalized Student's-t distribution, providing support for the Gaussianity assumption typically imposed by fMRI connectivity methods.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 24, 2021 12:00 AM.

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    Changes in Patients’ Desired Control of Their Deep Brain Stimulation and Subjective Global Control Over the Course of Deep Brain Stimulation

    Objective: To examine changes in patients’ desired control of the deep brain stimulator (DBS) and perception of global life control throughout DBS.

    Methods: A consecutive cohort of 52 patients with Parkinson’s disease (PD) was recruited to participate in a prospective longitudinal study over three assessment points (pre-surgery, post-surgery months 3 and 6). Semi-structured interviews assessing participants’ desire for stimulation control and perception of global control were conducted at all three points. Qualitative data were coded using content analysis. Visual analog scales were embedded in the interviews to quantify participants’ perceptions of control over time.

    Results: Participants reported significant increases in their perception of global control over time and significant declines in their desired control of the stimulation. These changes were unrelated to improvements in motor symptoms. Improvements in global control were negatively correlated with a decline in desired stimulation control. Qualitative data indicate that participants have changed, nuanced levels of desired control over their stimulators. Increased global life control following DBS may be attributed to increased control over PD symptoms, increased ability to engage in valued activities, and increased overall self-regulation, while other domains related to global control remained unaffected by DBS.

    Conclusions: There are few empirical data documenting patients’ desire for stimulation control throughout neuromodulation and how stimulation control is related to other aspects of control despite the growing application of neuromodulation devices to treat a variety of disorders. Our data highlight distinctions in different types of control and have implications for the development of patient-controlled neurostimulation devices.

    in Frontiers in Human Neuroscience on February 24, 2021 12:00 AM.

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    Cognitive Impairment in Adolescent Major Depressive Disorder With Nonsuicidal Self-Injury: Evidence Based on Multi-indicator ERPs

    The lifetime prevalence of major depressive disorder (MDD) in adolescents is reported to be as high as 20%; thus, MDD constitutes a significant social and public health burden. MDD is often associated with nonsuicidal self-injury (NSSI) behavior, but the contributing factors including cognitive function have not been investigated in detail. To this end, the present study evaluated cognitive impairment and psychosocial factors in associated with MDD with NSSI behavior. Eighteen and 21 drug-naïve patients with first-episode MDD with or without NSSI (NSSI+/– group) and 24 healthy control subjects (HC) were enrolled in the study. The Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Adolescent Self-injury Questionnaire, Beck Scale for Suicide Ideation–Chinese Version (BSI-CV), Shame Scale for Middle School Students, Sensation Seeking Scale (SSS) and Childhood Trauma Questionnaire (CTQ) were used to assess depression-related behaviors, and event-related potentials (ERPs) were recorded as a measure of cognitive function. The latency of the N1, N2, P3a, P3b, and P50 components of ERPs at the Cz electrode point; P50 amplitude and P50 inhibition (S1/S2) showed significant differences between the 3 groups. CTQ scores also differed across three groups, and the NSSI– and NSSI+ groups showed significant differences in scores on the Shame Scale for Middle School Students. Thus, cognitive function was impaired in adolescents with MDD with NSSI behavior, which was mainly manifested as memory decline, attention and executive function deficits, and low anti-interference ability. We also found that childhood abuse, lack of social support, and a sense of shame contributed to NSSI behavior. These findings provide insight into the risk factors for MDD with NSSI behavior, which can help mental health workers more effectively diagnose and treat these patients.

    in Frontiers in Human Neuroscience on February 24, 2021 12:00 AM.

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    Infantile Iron Deficiency Affects Brain Development in Monkeys Even After Treatment of Anemia

    A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia (IDA) has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate the neural effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1–2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging (DTI) measures from the ID infants were compared with monkeys who remained continuously iron sufficient (IS). A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter (GM) and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes (WM) was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID.

    in Frontiers in Human Neuroscience on February 24, 2021 12:00 AM.

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    Epileptic High-Frequency Oscillations in Intracranial EEG Are Not Confounded by Cognitive Tasks

    Rationale: High-frequency oscillations (HFOs) in intracranial EEG (iEEG) are used to delineate the epileptogenic zone during presurgical diagnostic assessment in patients with epilepsy. HFOs are historically divided into ripples (80–250 Hz), fast ripples (FR, >250 Hz), and their co-occurrence (FRandR). In a previous study, we had validated the rate of FRandRs during deep sleep to predict seizure outcome. Here, we ask whether epileptic FRandRs might be confounded by physiological FRandRs that are unrelated to epilepsy.

    Methods: We recorded iEEG in the medial temporal lobe MTL (hippocampus, entorhinal cortex, and amygdala) in 17 patients while they performed cognitive tasks. The three cognitive tasks addressed verbal working memory, visual working memory, and emotional processing. In our previous studies, these tasks activated the MTL. We re-analyzed the data of these studies with the automated detector that focuses on the co-occurrence of ripples and FRs (FRandR).

    Results: For each task, we identified those channels in which the HFO rate was modulated during the task condition compared to the control condition. However, the number of these channels did not exceed the chance level. Interestingly, even during wakefulness, the HFO rate was higher for channels within the seizure onset zone (SOZ) than for channels outside the SOZ.

    Conclusion: Our prospective definition of an epileptic HFO, the FRandR, is not confounded by physiological HFOs that might be elicited by our cognitive tasks. This is reassuring for the clinical use of FRandR as a biomarker of the EZ.

    in Frontiers in Human Neuroscience on February 24, 2021 12:00 AM.

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    Semantic Grounding of Novel Spoken Words in the Primary Visual Cortex

    Embodied theories of grounded semantics postulate that, when word meaning is first acquired, a link is established between symbol (word form) and corresponding semantic information present in modality-specific—including primary—sensorimotor cortices of the brain. Direct experimental evidence documenting the emergence of such a link (i.e., showing that presentation of a previously unknown, meaningless word sound induces, after learning, category-specific reactivation of relevant primary sensory or motor brain areas), however, is still missing. Here, we present new neuroimaging results that provide such evidence. We taught participants aspects of the referential meaning of previously unknown, senseless novel spoken words (such as “Shruba” or “Flipe”) by associating them with either a familiar action or a familiar object. After training, we used functional magnetic resonance imaging to analyze the participants’ brain responses to the new speech items. We found that hearing the newly learnt object-related word sounds selectively triggered activity in the primary visual cortex, as well as secondary and higher visual areas.These results for the first time directly document the formation of a link between the novel, previously meaningless spoken items and corresponding semantic information in primary sensory areas in a category-specific manner, providing experimental support for perceptual accounts of word-meaning acquisition in the brain.

    in Frontiers in Human Neuroscience on February 24, 2021 12:00 AM.

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    Local Homeostatic Regulation of the Spectral Radius of Echo-State Networks

    Recurrent cortical networks provide reservoirs of states that are thought to play a crucial role for sequential information processing in the brain. However, classical reservoir computing requires manual adjustments of global network parameters, particularly of the spectral radius of the recurrent synaptic weight matrix. It is hence not clear if the spectral radius is accessible to biological neural networks. Using random matrix theory, we show that the spectral radius is related to local properties of the neuronal dynamics whenever the overall dynamical state is only weakly correlated. This result allows us to introduce two local homeostatic synaptic scaling mechanisms, termed flow control and variance control, that implicitly drive the spectral radius toward the desired value. For both mechanisms the spectral radius is autonomously adapted while the network receives and processes inputs under working conditions. We demonstrate the effectiveness of the two adaptation mechanisms under different external input protocols. Moreover, we evaluated the network performance after adaptation by training the network to perform a time-delayed XOR operation on binary sequences. As our main result, we found that flow control reliably regulates the spectral radius for different types of input statistics. Precise tuning is however negatively affected when interneural correlations are substantial. Furthermore, we found a consistent task performance over a wide range of input strengths/variances. Variance control did however not yield the desired spectral radii with the same precision, being less consistent across different input strengths. Given the effectiveness and remarkably simple mathematical form of flow control, we conclude that self-consistent local control of the spectral radius via an implicit adaptation scheme is an interesting and biological plausible alternative to conventional methods using set point homeostatic feedback controls of neural firing.

    in Frontiers in Computational Neuroscience on February 24, 2021 12:00 AM.

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    Real Time Generation of Three Dimensional Patterns for Multiphoton Stimulation

    The advent of optogenetics has revolutionized experimental research in the field of Neuroscience and the possibility to selectively stimulate neurons in 3D volumes has opened new routes in the understanding of brain dynamics and functions. The combination of multiphoton excitation and optogenetic methods allows to identify and excite specific neuronal targets by means of the generation of cloud of excitation points. The most widely employed approach to produce the points cloud is through a spatial light modulation (SLM) which works with a refresh rate of tens of Hz. However, the computational time requested to calculate 3D patterns ranges between a few seconds and a few minutes, strongly limiting the overall performance of the system. The maximum speed of SLM can in fact be employed either with high quality patterns embedded into pre-calculated sequences or with low quality patterns for real time update. Here, we propose the implementation of a recently developed compressed sensing Gerchberg-Saxton algorithm on a consumer graphical processor unit allowing the generation of high quality patterns at video rate. This, would in turn dramatically reduce dead times in the experimental sessions, and could enable applications previously impossible, such as the control of neuronal network activity driven by the feedback from single neurons functional signals detected through calcium or voltage imaging or the real time compensation of motion artifacts.

    in Frontiers in Cellular Neuroscience on February 24, 2021 12:00 AM.

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    Differential Macrophage Responses in Affective Versus Non-Affective First-Episode Psychosis Patients

    Increased innate immune activation and inflammation are common findings in psychotic and affective (mood) disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), including increased numbers and activation of monocytes and macrophages. These findings often differ depending on the disorder, for example, we previously found increases in circulating inflammatory cytokines associated with monocytes and macrophages in SCZ, while BD had increases in anti-inflammatory cytokines. Despite these differences, few studies have specifically compared immune dysfunction in affective versus non-affective psychotic disorders and none have compared functional monocyte responses across these disorders. To address this, we recruited 25 first episode psychosis (FEP) patients and 23 healthy controls (HC). FEP patients were further grouped based on the presence (AFF) or absence (NON) of mood disorder. We isolated peripheral blood mononuclear cells and cultured them for 1 week with M-CSF to obtain monocyte-derived macrophages. These cells were then stimulated for 24 h to skew them to inflammatory and alternative phenotypes, in order to identify differences in these responses. Following stimulation with LPS and LPS plus IFNγ, we found that macrophages from the NON-group had diminished inflammatory responses compared to both HC and AFF groups. Interestingly, when skewing macrophages to an alternative phenotype using LPS plus IL-4, the AFF macrophages increased production of inflammatory cytokines. Receiver operating curve analysis showed predictive power of inflammatory cytokine concentrations after LPS stimulation in the AFF group versus NON-group. Our results suggest dysfunctional monocyte responses in both affective and non-affective psychotic disorder, with varying types of immune dysfunction depending on the presence or absence of a mood component.

    in Frontiers in Cellular Neuroscience on February 24, 2021 12:00 AM.

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    Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

    Parkinson’s disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder’s neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, “Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall.” We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Bone-Derived Factors as Potential Biomarkers for Parkinson’s Disease

    Background: Parkinson’s disease (PD) and osteoporosis are both common aging diseases. It is reported that PD has a close relationship with osteoporosis and bone secretory proteins may be involved in disease progression.

    Objectives: To detect the bone-derived factors in plasma and cerebrospinal fluid (CSF) of patients with PD and evaluate their correlations with C-reaction protein (CRP) level, motor impairment, and Hoehn-Yahr (HY) stage of the disease.

    Methods: We included 250 PD patients and 250 controls. Levels of osteocalcin (OCN), osteopontin (OPN), osteoprotegerin (OPG), Sclerostin (SO), Bone morphogenetic protein 2 (BMP2), and Dickkopf-1 (DKK-1) in plasma and CSF were measured by custom protein antibody arrays. Data were analyzed using Mann–Whitney U-test and Spearman’s receptor activator of NF-κB (RANK) correlation.

    Results: Plasma levels of OCN and OPN were correlated with CRP levels and HY stage and motor impairment of PD. Furthermore, the plasma assessment with CSF detection may enhance their potential prediction on PD.

    Conclusions: OCN and OPN may serve as potential biomarkers for PD. The inflammation response may be involved in the cross-talk between the two factors and PD.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Blood Hemoglobin, in-vivo Alzheimer Pathologies, and Cognitive Impairment: A Cross-Sectional Study

    Background: Despite known associations between low blood hemoglobin level and Alzheimer's disease (AD) or cognitive impairment, the underlying neuropathological links are poorly understood. We aimed to examine the relationships of blood hemoglobin levels with in vivo AD pathologies (i.e., cerebral beta-amyloid [Aβ] deposition, tau deposition, and AD-signature degeneration) and white matter hyperintensities (WMHs), which are a measure of cerebrovascular injury. We also investigated the association between hemoglobin level and cognitive performance, and then assessed whether such an association is mediated by brain pathologies.

    Methods: A total of 428 non-demented older adults underwent comprehensive clinical assessments, hemoglobin level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Episodic memory score and global cognition scores were also measured.

    Results: A lower hemoglobin level was significantly associated with reduced AD-signature cerebral glucose metabolism (AD-CM), but not Aβ deposition, tau deposition, or WMH volume. A lower hemoglobin level was also significantly associated with poorer episodic memory and global cognition scores, but such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a moderating effect.

    Conclusion: The present findings suggest that low blood hemoglobin in older adults is associated with cognitive decline via reduced brain metabolism, which seems to be independent of those aspects of AD-specific protein pathologies and cerebrovascular injury that are reflected in PET and MRI measures.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Aging Alters Daily and Regional Calretinin Neuronal Expression in the Rat Non-image Forming Visual Thalamus

    Aging affects the overall physiology, including the image-forming and non-image forming visual systems. Among the components of the latter, the thalamic retinorecipient inter-geniculate leaflet (IGL) and ventral lateral geniculate (vLGN) nucleus conveys light information to subcortical regions, adjusting visuomotor, and circadian functions. It is noteworthy that several visual related cells, such as neuronal subpopulations in the IGL and vLGN are neurochemically characterized by the presence of calcium binding proteins. Calretinin (CR), a representative of such proteins, denotes region-specificity in a temporal manner by variable day–night expression. In parallel, age-related brain dysfunction and neurodegeneration are associated with abnormal intracellular concentrations of calcium. Here, we investigated whether daily changes in the number of CR neurons are a feature of the aged IGL and vLGN in rats. To this end, we perfused rats, ranging from 3 to 24 months of age, within distinct phases of the day, namely zeitgeber times (ZTs). Then, we evaluated CR immunolabeling through design-based stereological cell estimation. We observed distinct daily rhythms of CR expression in the IGL and in both the retinorecipient (vLGNe) and non-retinorecipient (vLGNi) portions of the vLGN. In the ZT 6, the middle of the light phase, the CR cells are reduced with aging in the IGL and vLGNe. In the ZT 12, the transition between light to dark, an age-related CR loss was found in all nuclei. While CR expression predominates in specific spatial domains of vLGN, age-related changes appear not to be restricted at particular portions. No alterations were found in the dark/light transition or in the middle of the dark phase, ZTs 0, and 18, respectively. These results are relevant in the understanding of how aging shifts the phenotype of visual related cells at topographically organized channels of visuomotor and circadian processing.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Resilience to Plasma and Cerebrospinal Fluid Amyloid-β in Cognitively Normal Individuals: Findings From Two Cohort Studies

    Objective: To define resilience metrics for cognitive decline based on plasma and cerebrospinal fluid (CSF) amyloid-β (Aβ) and examine the demographic, genetic, and neuroimaging factors associated with interindividual differences among metrics of resilience and to demonstrate the ability of such metrics to predict the diagnostic conversion to mild cognitive impairment (MCI).

    Methods: In this study, cognitively normal (CN) participants with Aβ-positive were included from the Sino Longitudinal Study on Cognitive Decline (SILCODE, n = 100) and Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 144). Using a latent variable model of data, metrics of resilience [brain resilience (BR), cognitive resilience (CR), and global resilience (GR)] were defined based on the plasma Aβ and CSF Aβ. Linear regression analyses were applied to investigate the association between characteristics of individuals (age, sex, educational level, genetic, and neuroimaging factors) and their resilience. The plausibility of these metrics was tested using linear mixed-effects models and Cox regression models in longitudinal analyses. We also compared the effectiveness of these metrics with conventional metrics in predicting the clinical progression.

    Results: Although individuals in the ADNI cohort were older (74.68 [5.65] vs. 65.38 [4.66], p < 0.001) and had higher educational levels (16.3 [2.6] vs. 12.6 [2.8], p < 0.001) than those in the SILCODE cohort, similar loadings between resilience and its indicators were found within both models. BR and GR were mainly associated with age, women, and brain volume in both cohorts. Prediction models showed that higher CR and GR were related to better cognitive performance, and specifically, all types of resilience to CSF Aβ could predict longitudinal cognitive decline.

    Conclusion: Different phenotypes of resilience depending on cognition and brain volumes were associated with different factors. Such comprehensive resilience provided insight into the mechanisms of susceptibility for Alzheimer's disease (AD) at the individual level, and interindividual differences in resilience had the potential to predict the disease progression in CN people.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Analysis of Circulating Microvesicles Levels and Effects of Associated Factors in Elderly Patients With Obstructive Sleep Apnea

    Background: The incidence of obstructive sleep apnea (OSA) in the elderly is high, and the disorder is associated with a variety of chronic diseases. Microvesicles (MVs) are extracellular vesicles secreted by various cells during stimulation or apoptosis that play an important role in the pathogenesis of OSA. However, concentrations of circulating MVs in elderly patients with OSA remain unclear.

    Methods: Patients aged >60 years old were recruited and underwent polysomnography. Circulating plasma MV concentrations, including annexin V+MVs, endothelial MVs (EMVs), platelet MVs (PMVs), and leukocyte MVs (LMVs) levels, were measured using a flow cytometer with different labeling methods. Potential factors affecting the concentration of circulating MVs in elderly patients with OSA were determined via Spearman's correlation and multiple linear regression analysis.

    Results: Levels of circulating MVs, including both single- (annexin V+MVs, CD144+EMVs, CD41a+PMVs, and CD45+LMVs) and dual-labeled MVs (annexin V+CD144+EMVs), were elevated in elderly patients with OSA. Circulating MVs were positively correlated with OSA severity (AHI, ODI, and SPO2min). To some extent, obesity affected the MV concentrations in elderly patients with OSA. In addition, age and comorbidities may be associated with MV levels, but the correlations between the MV levels and age or comorbidities were not significant.

    Conclusion: Concentrations of circulating MVs in elderly patients with OSA are associated with the labeling method used, OSA severity, and obesity. The effects of age and comorbidities on circulating MV levels require further verification using a larger sample size.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Large-Scale Morphological Network Efficiency of Human Brain: Cognitive Intelligence and Emotional Intelligence

    Network efficiency characterizes how information flows within a network, and it has been used to study the neural basis of cognitive intelligence in adolescence, young adults, and elderly adults, in terms of the white matter in the human brain and functional connectivity networks. However, there were few studies investigating whether the human brain at different ages exhibited different underpins of cognitive and emotional intelligence (EI) from young adults to the middle-aged group, especially in terms of the morphological similarity networks in the human brain. In this study, we used 65 datasets (aging 18–64), including sMRI and behavioral measurements, to study the associations of network efficiency with cognitive intelligence and EI in young adults and the middle-aged group. We proposed a new method of defining the human brain morphological networks using the morphological distribution similarity (including cortical volume, surface area, and thickness). Our results showed inverted age × network efficiency interactions in the relationship of surface-area network efficiency with cognitive intelligence and EI: a negative age × global efficiency (nodal efficiency) interaction in cognitive intelligence, while a positive age × global efficiency (nodal efficiency) interaction in EI. In summary, this study not only proposed a new method of morphological similarity network but also emphasized the developmental effects on the brain mechanisms of intelligence from young adult to middle-aged groups and may promote mental health study on the middle-aged group in the future.

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology

    Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson’s disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).

    in Frontiers in Ageing Neuroscience on February 24, 2021 12:00 AM.

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    Glycine acylation and trafficking of a new class of bacterial lipoprotein by a composite secretion system

    Protein acylation is critical for many cellular functions across all domains of life. In bacteria, lipoproteins have important roles in virulence and are targets for the development of antimicrobials and vaccines. Bacterial lipoproteins are secreted from the cytosol via the Sec pathway and acylated on an N-terminal cysteine residue through the action of three enzymes. In Gram-negative bacteria, the Lol pathway transports lipoproteins to the outer membrane. Here we demonstrate that the Aat secretion system is a composite system sharing similarity with elements of a type I secretion systems and the Lol pathway. During secretion, the AatD subunit acylates the substrate CexE on a highly conserved N-terminal glycine residue. Mutations disrupting glycine acylation interfere with membrane incorporation and trafficking. Our data reveal CexE as the first member of a new class of glycine-acylated lipoprotein, while Aat represents a new secretion system that displays the substrate lipoprotein on the cell surface.

    in eLife on February 24, 2021 12:00 AM.

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    Real time monitoring of peptidoglycan synthesis by membrane-reconstituted penicillin binding proteins

    Peptidoglycan is an essential component of the bacterial cell envelope that surrounds the cytoplasmic membrane to protect the cell from osmotic lysis. Important antibiotics such as β-lactams and glycopeptides target peptidoglycan biosynthesis. Class A penicillin binding proteins are bifunctional membrane-bound peptidoglycan synthases that polymerize glycan chains and connect adjacent stem peptides by transpeptidation. How these enzymes work in their physiological membrane environment is poorly understood. Here we developed a novel FRET-based assay to follow in real time both reactions of class A PBPs reconstituted in liposomes or supported lipid bilayers and we applied this assay with PBP1B homologues from Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii in the presence or absence of their cognate lipoprotein activator. Our assay will allow unravelling the mechanisms of peptidoglycan synthesis in a lipid-bilayer environment and can be further developed to be used for high throughput screening for new antimicrobials.

    in eLife on February 24, 2021 12:00 AM.

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    Graphical-model framework for automated annotation of cell identities in dense cellular images

    Although identifying cell names in dense image stacks is critical in analyzing functional whole-brain data enabling comparison across experiments, unbiased identification is very difficult, and relies heavily on researchers' experiences. Here we present a probabilistic-graphical-model framework, CRF_ID, based on Conditional Random Fields, for unbiased and automated cell identification. CRF_ID focuses on maximizing intrinsic similarity between shapes. Compared to existing methods, CRF_ID achieves higher accuracy on simulated and ground-truth experimental datasets, and better robustness against challenging noise conditions common in experimental data. CRF_ID can further boost accuracy by building atlases from annotated data in highly computationally efficient manner, and by easily adding new features (e.g. from new strains). We demonstrate cell annotation in C. elegans images across strains, animal orientations, and tasks including gene-expression localization, multi-cellular and whole-brain functional imaging experiments. Together, these successes demonstrate that unbiased cell annotation can facilitate biological discovery, and this approach may be valuable to annotation tasks for other systems.

    in eLife on February 24, 2021 12:00 AM.

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    Specialized contributions of mid-tier stages of dorsal and ventral pathways to stereoscopic processing in macaque

    The division of labor between the dorsal and ventral visual pathways has been well studied, but not often with direct comparison at the single-neuron resolution with matched stimuli. Here we directly compared how single neurons in MT and V4, mid-tier areas of the two pathways, process binocular disparity, a powerful cue for 3D perception and actions. We found that MT neurons transmitted disparity signals more quickly and robustly, whereas V4 or its upstream neurons transformed the signals into sophisticated representations more prominently. Therefore, signaling speed and robustness were traded for transformation between the dorsal and ventral pathways. The key factor in this tradeoff was disparity-tuning shape: V4 neurons had more even-symmetric tuning than MT neurons. Moreover, the tuning symmetry predicted the degree of signal transformation across neurons similarly within each area, implying a general role of tuning symmetry in the stereoscopic processing by the two pathways.

    in eLife on February 24, 2021 12:00 AM.

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    Cerebellar transcranial direct current stimulation reconfigurates static and dynamic functional connectivity of the resting-state networks

    Transcranial direct current stimulation (tDCS) of the cerebellum dynamically modulates cerebello-thalamo-cortical excitability in a polarity-specific manner during motor, visuo- motor and cognitive tasks. It r...

    in Cerebellum and Ataxias on February 24, 2021 12:00 AM.

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    Cerebellar Dentate Connectivity Across Adulthood: A Large-Scale Resting State Functional Connectivity Investigation

    Cerebellar contributions to behavior in advanced age are of great interest and importance, given its role in motor and cognitive performance. There are differences and declines in cerebellar structure in advanced age, and cerebellar resting state connectivity is decreased. However, the work on this area to date has focused on the cerebellar cortex. The deep cerebellar nuclei provide the primary cerebellar inputs and outputs to the cortex, as well as the spinal and vestibular systems. In both human and non-human primate models, dentate networks can be dissociated such that dorsal region is associated with the motor cortex, while the ventral aspect is associated with the prefrontal cortex. However, whether or not dentato-thalamo-cortical networks differ across adulthood remains unknown. Here, using a large adult sample (n=591) from the Cambridge Center for Ageing and Neuroscience, we investigated dentate connectivity across adulthood. First, we replicated past work showing dissociable resting state networks in the dorsal and ventral aspects of the dentate. Second, in both seeds, we demonstrated connectivity decreases with age, indicating that connectivity differences extend beyond the cerebellar cortex. This expands our understanding of cerebellar circuitry in advanced age, and further underscores the potential importance of this structure in age-related performance differences.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Evaluating the reliability of human brain white matter tractometry

    The validity of research results depends on the reliability of analysis methods. In recent years, there have been concerns about the validity of research that uses diffusion-weighted MRI (dMRI) to understand human brain white matter connections in vivo, in part based on reliability of the analysis methods used in this field. We defined and assessed three dimensions of reliability in dMRI-based tractometry, an analysis technique that assesses the physical properties of white matter pathways: (1) reproducibility, (2) test-retest reliability and (3) robustness. To facilitate reproducibility, we provide software that automates tractometry (https://yeatmanlab.github.io/pyAFQ). In measurements from the Human Connectome Project, as well as clinical-grade measurements, we find that tractometry has high test-retest reliability that is comparable to most standardized clinical assessment tools. We find that tractometry is also robust: showing high reliability with different choices of analysis algorithms. Taken together, our results suggest that tractometry is a reliable approach to analysis of white matter connections. The overall approach taken here both demonstrates the specific trustworthiness of tractometry analysis and outlines what researchers can do to demonstrate the reliability of computational analysis pipelines in neuroimaging.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Selection of active defensive behaviors relies on extended amygdala dopamine D2 receptors

    The ability to efficiently switch from one defensive strategy to another maximizes an animals chance of survival. Here, we demonstrate that the selection of active defensive behaviors requires the coordinated activation of dopamine D2 receptor (D2R) signaling within the central extended amygdala (EA) comprising the nucleus accumbens, the oval bed nucleus stria terminals and the central amygdala. We find that discriminative learning between predictive and non-predictive threat auditory stimuli is unaltered in mice carrying a temporally-controlled deletion of D2R within output neurons of the EA. In contrast, intact EA D2R signaling is required for active avoidance learning and innate flight responses triggered by a visual threat stimulus (looming). Consequently, conditional D2R knockout mice biased defensive responses toward passive defensive strategies. Altogether, these findings identify EA D2R signaling as an important mechanism by which DA regulates the switch from passive to active defensive behaviors, regardless whether of learned or innate threat.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    An ultrasensitive GRAB sensor for detecting extracellular ATP in vitro and in vivo

    The purinergic transmitter ATP (adenosine 5'-triphosphate) plays an essential role in both the central and peripheral nervous systems, and the ability to directly measure extracellular ATP in real time will increase our understanding of its physiological functions. We developed an ultrasensitive GPCR Activation-Based ATP sensor called GRABATP1.0, with a robust fluorescence response to extracellular ATP when expressed in several cell types. This sensor has sub-second kinetics, ATP affinity in the range of tens of nanomolar, and can be used to localize ATP release with subcellular resolution. Using this sensor, we monitored ATP release under a variety of in vitro and in vivo conditions, including primary hippocampal neurons, a zebrafish model of injury-induced ATP release, and LPS-induced ATP-release events in individual astrocytes in the mouse cortex measured using in vivo two-photon imaging. Thus, the GRABATP1.0 sensor is a sensitive, versatile tool for monitoring ATP release and dynamics under both physiological and pathophysiological conditions.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Eye-Region Specific Ribbon Tuning Supports Distinct Modes of Synaptic Transmission in Same-Type Cone-Photoreceptors

    Summary. Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous ''dual-colour'' 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Characterization of late structural maturation with a neuroanatomical marker that considers both cortical thickness and intracortical myelination

    The cortical ribbon changes throughout a person's lifespan, with the most significant changes occurring during crucial development and aging periods. Changes during adulthood are rarely investigated due to the scarcity of neuroimaging data during this period. After one factor of this thinning process is intense ongoing intracortical myelination (MYEL). Here, we report age-related changes in CT, MYEL, and their ratio in 447 participants aged 18 to 57 years (BIL&GIN cohort). We propose the CT/MYEL ratio to be a multimodal cortical maturation index (MATUR) capable of reflecting 1) stages during which CT and MYEL patterns diverge and 2) the regional differences in cortical maturation that occur in adulthood. Age mainly decreased CT in all cortical regions, with larger reductions occurring in the bilateral insular lobes, temporal and frontal poles, and cingulate cortices. Age led to a linear increase in MYEL in the entire cortex and larger increases in the primary motor, auditory, and visual cortices. The effects of age on the MATUR index were characterized by both linear and quadratic components. The linear component mimicked the pattern found in CT, with 1) a robust amplification of the global and regional effects of age on CT and 2) evidence of new bilateral linear decreases in the frontal and cortical cortices. Most importantly, age exhibited additional large quadratic effects on the MATUR index in the bilateral frontal (more prominent in the right hemisphere), parietal, temporal, and cingulate regions that were not highlighted by the CT metric. Thus, the MATUR index was more sensitive to age-related cortical structural changes during adulthood than was either CT or MYEL alone. As evidenced by the large quadratic component of the effect of age, the newly proposed maturation index dramatically improved the characterization of the regional cortical territories, uncovering the latest brain maturation steps that occur before stabilization and deterioration occur in mid- and late adulthood.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Astrocyte nanoscale morphology controls Ca2+ signals at tripartite synapses

    Ca2+ signals in astrocytes can trigger the modulation of neuronal activity. Recent developments in Ca2+ imaging and super-resolution microscopy have allowed to characterize the complex morphology of astrocyte branchlets that communicate with neurons and the associated Ca2+ microdomains. Here, we use computational tools to investigate the causal relationship between branchlet morphology and spatio-temporal profile of Ca2+ signals. 3D reticular branchlet geometries were designed, alternating between large (nodes) and thinner cellular compartments (shafts). Simulations confirm experimental observations that a decreased shaft width is associated with a decreased diffusion flux from nodes, enhancing local Ca2+ activity. Upon successive neuronal stimuli, a decreased shaft width facilitates signal propagation in astrocyte branchlets. We further identify parameters that decrease local Ca2+ activity, such as a discontinuous ER geometry and an increased Ca2+ buffering. Overall, this study proposes key parameters that regulate Ca2+ activity locally, potentially favoring neuron-astrocyte communication at tripartite synapses.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Cerebellar connectivity maps embody individual adaptive behavior

    From planification to execution, cerebellar microcircuits encode different features of skilled movements. However, it is unknown whether cerebellar synaptic connectivity maps encode movement features in a motor context specific manner. Here we investigated the spatial organization of excitatory synaptic connectivity in mice cerebellar cortex in different locomotor contexts: during development and in normal, trained or altered locomotor conditions. We combined optical, electrophysiological and graph modelling approaches to describe synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs). Synaptic map maturation during development revealed a critical period in juvenile animals before the establishment of a stereotyped functional organization in adults. However, different locomotor conditions lead to specific GC-PC connectivity maps in PCs. Ultimately, we demonstrated that the variability in connectivity maps directly accounts for individual specific behavioral features of mice locomotion, suggesting that GC-PC networks encode a general motor context as well as individual specific internal models underlying motor adaptation.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Distrust Before First Sight: Knowledge- and Appearance-Based Effects of Trustworthiness on the Visual Consciousness of Faces

    Not all visual stimuli processed by the brain reach the level of conscious perception. Previous research has shown that the emotional value of a stimulus is one of the factors that can affect whether it is consciously perceived. Here, we investigated whether social-affective knowledge influences a face's chance to reach visual consciousness. Furthermore, we took into account the impact of facial appearance. Faces differing in facial trustworthiness (i.e., being perceived as more or less trustworthy based on appearance) were associated with neutral or negative socially relevant information. Subsequently, an attentional blink task was administered to examine whether the manipulated factors affect the faces' chance to reach visual consciousness under conditions of reduced attentional resources. Participants showed enhanced detection of faces associated with negative as compared to neutral social information. In event-related potentials (ERPs), this was accompanied by effects in the time range of the early posterior negativity (EPN) component. These findings indicate that social-affective person knowledge is processed already before or during attentional selection and can affect which faces are prioritized for access to visual consciousness. In contrast, no clear evidence for an impact of facial trustworthiness during the attentional blink was found. This study was pre-registered using the Open Science Framework (OSF).

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Scopolamine blocks context-dependent reinstatement of fear responses in rats

    Return of fear poses a problem for extinction-based therapies of clinical anxiety. Experimental research has discovered several pathways to return of fear, one of which is known as reinstatement. Here, we evaluated in rats the potential of scopolamine, a non-selective muscarinic receptor antagonist that is also safe for use in humans, to prevent the reinstatement of extinguished fear. We conducted three experiments with a total sample of 96 female rats. All rats went through a fear acquisition session (tone-shock pairings, CS-US), followed by two extinction sessions (CS only) and a post-extinction fear memory test. Twenty-four hours later, rats were placed in the same or a different context from extinction and received two unsignaled foot shock (US) presentations. On the following day, CS-evoked freezing returned when the reinstating USs had occurred in the same context compared to a different context (context-dependent reinstatement, Experiment 1). Systemic administration of scopolamine before or after the reinstating USs blocked the return of CS-evoked freezing on the following day (Experiments 2 and 3). Our findings suggest that administering scopolamine around the time of an aversive experience could prevent relapse of extinguished fears in humans.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

    The nervous system is a complex network of cells whose interactions provide circuitry necessary for an organism to perceive and move through its environment. Revealing the molecular basis of how neurons and non-neuronal glia communicate is essential for understanding neural development, behavior, and abnormalities of the nervous system. BMP signaling in motor neurons, activated in part by retrograde signals from muscle expressed Gbb (BMP5/6/7) has been implicated in synaptic growth, function and plasticity in Drosophila melanogaster. Through loss-of-function studies, we establish Gbb as a critical mediator of glia to neuron signaling important for proper synaptic growth. Furthermore, the BMP2/4 ortholog, Dpp, expressed in a subset of motor neurons, acts by autocrine signaling to also facilitate neuromuscular junction (NMJ) growth at specific muscle innervation sites. In addition to signaling from glia to motor neurons, autocrine Gbb induces signaling in larval VNC glia which strongly express the BMP type II receptor, Wit. In addition, to Dpps autocrine motor neuron signaling, Dpp also engages in paracrine signaling, to adjacent glia but not to neighboring motor neurons. In one type of dorsal midline motor neuron, RP2, dpp transcription is under tight regulation, as its expression is under autoregulatory control in RP2 but not aCC neurons. Taken together our findings indicate that bi-directional BMP signaling, mediated by two different ligands, facilitates communication between glia and neurons. Gbb, prominently expressed in glia, and Dpp acting from a discrete set of neurons induce active Smad-dependent BMP signaling to influence bouton number during neuromuscular junction growth.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Widespread ripples synchronize human cortical activity

    Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in cortex during sleep. Here, using human intracranial recordings, we show that ripples are also ubiquitous in the cortex during both waking and non-rapid eye movement sleep. During sleep, cortical ripples are generated on the down-to-upstate transition with phase-locked firing patterns indicating generation by pyramidal-interneuron feedback. They mark recurrence of spatiotemporal patterns from preceding waking, and group co-firing to facilitate plasticity. During waking, cortical ripples co-occur with hippocampal ripples during local activity peaks, and co-occur preceding memory recall. During sleep and waking, cortical ripples co-occur and phase-synchronize across widespread locations, including between hemispheres, providing a possible substrate for event-integration during memory and more generally in cognition.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Altered environmental perception by parental stress and depression vulnerability: impact on mothers and offspring

    Depressive mothers often find the mother-child interaction to be challenging. Parental stress may further impair mother-child attachment, which may increase the risk of negative developmental consequences. We used rats with different vulnerability to depression (Wistar and Kyoto) to investigate the impact of stress (maternal separation-MS) on maternal behaviour and adolescent offspring cognition. MS in Kyoto dams increased pup-contact, resulting in higher oxytocin levels and lower anxiety-like behaviour after weaning, while worsening their adolescent offspring cognitive behaviour. Whereas MS in Wistar dams elicited higher quality of pup-directed behaviour, increasing Brain-Derived Neurotrophic Factor (BDNF) in the offspring, which seems to have prevented a negative impact on cognition. Hypothalamic oxytocin seems to impact the salience of the social environment cues (as negative for Kyoto) leading to different coping strategies. Our findings highlight the importance of contextual and individual factors in the understanding of the oxytocin role in modulating maternal behaviour and stress regulatory processes.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Automated classification of signal sources in mesoscale calcium imaging

    Functional imaging of neural cell populations is critical for mapping intra- and inter-regional network dynamics across the neocortex. Recently we showed that an unsupervised machine learning decomposition of densely sampled recordings of cortical calcium dynamics results in a collection of components comprised of neuronal signal sources distinct from optical, movement, and vascular artifacts. Here we build a supervised learning classifier that automatically separates neural activity and artifact components, using a set of extracted spatial and temporal metrics that characterize the respective components. We demonstrate that the performance of the machine classifier matches human identification of signal components in novel data sets. Further, we analyze control data recorded in glial cell reporter and non-fluorescent mouse lines that validates human and machine identification of functional component class. This combined workflow of data-driven video decomposition and machine classification of signal sources will aid robust and scalable mapping of complex cerebral dynamics.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Deep Brain Stimulation for Parkinson's Disease Induces Spontaneous Cortical Hypersynchrony In Extended Motor and Cognitive Networks

    The mechanism of action of deep brain stimulation (DBS) for Parkinson's disease remains unclear. Studies have shown that DBS decreases pathological beta hypersynchrony between the basal ganglia and motor cortex. However, little is known about DBS's effects on long range corticocortical synchronization. Here, we use machine learning combined with spectral graph theory to compare resting-state cortical connectivity between the off and on-stimulation states and compare these differences to healthy controls. We found that turning DBS on increased high beta and gamma band coherence in a cortical circuit spanning the motor, occipitoparietal, middle temporal, and prefrontal cortices. We found no significant difference between DBS-off and controls in this network with multivariate pattern classification showing that the brain connectivity pattern in control subjects is more like those during DBS-off than DBS-on. These results show that therapeutic DBS increases spontaneous high beta-gamma synchrony in a network that couples motor areas to broader cognitive systems.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Neural correlates of subsequent memory-related gaze reinstatement

    Mounting evidence linking gaze reinstatement- the recapitulation of encoding-related gaze patterns during retrieval- to behavioral measures of memory suggests that eye movements play an important role in mnemonic processing. Yet, the nature of the gaze scanpath, including its informational content and neural correlates, has remained in question. In the present study, we examined eye movement and neural data from a recognition memory task to further elucidate the behavioral and neural bases of functional gaze reinstatement. Consistent with previous work, gaze reinstatement during retrieval of freely-viewed scene images was greater than chance and predictive of recognition memory performance. Gaze reinstatement was also associated with viewing of informationally salient image regions at encoding, suggesting that scanpaths may encode and contain high-level scene content. At the brain level, gaze reinstatement was predicted by encoding-related activity in the occipital pole and basal ganglia, neural regions associated with visual processing and oculomotor control. Finally, cross-voxel brain pattern similarity analysis revealed overlapping subsequent memory and subsequent gaze reinstatement modulation effects in the parahippocampal place area and hippocampus, in addition to the occipital pole and basal ganglia. Together, these findings suggest that encoding-related activity in brain regions associated with scene processing, oculomotor control, and memory supports the formation, and subsequent recapitulation, of functional scanpaths. More broadly, these findings lend support to the assertion of Scanpath Theory that eye movements both encode, and are themselves embedded in, mnemonic representations.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Mental individuation of imagined finger movements can be achieved using TMS-based neurofeedback

    Neurofeedback (NF) in combination with motor imagery (MI) can be used for training individuals to volitionally modulate sensorimotor activity without producing overt movements. However, until now, NF methods were of limited utility for mentally training specific hand and finger actions. Here we employed a novel transcranial magnetic stimulation (TMS) based protocol to probe and detect MI-induced motor activity patterns in the primary motor cortex (M1) with the aim to reinforce selective facilitation of single finger representations. We showed that TMS-NF training but not MI training with uninformative feedback enabled participants to selectively upregulate corticomotor excitability of one finger, while simultaneously downregulating excitability of other finger representations within the same hand. Successful finger individuation during MI was accompanied by strong desynchronisation of sensorimotor brain rhythms, particularly in the beta band, as measured by electroencephalography. Additionally, informative TMS-NF promoted more dissociable EEG activation patterns underlying single finger MI, when compared to MI of the control group where no such feedback was provided. Our findings suggest that selective TMS-NF is a new approach for acquiring the ability of finger individuation even if no overt movements are performed. This might offer new treatment modality for rehabilitation after stroke or spinal cord injury.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause

    Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ER, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (Vehicle). Rats initially receiving estradiol received either another estradiol (Continuous Estradiol) or a vehicle (Previous Estradiol) capsule. One month later, hippocampal genes and proteins were analyzed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ER and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ER as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    INSULIN-LIKE GROWTH FACTOR I SENSITIZATION REJUVENATES SLEEP PATTERNS IN OLD MICE

    Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast lectrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG stimulation and activation of orexin neurons by systemic IGF-I is abrogated in old mice. Moreover, stimulation of orthodromically activated LH neurons by either systemic or local IGF-I in young mice is absent in old mice. As orexin neurons of old mice show markedly increased IGF-I receptor (IGF-IR) levels, suggesting loss of sensitivity to IGF-I, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    Small-molecule inhibitors of the RNA m6A demethylase FTO potently support the survival of dopamine neurons

    The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, is an important regulator of central nervous system development, neuronal signalling and disease. We present here the target-tailored development and biological characterization of small-molecule inhibitors of FTO. The active compounds were identified using high-throughput molecular docking and molecular dynamics screening of the ZINC compound library. In FTO binding and activity-inhibition assays the two best inhibitors demonstrated Kd = 185 nM; IC50 = 1.46 mkM (compound 2) and Kd = 337 nM; IC50 = 28.9 mkM (compound 3). Importantly, the treatment of mouse midbrain dopamine neurons with the compounds promoted cellular survival and rescued them from growth factor deprivation induced apoptosis already at nanomolar concentrations. Moreover, these inhibitors demonstrated good blood-brain-barrier penetration in the model system, 31.7% and 30.8%, respectively. The compounds 2 and 3 protected dopamine neurons with greater potency than our recently developed alkylation repair homolog protein 5 (AlkBH5) m6A demethylase inhibitors. Inhibition of m6A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m6A RNAs in neurogenesis and neuroregeneration. Further refinement of the lead compounds identified in this study, can also lead to unprecedented breakthroughs in the treatment of neurodegenerative diseases.

    in bioRxiv: Neuroscience on February 24, 2021 12:00 AM.

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    In This Issue [This Week in PNAS]

    BIOCHEMISTRY Mapping proteolytic neo-N termini at the surface of living cells Fluorescence image of HEK293T cells expressing subtiligase-TM. Subtiligase-TM expression is shown in red, cell surface labeling activity is shown in green, and the overlap between the two is shown in yellow. Proteolysis of cell surface proteins is an important...

    in PNAS on February 23, 2021 04:50 PM.

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    Linking human behaviors and infectious diseases [Population Biology]

    Human behaviors determine outbreak trajectories of infectious diseases. This fundamental relationship underlies why broad behavioral interventions (BIs) are effective tools in outbreak management. BIs target an overall reduction in contacts and behaviors that enable pathogen transmission as a nonspecific solution for preventing new infections. Despite that, there is a lot...

    in PNAS on February 23, 2021 04:26 PM.

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    Unifying chemical and biological perspectives of carbon accumulation in the environment [Ecology]

    Heterotrophic microorganisms are fiendishly clever at degrading all shapes and sizes of organic compounds to extract the energy they need to build biomass. Every year marine phytoplankton fix ∼50 billion tons of carbon dioxide into organic matter, and every year marine heterotrophs respire nearly all of this organic matter back...

    in PNAS on February 23, 2021 04:26 PM.

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    Berni Julian Alder, theoretical physicist and inventor of molecular dynamics, 1925-2020 [Retrospectives]

    Berni Julian Alder, one of the leading figures in the invention of molecular dynamics simulations used for a wide array of problems in physics and chemistry, died on September 7, 2020. His career, spanning more than 65 years, transformed statistical mechanics, many body physics, the study of chemistry, and the...

    in PNAS on February 23, 2021 04:26 PM.

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    ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts [Immunology and Inflammation]

    HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal–fetal interface. The mode of its regulation is of considerable interest in connection with...

    in PNAS on February 23, 2021 04:26 PM.

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    The echo chamber effect on social media [Psychological and Cognitive Sciences]

    Social media may limit the exposure to diverse perspectives and favor the formation of groups of like-minded users framing and reinforcing a shared narrative, that is, echo chambers. However, the interaction paradigms among users and feed algorithms greatly vary across social media platforms. This paper explores the key differences between...

    in PNAS on February 23, 2021 04:26 PM.

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    Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking [Neuroscience]

    Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system. Inhibitory synaptic transmission plays an important role in maintaining this balance. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and...

    in PNAS on February 23, 2021 04:26 PM.

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    Oviposition-promoting pars intercerebralis neurons show period-dependent photoperiodic changes in their firing activity in the bean bug [Physiology]

    Animals show photoperiodic responses in physiology and behavior to adapt to seasonal changes. Recent genetic analyses have demonstrated the significance of circadian clock genes in these responses. However, the importance of clock genes in photoperiodic responses at the cellular level and the physiological roles of the cellular responses are poorly...

    in PNAS on February 23, 2021 04:26 PM.

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    A tandem activity-based sensing and labeling strategy enables imaging of transcellular hydrogen peroxide signaling [Biochemistry]

    Reactive oxygen species (ROS) like hydrogen peroxide (H2O2) are transient species that have broad actions in signaling and stress, but spatioanatomical understanding of their biology remains insufficient. Here, we report a tandem activity-based sensing and labeling strategy for H2O2 imaging that enables capture and permanent recording of localized H2O2 fluxes....

    in PNAS on February 23, 2021 04:26 PM.

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    Intracellular pathways for lignin catabolism in white-rot fungi [Systems Biology]

    Lignin is a biopolymer found in plant cell walls that accounts for 30% of the organic carbon in the biosphere. White-rot fungi (WRF) are considered the most efficient organisms at degrading lignin in nature. While lignin depolymerization by WRF has been extensively studied, the possibility that WRF are able to...

    in PNAS on February 23, 2021 04:26 PM.

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    Rapid Ca2+ channel accumulation contributes to cAMP-mediated increase in transmission at hippocampal mossy fiber synapses [Neuroscience]

    The cyclic adenosine monophosphate (cAMP)-dependent potentiation of neurotransmitter release is important for higher brain functions such as learning and memory. To reveal the underlying mechanisms, we applied paired pre- and postsynaptic recordings from hippocampal mossy fiber-CA3 synapses. Ca2+ uncaging experiments did not reveal changes in the intracellular Ca2+ sensitivity for...

    in PNAS on February 23, 2021 04:26 PM.

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    Heritability of individualized cortical network topography [Psychological and Cognitive Sciences]

    Human cortex is patterned by a complex and interdigitated web of large-scale functional networks. Recent methodological breakthroughs reveal variation in the size, shape, and spatial topography of cortical networks across individuals. While spatial network organization emerges across development, is stable over time, and is predictive of behavior, it is not...

    in PNAS on February 23, 2021 04:26 PM.

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    Primitive selection of the fittest emerging through functional synergy in nucleopeptide networks [Biophysics and Computational Biology]

    Many fundamental cellular and viral functions, including replication and translation, involve complex ensembles hosting synergistic activity between nucleic acids and proteins/peptides. There is ample evidence indicating that the chemical precursors of both nucleic acids and peptides could be efficiently formed in the prebiotic environment. Yet, studies on nonenzymatic replication, a...

    in PNAS on February 23, 2021 04:26 PM.

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    Operando characterization of conductive filaments during resistive switching in Mott VO2 [Applied Physical Sciences]

    Vanadium dioxide (VO2) has attracted much attention owing to its metal–insulator transition near room temperature and the ability to induce volatile resistive switching, a key feature for developing novel hardware for neuromorphic computing. Despite this interest, the mechanisms for nonvolatile switching functioning as synapse in this oxide remain not understood....

    in PNAS on February 23, 2021 04:26 PM.

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    Conflicting shape percepts explained by perception cognition distinction [Social Sciences]

    Morales et al. (1) show that a front-facing ellipse is more quickly identified among front-facing circles than rotated circles, leading them to conclude that vision has a dual character: A rotated circle is perceived both as a perspectival two-dimensional (2D) ellipse and as a 3D circle. We have two concerns....

    in PNAS on February 23, 2021 04:25 PM.

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    Fast convergence rates of deep neural networks for classification

    Publication date: Available online 23 February 2021

    Source: Neural Networks

    Author(s): Yongdai Kim, Ilsang Ohn, Dongha Kim

    in Neural Networks on February 23, 2021 02:00 PM.

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    End-to-end novel visual categories learning via auxiliary self-supervision

    Publication date: Available online 23 February 2021

    Source: Neural Networks

    Author(s): Yuanyuan Qing, Yijie Zeng, Qi Cao, Guang-Bin Huang

    in Neural Networks on February 23, 2021 02:00 PM.

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    Convergence of the RMSProp deep learning method with penalty for nonconvex optimization

    Publication date: Available online 23 February 2021

    Source: Neural Networks

    Author(s): Dongpo Xu, Shengdong Zhang, Huisheng Zhang, Danilo P. Mandic

    in Neural Networks on February 23, 2021 02:00 PM.

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    Hybridized distance- and contact-based hierarchical structure modeling for folding soluble and membrane proteins

    by Rahmatullah Roche, Sutanu Bhattacharya, Debswapna Bhattacharya

    Crystallography and NMR system (CNS) is currently a widely used method for fragment-free ab initio protein folding from inter-residue distance or contact maps. Despite its widespread use in protein structure prediction, CNS is a decade-old macromolecular structure determination system that was originally developed for solving macromolecular geometry from experimental restraints as opposed to predictive modeling driven by interaction map data. As such, the adaptation of the CNS experimental structure determination protocol for ab initio protein folding is intrinsically anomalous that may undermine the folding accuracy of computational protein structure prediction. In this paper, we propose a new CNS-free hierarchical structure modeling method called DConStruct for folding both soluble and membrane proteins driven by distance and contact information. Rigorous experimental validation shows that DConStruct attains much better reconstruction accuracy than CNS when tested with the same input contact map at varying contact thresholds. The hierarchical modeling with iterative self-correction employed in DConStruct scales at a much higher degree of folding accuracy than CNS with the increase in contact thresholds, ultimately approaching near-optimal reconstruction accuracy at higher-thresholded contact maps. The folding accuracy of DConStruct can be further improved by exploiting distance-based hybrid interaction maps at tri-level thresholding, as demonstrated by the better performance of our method in folding free modeling targets from the 12th and 13th rounds of the Critical Assessment of techniques for protein Structure Prediction (CASP) experiments compared to popular CNS- and fragment-based approaches and energy-minimization protocols, some of which even using much finer-grained distance maps than ours. Additional large-scale benchmarking shows that DConStruct can significantly improve the folding accuracy of membrane proteins compared to a CNS-based approach. These results collectively demonstrate the feasibility of greatly improving the accuracy of ab initio protein folding by optimally exploiting the information encoded in inter-residue interaction maps beyond what is possible by CNS.

    in PLoS Computational Biology on February 23, 2021 02:00 PM.

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    Evolution of heterogeneous perceptual limits and indifference in competitive foraging

    by Richard P. Mann

    The collective behaviour of animal and human groups emerges from the individual decisions and actions of their constituent members. Recent research has revealed many ways in which the behaviour of groups can be influenced by differences amongst their constituent individuals. The existence of individual differences that have implications for collective behaviour raises important questions. How are these differences generated and maintained? Are individual differences driven by exogenous factors, or are they a response to the social dilemmas these groups face? Here I consider the classic case of patch selection by foraging agents under conditions of social competition. I introduce a multilevel model wherein the perceptual sensitivities of agents evolve in response to their foraging success or failure over repeated patch selections. This model reveals a bifurcation in the population, creating a class of agents with no perceptual sensitivity. These agents exploit the social environment to avoid the costs of accurate perception, relying on other agents to make fitness rewards insensitive to the choice of foraging patch. This provides a individual-based evolutionary basis for models incorporating perceptual limits that have been proposed to explain observed deviations from the Ideal Free Distribution (IFD) in empirical studies, while showing that the common assumption in such models that agents share identical sensory limits is likely false. Further analysis of the model shows how agents develop perceptual strategic niches in response to environmental variability. The emergence of agents insensitive to reward differences also has implications for societal resource allocation problems, including the use of financial and prediction markets as mechanisms for aggregating collective wisdom.

    in PLoS Computational Biology on February 23, 2021 02:00 PM.

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    Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

    by Sarah A. Head, Xavier Hernandez-Alias, Jae-Seong Yang, Ludovica Ciampi, Violeta Beltran-Sastre, Antonio Torres-Méndez, Manuel Irimia, Martin H. Schaefer, Luis Serrano

    RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3–27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.

    in PLoS Biology on February 23, 2021 02:00 PM.

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    Multiple-shooting adjoint method for whole-brain dynamic causal modeling. (arXiv:2102.11013v1 [q-bio.NC])

    Dynamic causal modeling (DCM) is a Bayesian framework to infer directed connections between compartments, and has been used to describe the interactions between underlying neural populations based on functional neuroimaging data. DCM is typically analyzed with the expectation-maximization (EM) algorithm. However, because the inversion of a large-scale continuous system is difficult when noisy observations are present, DCM by EM is typically limited to a small number of compartments ($<10$). Another drawback with the current method is its complexity; when the forward model changes, the posterior mean changes, and we need to re-derive the algorithm for optimization. In this project, we propose the Multiple-Shooting Adjoint (MSA) method to address these limitations. MSA uses the multiple-shooting method for parameter estimation in ordinary differential equations (ODEs) under noisy observations, and is suitable for large-scale systems such as whole-brain analysis in functional MRI (fMRI). Furthermore, MSA uses the adjoint method for accurate gradient estimation in the ODE; since the adjoint method is generic, MSA is a generic method for both linear and non-linear systems, and does not require re-derivation of the algorithm as in EM. We validate MSA in extensive experiments: 1) in toy examples with both linear and non-linear models, we show that MSA achieves better accuracy in parameter value estimation than EM; furthermore, MSA can be successfully applied to large systems with up to 100 compartments; and 2) using real fMRI data, we apply MSA to the estimation of the whole-brain effective connectome and show improved classification of autism spectrum disorder (ASD) vs. control compared to using the functional connectome. The package is provided \url{https://jzkay12.github.io/TorchDiffEqPack}

    in arXiv: Quantitative Biology: Neurons and Cognition on February 23, 2021 01:30 AM.

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    Coherence of Working Memory Study Between Deep Neural Network and Neurophysiology. (arXiv:2102.10994v1 [q-bio.NC])

    The auto feature extraction capability of deep neural networks (DNN) endows them the potentiality for analysing complicated electroencephalogram (EEG) data captured from brain functionality research. This work investigates the potential coherent correspondence between the region-of-interest (ROI) for DNN to explore, and ROI for conventional neurophysiological oriented methods to work with, exemplified in the case of working memory study. The attention mechanism induced by global average pooling (GAP) is applied to a public EEG dataset of working memory, to unveil these coherent ROIs via a classification problem. The result shows the alignment of ROIs from different research disciplines. This work asserts the confidence and promise of utilizing DNN for EEG data analysis, albeit in lack of the interpretation to network operations.

    in arXiv: Quantitative Biology: Neurons and Cognition on February 23, 2021 01:30 AM.

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    Combining Spiking Neural Network and Artificial Neural Network for Enhanced Image Classification. (arXiv:2102.10592v1 [cs.NE])

    With the continued innovations of deep neural networks, spiking neural networks (SNNs) that more closely resemble biological brain synapses have attracted attention owing to their low power consumption. However, for continuous data values, they must employ a coding process to convert the values to spike trains. Thus, they have not yet exceeded the performance of artificial neural networks (ANNs), which handle such values directly. To this end, we combine an ANN and an SNN to build versatile hybrid neural networks (HNNs) that improve the concerned performance.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    Genetic Meta-Structure Search for Recommendation on Heterogeneous Information Network. (arXiv:2102.10550v1 [cs.IR])

    In the past decade, the heterogeneous information network (HIN) has become an important methodology for modern recommender systems. To fully leverage its power, manually designed network templates, i.e., meta-structures, are introduced to filter out semantic-aware information. The hand-crafted meta-structure rely on intense expert knowledge, which is both laborious and data-dependent. On the other hand, the number of meta-structures grows exponentially with its size and the number of node types, which prohibits brute-force search. To address these challenges, we propose Genetic Meta-Structure Search (GEMS) to automatically optimize meta-structure designs for recommendation on HINs. Specifically, GEMS adopts a parallel genetic algorithm to search meaningful meta-structures for recommendation, and designs dedicated rules and a meta-structure predictor to efficiently explore the search space. Finally, we propose an attention based multi-view graph convolutional network module to dynamically fuse information from different meta-structures. Extensive experiments on three real-world datasets suggest the effectiveness of GEMS, which consistently outperforms all baseline methods in HIN recommendation. Compared with simplified GEMS which utilizes hand-crafted meta-paths, GEMS achieves over $6\%$ performance gain on most evaluation metrics. More importantly, we conduct an in-depth analysis on the identified meta-structures, which sheds light on the HIN based recommender system design.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    STDP enhances learning by backpropagation in a spiking neural network. (arXiv:2102.10530v1 [cs.NE])

    A semi-supervised learning method for spiking neural networks is proposed. The proposed method consists of supervised learning by backpropagation and subsequent unsupervised learning by spike-timing-dependent plasticity (STDP), which is a biologically plausible learning rule. Numerical experiments show that the proposed method improves the accuracy without additional labeling when a small amount of labeled data is used. This feature has not been achieved by existing semi-supervised learning methods of discriminative models. It is possible to implement the proposed learning method for event-driven systems. Hence, it would be highly efficient in real-time problems if it were implemented on neuromorphic hardware. The results suggest that STDP plays an important role other than self-organization when applied after supervised learning, which differs from the previous method of using STDP as pre-training interpreted as self-organization.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    Neural Sampling Machine with Stochastic Synapse allows Brain-like Learning and Inference. (arXiv:2102.10477v1 [cond-mat.dis-nn])

    Many real-world mission-critical applications require continual online learning from noisy data and real-time decision making with a defined confidence level. Probabilistic models and stochastic neural networks can explicitly handle uncertainty in data and allow adaptive learning-on-the-fly, but their implementation in a low-power substrate remains a challenge. Here, we introduce a novel hardware fabric that implements a new class of stochastic NN called Neural-Sampling-Machine that exploits stochasticity in synaptic connections for approximate Bayesian inference. Harnessing the inherent non-linearities and stochasticity occurring at the atomic level in emerging materials and devices allows us to capture the synaptic stochasticity occurring at the molecular level in biological synapses. We experimentally demonstrate in-silico hybrid stochastic synapse by pairing a ferroelectric field-effect transistor -based analog weight cell with a two-terminal stochastic selector element. Such a stochastic synapse can be integrated within the well-established crossbar array architecture for compute-in-memory. We experimentally show that the inherent stochastic switching of the selector element between the insulator and metallic state introduces a multiplicative stochastic noise within the synapses of NSM that samples the conductance states of the FeFET, both during learning and inference. We perform network-level simulations to highlight the salient automatic weight normalization feature introduced by the stochastic synapses of the NSM that paves the way for continual online learning without any offline Batch Normalization. We also showcase the Bayesian inferencing capability introduced by the stochastic synapse during inference mode, thus accounting for uncertainty in data. We report 98.25%accuracy on standard image classification task as well as estimation of data uncertainty in rotated samples.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    Automatic Programming Through Combinatorial Evolution. (arXiv:2102.10475v1 [cs.SE])

    It has been already shown that combinatorial evolution - the creation of new things through the combination of existing things - can be a powerful way to evolve rather than design technical objects such as electronic circuits in a computer simulation. Intriguingly, only a few iterations seem to be required to already achieve complex objects. In the present paper we want to employ combinatorial evolution in software development. Our research question is whether it is possible to generate computer programs of increasing complexity using automatic programming through combinatorial evolution. Specifically, we ask what kind of basic code blocks are needed at the beginning, how are these code blocks implemented to allow them to combine, and how can code complexity be measured. We implemented a computer program simulating combinatorial evolution of code blocks stored in a database to make them available for combinations. Automatic programming is achieved by evaluating regular expressions. We found that reserved key words of a programming language are suitable for defining the basic code blocks at the beginning of the simulation. We also found that placeholders can be used to combine code blocks and that code complexity can be described in terms of the importance to the programming language. As in the previous combinatorial evolution simulation of electronic circuits, complexity increased from simple keywords and special characters to more complex variable declarations, to class definitions, to methods, and to classes containing methods and variable declarations. Combinatorial evolution, therefore, seems to be a promising approach for automatic programming.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    Multi-Phase Locking Value: A Generalized Method for Determining Instantaneous Multi-frequency Phase Coupling. (arXiv:2102.10471v1 [q-bio.NC])

    Many physical, biological and neural systems behave as coupled oscillators, with characteristic phase coupling across different frequencies. Methods such as $n:m$ phase locking value and bi-phase locking value have previously been proposed to quantify phase coupling between two resonant frequencies (e.g. $f$, $2f/3$) and across three frequencies (e.g. $f_1$, $f_2$, $f_1+f_2$), respectively. However, the existing phase coupling metrics have their limitations and limited applications. They cannot be used to detect or quantify phase coupling across multiple frequencies (e.g. $f_1$, $f_2$, $f_3$, $f_4$, $f_1+f_2+f_3-f_4$), or coupling that involves non-integer multiples of the frequencies (e.g. $f_1$, $f_2$, $2f_1/3+f_2/3$). To address the gap, this paper proposes a generalized approach, named multi-phase locking value (M-PLV), for the quantification of various types of instantaneous multi-frequency phase coupling. Different from most instantaneous phase coupling metrics that measure the simultaneous phase coupling, the proposed M-PLV method also allows the detection of delayed phase coupling and the associated time lag between coupled oscillators. The M-PLV has been tested on cases where synthetic coupled signals are generated using white Gaussian signals, and a system comprised of multiple coupled R\"ossler oscillators. Results indicate that the M-PLV can provide a reliable estimation of the time window and frequency combination where the phase coupling is significant, as well as a precise determination of time lag in the case of delayed coupling. This method has the potential to become a powerful new tool for exploring phase coupling in complex nonlinear dynamic systems.

    in arXiv: Quantitative Biology: Neurons and Cognition on February 23, 2021 01:30 AM.

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    MHDeep: Mental Health Disorder Detection System based on Body-Area and Deep Neural Networks. (arXiv:2102.10435v1 [cs.LG])

    Mental health problems impact quality of life of millions of people around the world. However, diagnosis of mental health disorders is a challenging problem that often relies on self-reporting by patients about their behavioral patterns. Therefore, there is a need for new strategies for diagnosis of mental health problems. The recent introduction of body-area networks consisting of a plethora of accurate sensors embedded in smartwatches and smartphones and deep neural networks (DNNs) points towards a possible solution. However, disease diagnosis based on WMSs and DNNs, and their deployment on edge devices, remains a challenging problem. To this end, we propose a framework called MHDeep that utilizes commercially available WMSs and efficient DNN models to diagnose three important mental health disorders: schizoaffective, major depressive, and bipolar. MHDeep uses eight different categories of data obtained from sensors integrated in a smartwatch and smartphone. Due to limited available data, MHDeep uses a synthetic data generation module to augment real data with synthetic data drawn from the same probability distribution. We use the synthetic dataset to pre-train the DNN models, thus imposing a prior on the weights. We use a grow-and-prune DNN synthesis approach to learn both the architecture and weights during the training process. We use three different data partitions to evaluate the MHDeep models trained with data collected from 74 individuals. We conduct data instance level and patient level evaluations. MHDeep achieves an average test accuracy of 90.4%, 87.3%, and 82.4%, respectively, for classifications between healthy instances and schizoaffective disorder instances, major depressive disorder instances, and bipolar disorder instances. At the patient level, MHDeep DNNs achieve an accuracy of 100%, 100%, and 90.0% for the three mental health disorders, respectively.

    in arXiv: Computer Science: Neural and Evolutionary Computing on February 23, 2021 01:30 AM.

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    Entering a new era of quantifying glutamate clearance in health and disease

    Abstract Glutamate transporter proteins, expressed on both neurons and glia, serve as the main gatekeepers that dictate the spatial and temporal actions of extracellular glutamate. Glutamate is essential to the function of the healthy brain yet paradoxically contributes to the toxicity associated with many neurodegenerative diseases. Rapid transporter‐mediated glutamate uptake, primarily occurring at astrocytic processes, tightens the efficiency of excitatory network activity and prevents toxic glutamate build‐up in the extracellular space. Glutamate transporter dysfunction is thought to underlie myriad central nervous system (CNS) diseases including Alzheimer and Huntington disease. Over the past few decades, techniques such as biochemical uptake assays and electrophysiological recordings of transporter currents from individual astrocytes have revealed the remarkable ability of the CNS to efficiently clear extracellular glutamate. In more recent years, the rapidly evolving glutamate‐sensing “sniffers” now allow researchers to visualize real‐time glutamate transients on a millisecond time scale with single synapse spatial resolution in defined cell populations. As we transition to an increased reliance on optical‐based methods of glutamate visualization and quantification, it is of utmost importance to understand not only the advantages that glutamate biosensors bring to the table but also the associated caveats and their implications for data interpretation. In this review, we summarize the strengths and limitations of the commonly used methods to quantify glutamate uptake. We then discuss what these techniques, when viewed as a complementary whole, have told us about the brain's ability to regulate glutamate levels, in both health and in the context of neurodegenerative disease.

    in Journal of Neuroscience Research on February 23, 2021 12:58 AM.

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    Publisher Correction: Nanometric axial localization of single fluorescent molecules with modulated excitation

    Nature Photonics, Published online: 23 February 2021; doi:10.1038/s41566-021-00781-3

    Publisher Correction: Nanometric axial localization of single fluorescent molecules with modulated excitation

    in Nature Photomics on February 23, 2021 12:00 AM.

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    Reflected phonons reveal strong coupling

    Nature Photonics, Published online: 23 February 2021; doi:10.1038/s41566-021-00773-3

    A new paradigm is emerging in which molecular properties are controlled by modifying the local electromagnetic environment, rather than the traditional approach of changing their composition or structure. Now, a tool to investigate such effects has been demonstrated that should accelerate progress in this exciting field.

    in Nature Photomics on February 23, 2021 12:00 AM.

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    Author Correction: An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21726-y

    Author Correction: An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine

    in Nature Communications on February 23, 2021 12:00 AM.

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    Publisher Correction: Rapid 14C excursion at 3372-3371 BCE not observed at two different locations

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21647-w

    Publisher Correction: Rapid 14C excursion at 3372-3371 BCE not observed at two different locations

    in Nature Communications on February 23, 2021 12:00 AM.

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    Author Correction: Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21616-3

    Author Correction: Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF

    in Nature Communications on February 23, 2021 12:00 AM.

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    Author Correction: Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21556-y

    Author Correction: Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma

    in Nature Communications on February 23, 2021 12:00 AM.

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    Local computational methods to improve the interpretability and analysis of cryo-EM maps

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21509-5

    Here, the authors present two local methods for analyzing cryo-EM maps: LocSpiral and LocBSharpen that enhance high-resolution features of cryoEM maps, while preventing map distortions. They also introduce LocBFactor and LocOccupancy, which allow obtaining local B-factors and electron density occupancy maps from cryo-EM reconstructions and the authors demonstrate that these methods improve the interpretability and analysis of cryo-EM maps using different test cases among them recent SARS-CoV-2 spike glycoprotein structures.

    in Nature Communications on February 23, 2021 12:00 AM.

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    Enantioselective construction of six- and seven-membered triorgano-substituted silicon-stereogenic heterocycles

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21489-6

    Enantioenriched medium-sized silicon-stereogenic heterocycles are in high demand due to the potential use in functional materials. Here, the authors show a rhodium-catalyzed enantioselective synthesis of six- and seven-membered tri-organosubstituted silicon-stereogenic heterocycles.

    in Nature Communications on February 23, 2021 12:00 AM.

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    A new global ice sheet reconstruction for the past 80 000 years

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21469-w

    The configuration of past ice sheets, and therefore sea level, is highly uncertain. Here, the authors provide a global reconstruction of ice sheets for the past 80,000 years that allows to test proxy based sea level reconstructions and helps to reconcile disagreements with sea level changes inferred from models.

    in Nature Communications on February 23, 2021 12:00 AM.

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    Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21445-4

    Several mechanisms of resistance to T cell-engaging therapies have been described for solid tumors. Here, by using T cell bispecific antibodies and chimeric antigen receptors (CAR) T cells targeting HER2, the authors show that cancer cell intrinsic disruption of interferon-gamma signalling, including downregulation of JAK2, confers resistance to T-cell mediated cytotoxicity.

    in Nature Communications on February 23, 2021 12:00 AM.

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    Reply to “A Thermodynamic assessment of the reported room-temperature chemical synthesis of C2

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21439-2

    Reply to “A Thermodynamic assessment of the reported room-temperature chemical synthesis of C2

    in Nature Communications on February 23, 2021 12:00 AM.

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    A thermodynamic assessment of the reported room-temperature chemical synthesis of C2

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21433-8

    A thermodynamic assessment of the reported room-temperature chemical synthesis of C2

    in Nature Communications on February 23, 2021 12:00 AM.

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    Sniffing speeds up chemical detection by controlling air-flows near sensors

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-021-21405-y

    Sniff frequency naturally varies with animal type due to allometric scaling. Using data from live animals and a machine olfactory system, Spencer et al. reveal a deeper reason for sniffing with implications for designing gas detectors: the sniff is adapted to efficient odor detection.

    in Nature Communications on February 23, 2021 12:00 AM.

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    Continent-wide tree fecundity driven by indirect climate effects

    Nature Communications, Published online: 23 February 2021; doi:10.1038/s41467-020-20836-3

    Disentangling the various pathways by which climate change may drive community shifts in real-world ecosystems is challenging. Here the authors apply a trend attribution approach to a large dataset from the MASTIF database to assess the contribution of direct and indirect effects of climate on tree fecundity in North America, finding that the latter dominate trends by affecting tree growth and size and thereby fecundity.

    in Nature Communications on February 23, 2021 12:00 AM.

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    Poly I:C Activated Microglia Disrupt Perineuronal Nets and Modulate Synaptic Balance in Primary Hippocampal Neurons in vitro

    Perineuronal nets (PNNs) are specialized, reticular structures of the extracellular matrix (ECM) that can be found covering the soma and proximal dendrites of a neuronal subpopulation. Recent studies have shown that PNNs can highly influence synaptic plasticity and are disrupted in different neuropsychiatric disorders like schizophrenia. Interestingly, there is a growing evidence that microglia can promote the loss of PNNs and contribute to neuropsychiatric disorders. Based on this knowledge, we analyzed the impact of activated microglia on hippocampal neuronal networks in vitro. Therefore, primary cortical microglia were cultured and stimulated via polyinosinic-polycytidylic acid (Poly I:C; 50 μg/ml) administration. The Poly I:C treatment induced the expression and secretion of different cytokines belonging to the CCL- and CXCL-motif chemokine family as well as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In addition, the expression of matrix metalloproteinases (MMPs) could be verified via RT-PCR analysis. Embryonic hippocampal neurons were then cultured for 12 days in vitro (DIV) and treated for 24 h with microglial conditioned medium. Interestingly, immunocytochemical staining of the PNN component Aggrecan revealed a clear disruption of PNNs accompanied by a significant increase of glutamatergic and a decrease of γ-aminobutyric acid-(GABA)ergic synapse numbers on PNN wearing neurons. In contrast, PNN negative neurons showed a significant reduction in both, glutamatergic and GABAergic synapses. Electrophysiological recordings were performed via multielectrode array (MEA) technology and unraveled a significantly increased spontaneous network activity that sustained also 24 and 48 h after the administration of microglia conditioned medium. Taken together, we could observe a strong impact of microglial secreted factors on PNN integrity, synaptic plasticity and electrophysiological properties of cultured neurons. Our observations might enhance the understanding of neuron-microglia interactions considering the ECM.

    in Frontiers in Synaptic Neuroscience on February 23, 2021 12:00 AM.

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    Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy

    Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.

    in Frontiers in Molecular Neuroscience on February 23, 2021 12:00 AM.

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    Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

    Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.

    in Frontiers in Neuroscience: Neurodegeneration on February 23, 2021 12:00 AM.

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    Stable Anatomy Detection in Multimodal Imaging Through Sparse Group Regularization: A Comparative Study of Iron Accumulation in the Aging Brain

    Multimodal neuroimaging provides a rich source of data for identifying brain regions associated with disease progression and aging. However, present studies still typically analyze modalities separately or aggregate voxel-wise measurements and analyses to the structural level, thus reducing statistical power. As a central example, previous works have used two quantitative MRI parameters—R2* and quantitative susceptibility (QS)—to study changes in iron associated with aging in healthy and multiple sclerosis subjects, but failed to simultaneously account for both. In this article, we propose a unified framework that combines information from multiple imaging modalities and regularizes estimates for increased interpretability, generalizability, and stability. Our work focuses on joint region detection problems where overlap between effect supports across modalities is encouraged but not strictly enforced. To achieve this, we combine L1 (lasso), total variation (TV), and L2 group lasso penalties. While the TV penalty encourages geometric regularization by controlling estimate variability and support boundary geometry, the group lasso penalty accounts for similarities in the support between imaging modalities. We address the computational difficulty in this regularization scheme with an alternating direction method of multipliers (ADMM) optimizer. In a neuroimaging application, we compare our method against independent sparse and joint sparse models using a dataset of R2* and QS maps derived from MRI scans of 113 healthy controls: our method produces clinically-interpretable regions where specific iron changes are associated with healthy aging. Together with results across multiple simulation studies, we conclude that our approach identifies regions that are more strongly associated with the variable of interest (e.g., age), more accurate, and more stable with respect to training data variability. This work makes progress toward a stable and interpretable multimodal imaging analysis framework for studying disease-related changes in brain structure and can be extended for classification and disease prediction tasks.

    in Frontiers in Human Neuroscience on February 23, 2021 12:00 AM.

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    Eros, Beauty, and Phon-Aesthetic Judgements of Language Sound. We Like It Flat and Fast, but Not Melodious. Comparing Phonetic and Acoustic Features of 16 European Languages

    This article concerns sound aesthetic preferences for European foreign languages. We investigated the phonetic-acoustic dimension of the linguistic aesthetic pleasure to describe the “music” found in European languages. The Romance languages, French, Italian, and Spanish, take a lead when people talk about melodious language – the music-like effects in the language (a.k.a., phonetic chill). On the other end of the melodiousness spectrum are German and Arabic that are often considered sounding harsh and un-attractive. Despite the public interest, limited research has been conducted on the topic of phonaesthetics, i.e., the subfield of phonetics that is concerned with the aesthetic properties of speech sounds (Crystal, 2008). Our goal is to fill the existing research gap by identifying the acoustic features that drive the auditory perception of language sound beauty. What is so music-like in the language that makes people say “it is music in my ears”? We had 45 central European participants listening to 16 auditorily presented European languages and rating each language in terms of 22 binary characteristics (e.g., beautiful – ugly and funny – boring) plus indicating their language familiarities, L2 backgrounds, speaker voice liking, demographics, and musicality levels. Findings revealed that all factors in complex interplay explain a certain percentage of variance: familiarity and expertise in foreign languages, speaker voice characteristics, phonetic complexity, musical acoustic properties, and finally musical expertise of the listener. The most important discovery was the trade-off between speech tempo and so-called linguistic melody (pitch variance): the faster the language, the flatter/more atonal it is in terms of the pitch (speech melody), making it highly appealing acoustically (sounding beautiful and sexy), but not so melodious in a “musical” sense.

    in Frontiers in Human Neuroscience on February 23, 2021 12:00 AM.

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    Development and Validation of a Dynamic Nomogram to Predict the Risk of Neonatal White Matter Damage

    Purpose

    White matter damage (WMD) was defined as the appearance of rough and uneven echo enhancement in the white matter around the ventricle. The aim of this study was to develop and validate a risk prediction model for neonatal WMD.

    Materials and Methods

    We collected data for 1,733 infants hospitalized at the Department of Neonatology at The First Affiliated Hospital of Zhengzhou University from 2017 to 2020. Infants were randomly assigned to training (n = 1,216) or validation (n = 517) cohorts at a ratio of 7:3. Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to establish a risk prediction model and web-based risk calculator based on the training cohort data. The predictive accuracy of the model was verified in the validation cohort.

    Results

    We identified four variables as independent risk factors for brain WMD in neonates by multivariate logistic regression and LASSO analysis, including gestational age, fetal distress, prelabor rupture of membranes, and use of corticosteroids. These were used to establish a risk prediction nomogram and web-based calculator (https://caowenjun.shinyapps.io/dynnomapp/). The C-index of the training and validation sets was 0.898 (95% confidence interval: 0.8745–0.9215) and 0.887 (95% confidence interval: 0.8478–0.9262), respectively. Decision tree analysis showed that the model was highly effective in the threshold range of 1–61%. The sensitivity and specificity of the model were 82.5 and 81.7%, respectively, and the cutoff value was 0.099.

    Conclusion

    This is the first study describing the use of a nomogram and web-based calculator to predict the risk of WMD in neonates. The web-based calculator increases the applicability of the predictive model and is a convenient tool for doctors at primary hospitals and outpatient clinics, family doctors, and even parents to identify high-risk births early on and implementing appropriate interventions while avoiding excessive treatment of low-risk patients.

    in Frontiers in Human Neuroscience on February 23, 2021 12:00 AM.

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    Can Enhancing Neuronal Activity Improve Myelin Repair in Multiple Sclerosis?

    Enhanced neuronal activity in the healthy brain can induce de novo myelination and behavioral changes. As neuronal activity can be achieved using non-invasive measures, it may be of interest to utilize the innate ability of neuronal activity to instruct myelination as a novel strategy for myelin repair in demyelinating disorders such as multiple sclerosis (MS). Preclinical studies indicate that stimulation of neuronal activity in demyelinated lesions indeed has the potential to improve remyelination and that the stimulation paradigm is an important determinant of success. However, future studies will need to reveal the most efficient stimulation protocols as well as the biological mechanisms implicated. Nonetheless, clinical studies have already explored non-invasive brain stimulation as an attractive therapeutic approach that ameliorates MS symptomatology. However, whether symptom improvement is due to improved myelin repair remains unclear. In this mini-review, we discuss the neurobiological basis and potential of enhancing neuronal activity as a novel therapeutic approach in MS.

    in Frontiers in Cellular Neuroscience on February 23, 2021 12:00 AM.

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    High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions

    Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it’s model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia.

    Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines.

    Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation.

    Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.

    in Frontiers in Cellular Neuroscience on February 23, 2021 12:00 AM.

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    Emerging Roles of Extracellular Vesicles in the Central Nervous System: Physiology, Pathology, and Therapeutic Perspectives

    Extracellular vesicles or EVs are secreted by most, if not all, eukaryote cell types and recaptured by neighboring or distant cells. Their cargo, composed of a vast diversity of proteins, lipids, and nucleic acids, supports the EVs’ inter-cellular communication. The role of EVs in many cellular processes is now well documented both in physiological and pathological conditions. In this review, we focus on the role of EVs in the central nervous system (CNS) in physiological as well as pathological conditions such as neurodegenerative diseases or brain cancers. We also discuss the future of EVs in clinical research, in particular, their value as biomarkers as well as innovative therapeutic agents. While an increasing number of studies reveal EV research as a promising field, progress in the standardization of protocols and innovation in analysis as well as in research tools is needed to make a breakthrough in our understanding of their impact in the pathophysiology of the brain.

    in Frontiers in Cellular Neuroscience on February 23, 2021 12:00 AM.

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    Herpes Simplex Virus Type 1 Neuronal Infection Triggers the Disassembly of Key Structural Components of Dendritic Spines

    Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.

    in Frontiers in Cellular Neuroscience on February 23, 2021 12:00 AM.

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    Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

    Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the neocortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the murine neocortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the neocortex in several classes of glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration either in cortical layer formation, or in neuronal soma size and dendritic length. Furthermore, no significant quantitative changes were observed in the proteome of cortical synapses upon neuroserpin deficiency. We conclude that, although strongly expressed in the neocortex, absence of neuroserpin does not lead to gross developmental abnormalities, and does not perturb the composition of the cortical synaptic proteome.

    in Frontiers in Neuroanatomy on February 23, 2021 12:00 AM.

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    NEUBOrg: Artificially Induced Pluripotent Stem Cell-Derived Brain Organoid to Model and Study Genetics of Alzheimer’s Disease Progression

    Alzheimer’s disease (AD) is the most common type of neurodegenerative diseases. There are over 44 million people living with the disease worldwide. While there are currently no effective treatments for AD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of Alzheimer’s pathogenesis. Nevertheless, developing brain organoid models is expensive, time consuming and often does not reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids can overcome the current limitations. Induced whole brain organoids (aiWBO) will greatly expand our ability to model AD and can guide wet lab research. In this study, we have successfully developed and validated artificially induced a whole brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.1). Using NEUBorg platform, we have generated aiWBO simulations of AD and provided a novel approach to test genetic risk factors associated with AD progression and pathogenesis.

    in Frontiers in Ageing Neuroscience on February 23, 2021 12:00 AM.

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    Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

    The pathogenesis of Alzheimer’s disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aβ25–35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ25–35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ25–35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.

    in Frontiers in Ageing Neuroscience on February 23, 2021 12:00 AM.

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    Toxins, mutations and adaptations

    The toxins that some bacteria secrete to kill off rival species can also generate mutations that help toxin-resistant populations adapt to new environments.

    in eLife on February 23, 2021 12:00 AM.

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    A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide

    R-loops are three-stranded nucleic acid structures with essential roles in many nuclear processes. However, their unchecked accumulation is associated with genome instability and is observed in neurodevelopmental diseases and cancers. Genome-wide profiling of R-loops in normal and diseased cells can help identify locations of pathogenic R-loops and advance efforts to attenuate them. We present an antibody-independent R-loop detection strategy, BisMapR, that combines nuclease-based R-loop isolation with non-denaturing bisulfite chemistry to produce genome-wide profiles that retain strand information. BisMapR achieves greater resolution and is faster than existing strand-specific R-loop profiling strategies. In mouse embryonic stem cells, we apply BisMapR to find that gene promoters form R-loops in both directions and uncover a subset of active enhancers that, despite being bidirectionally transcribed, form R-loops exclusively on one strand. BisMapR reveals a previously unnoticed feature of active enhancers and provides a tool to systematically examine their mechanisms in gene expression.

    in eLife on February 23, 2021 12:00 AM.

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    Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin

    Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington’s disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in Drd1-expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs.

    in eLife on February 23, 2021 12:00 AM.

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    Exocyst-mediated membrane trafficking of the lissencephaly-associated ECM receptor dystroglycan is required for proper brain compartmentalization

    To assemble a brain, differentiating neurons must make proper connections and establish specialized brain compartments. Abnormal levels of cell adhesion molecules disrupt these processes. Dystroglycan (Dg) is a major non-integrin cell adhesion receptor, deregulation of which is associated with dramatic neuroanatomical defects such as lissencephaly type II, or cobblestone brain. The previously established Drosophila model for cobblestone encephaly was used to understand how Dg is regulated in the brain. During development, Dg has a spatiotemporally dynamic expression pattern, fine-tuning of which is crucial for accurate brain assembly. In addition, mass spectrometry analyses identified numerous components associated with Dg in neurons, including several proteins of the exocyst complex. Data show that exocyst-based membrane trafficking of Dg allows its distinct expression pattern, essential for proper brain morphogenesis. Further studies of the Dg neuronal interactome will allow identification of new factors involved in the development of dystroglycanopathies and advance disease diagnostics in humans.

    in eLife on February 23, 2021 12:00 AM.

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    Deficient spermiogenesis in mice lacking Rlim

    The X-linked gene Rlim plays major roles in female mouse development and reproduction, where it is crucial for the maintenance of imprinted X chromosome inactivation in extraembryonic tissues of embryos. However, while females carrying a systemic Rlim knockout (KO) die around implantation, male Rlim KO mice appear healthy and are fertile. Here we report an important role for Rlim in testis where it is highly expressed in post-meiotic round spermatids as well as in Sertoli cells. Systemic deletion of the Rlim gene results in lower numbers of mature sperm that contains excess cytoplasm, leading to decreased sperm motility and in vitro fertilization rates. Targeting the conditional Rlim cKO specifically to the spermatogenic cell lineage largely recapitulates this phenotype. These results reveal functions of Rlim in male reproduction specifically in round spermatids during spermiogenesis.

    in eLife on February 23, 2021 12:00 AM.

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    Viral load and contact heterogeneity predict SARS-CoV-2 transmission and super-spreading events

    SARS-CoV-2 is difficult to contain because many transmissions occur during pre-symptomatic infection. Unlike influenza, most SARS-CoV-2 infected people do not transmit while a small percentage infect large numbers of people. We designed mathematical models which link observed viral loads with epidemiologic features of each virus, including distribution of transmissions attributed to each infected person and duration between symptom onset in the transmitter and secondarily infected person. We identify that people infected with SARS-CoV-2 or influenza can be highly contagious for less than one day, congruent with peak viral load. SARS-CoV-2 super-spreader events occur when an infected person is shedding at a very high viral load and has a high number of exposed contacts. The higher predisposition of SARS-CoV-2 towards super-spreading events cannot be attributed to additional weeks of shedding relative to influenza. Rather, a person infected with SARS-CoV-2 exposes more people within equivalent physical contact networks, likely due to aerosolization.

    in eLife on February 23, 2021 12:00 AM.

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    COVID-19 CG enables SARS-CoV-2 mutation and lineage tracking by locations and dates of interest

    COVID-19 CG (covidcg.org) is an open resource for tracking SARS-CoV-2 single-nucleotide variations (SNVs), lineages, and clades using the virus genomes on the GISAID database while filtering by location, date, gene, and mutation of interest. COVID-19 CG provides significant time, labor, and cost-saving utility to projects on SARS-CoV-2 transmission, evolution, diagnostics, therapeutics, vaccines, and intervention tracking. Here, we describe case studies in which users can interrogate (1) SNVs in the SARS-CoV-2 spike receptor binding domain (RBD) across different geographical regions to inform the design and testing of therapeutics, (2) SNVs that may impact the sensitivity of commonly used diagnostic primers, and (3) the emergence of a dominant lineage harboring an S477N RBD mutation in Australia in 2020. To accelerate COVID-19 efforts, COVID-19 CG will be upgraded with new features for users to rapidly pinpoint mutations as the virus evolves throughout the pandemic and in response to therapeutic and public health interventions.

    in eLife on February 23, 2021 12:00 AM.

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    Dissecting phenotypic transitions in metastatic disease via photoconversion-based isolation

    Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. We developed PIC-IT, a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size – including single-metastatic cells – which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising microcolonies revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for an inflammatory-response phenotype associated with NF-κB/AP-1 signaling. Pharmacological inhibition of NF-κB depleted microcolonies but had no effect on macrometastases, suggesting microcolonies are particularly dependent on this pathway. PIC-IT thus enables systematic investigation of metastatic heterogeneity. Moreover, the technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible.

    in eLife on February 23, 2021 12:00 AM.

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    Molecular basis for functional connectivity between the voltage sensor and the selectivity filter gate in Shaker K+ channels

    In Shaker K+ channels, the S4-S5 linker couples the voltage sensor (VSD) and pore domain (PD). Another coupling mechanism is revealed using two W434F-containing channels: L361R:W434F and L366H:W434F. In L361R:W434F, W434F affects the L361R VSD seen as a shallower Q-V curve that crosses the G-V. In L366H:W434F, L366H relieves the W434F effect converting a non-conductive channel in a conductive one. We report a chain of residues connecting the VSD (S4) to the selectivity filter (SF) in the PD of an adjacent subunit as the molecular basis for voltage-sensor selectivity filter gate (VS-SF) coupling. Single alanine substitutions in this region (L409A, S411A, S412A or F433A) are enough to disrupt the VS-SF coupling, shown by the absence of Q-V and G-V crossing in L361R:W434F mutant and by the lack of ionic conduction in the L366H:W434F mutant. This residue chain defines a new coupling between the VSD and the PD in voltage-gated channels.

    in eLife on February 23, 2021 12:00 AM.

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    Three-dimensional reconstruction of a whole insect reveals its phloem sap-sucking mechanism at nano-resolution

    Using serial block face scanning electron microscopy (SBF-SEM), we report on the internal 3D structures of the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) at nanometer resolution for the first time. Within the reconstructed organs and tissues, we found many novel and fascinating internal structures in the planthopper such as naturally occurring three four-way rings connecting adjacent spiracles to facilitate efficient gas exchange, and fungal endosymbionts in a single huge insect cell occupying 22% of the abdomen volume to enable the insect to live on plant sap. To understand the muscle and stylet movement during phloem sap-sucking, the cephalic skeleton and muscles were reconstructed in feeding nymphs. The results revealed an unexpected contraction of the protractors of the stylets, and suggested a novel feeding model for the phloem sap-sucking.

    in eLife on February 23, 2021 12:00 AM.

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    Physically asymmetric division of the C. elegans zygote ensures invariably successful embryogenesis

    Asymmetric divisions that yield daughter cells of different sizes are frequent during early embryogenesis, but the importance of such a physical difference for successful development remains poorly understood. Here, we investigated this question using the first division of C. elegans embryos, which yields a large AB cell and a small P1 cell. We equalized AB and P1 sizes using acute genetic inactivation or optogenetic manipulation of the spindle positioning protein LIN-5. We uncovered that only some embryos tolerated equalization, and that there was a size asymmetry threshold for viability. Cell lineage analysis of equalized embryos revealed an array of defects, including faster cell cycle progression in P1 descendants, as well as defects in cell positioning, division orientation and cell fate. Moreover, equalized embryos were more susceptible to external compression. Overall, we conclude that unequal first cleavage is essential for invariably successful embryonic development of C. elegans.

    in eLife on February 23, 2021 12:00 AM.

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    A single-chain and fast-responding light-inducible Cre recombinase as a novel optogenetic switch

    Optogenetics enables genome manipulations with high spatiotemporal resolution, opening exciting possibilities for fundamental and applied biological research. Here, we report the development of LiCre, a novel light-inducible Cre recombinase. LiCre is made of a single flavin-containing protein comprising the AsLOV2 photoreceptor domain of Avena sativa fused to a Cre variant carrying destabilizing mutations in its N-terminal and C-terminal domains. LiCre can be activated within minutes of illumination with blue light, without the need of additional chemicals. When compared to existing photoactivatable Cre recombinases based on two split units, LiCre displayed faster and stronger activation by light as well as a lower residual activity in the dark. LiCre was efficient both in yeast, where it allowed us to control the production of β-carotene with light, and in human cells. Given its simplicity and performances, LiCre is particularly suited for fundamental and biomedical research, as well as for controlling industrial bioprocesses.

    in eLife on February 23, 2021 12:00 AM.

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    Neural basis underlying the trait of attachment anxiety and avoidance revealed by the amplitude of low-frequency fluctuations and resting-state functional connectivity

    Attachment theory demonstrates that early attachment experience shapes internal working models with mental representations of self and close relationships, which affects personality traits and interpersonal re...

    in BMC Neuroscience on February 23, 2021 12:00 AM.

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    Cellular, physiological, and behavioral validation of a CRFR1:Cre-tdTomato transgenic rat for use in basic neuroscience research

    Corticotropin-releasing factor type-1 receptors (CRFR1) are important for mediating the endocrine stress response, modulating synaptic transmission in the central nervous system, and are involved in mediating behaviors that include stress reactivity, anxiety, fear, pain, motivation, and addiction. Understanding the precise role of specific CRFR1 neuronal populations and circuits/networks in CRFR1-relevant behavior is limited by a lack of genetic access to CRFR1-expressing cells in rats. Here, we describe the generation and validation of a transgenic CRFR1:Cre-tdTomato rat line on a Wistar background. Within the central amygdala (CeA) of male and female CRFR1:Cre-tdTomato rats, we show that Crfr1 and Cre mRNA expression are highly colocalized and that CRFR1:Cre-tdTomato cells are largely confined to the medial subdivision of the CeA, consistent with CRF expression patterns in outbred animals. Using tdTomato fluorescent protein as a reporter, we measured membrane properties, inhibitory synaptic transmission, and CRF sensitivity in CeA CRFR1-expressing cells and found that these properties were similar to those previously reported in CRFR1:Cre mice, and that CeA CRFR1 neurons were excited by exogenous CRF application. We also show that stimulatory Gq-coupled DREADD receptors can be targeted to CeA CRFR1 cells via Cre-dependent expression and that these cells can be activated by clozapine-n-oxide (CNO) in vitro and in vivo. Finally, we report that DREADD-mediated activation of CeA CRFR1 cells increases anxiety-like behavior and increases nocifensive responses. Our results demonstrate the utility of this novel CRFR1:Cre-tdTomato transgenic rat line for studying the anatomy, physiology, and behavioral function of select CRFR1-expressing cell populations and circuits under normal conditions and in rat models of human disease.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pRab10

    Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinsons disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying disease-linked variant in LRRK2 (G2019S). Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    A tale of two gradients: Differences between the left and right hemispheres predict semantic cognition and visual reasoning

    Decomposition of whole-brain functional connectivity patterns reveals a principal gradient that captures the separation of sensorimotor cortex from heteromodal regions in the default mode network (DMN); this gradient captures the systematic order of networks on the cortical surface. Functional homotopy is strongest in sensorimotor areas, and weakest in heteromodal cortices, suggesting there may be differences between the left and right hemispheres (LH/RH) in the principal gradient, especially towards its apex. This study characterised hemispheric differences in the position of large-scale cortical networks along the principal gradient, and their functional significance. We collected resting-state fMRI and semantic and non-verbal reasoning task performance in 175+ healthy volunteers. We then extracted the principal gradient of connectivity for each participant and tested which networks showed significant hemispheric differences in gradient value. We investigated the functional associations of these differences by regressing participants' behavioural efficiency in tasks outside the scanner against their interhemispheric gradient difference for each network. LH showed a higher overall principal gradient value, consistent with its role in heteromodal semantic cognition. One frontotemporal control subnetwork was linked to individual differences in semantic cognition: when it was nearer heteromodal DMN on the principal gradient in LH, participants showed more efficient semantic retrieval. In contrast, when a dorsal attention subnetwork was closer to the heteromodal end of the principal gradient in RH, participants showed better visual reasoning. Lateralization of function may reflect differences in connectivity between control and heteromodal regions in LH, and attention and visual regions in RH.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    The Mesodiencephalic Junction as a Central Hub for Cerebro-Cerebellar Communication

    Most studies investigating the impact of cerebral cortex (CC) onto the cerebellum highlight the role of the pontine mossy fibre system. However, cerebro-cerebellar communication may also be mediated by the olivary climbing fibres via a hub in the mesodiencephalic junction (MDJ). Here, we show that rostromedial and caudal parts of mouse CC predominantly project to the principal olive via the rostroventral MDJ and that more rostrolateral CC regions prominently project to the rostral medial accessory olive via the caudodorsal MDJ. Moreover, transneuronal tracing results show that the cerebellar nuclei innervate the olivary-projecting neurons in the MDJ that receive input from CC, and that they adhere to the same topographical relations. By unravelling these topographic and dense, mono- and disynaptic projections from the CC through the MDJ and inferior olive to the cerebellum, this work establishes that cerebro-cerebellar communication can be mediated by both the mossy fibre and climbing fibre system.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques

    SARS-CoV-2 may cause acute respiratory disease, but the infection can also initiate neurological symptoms. Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus' capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans Lewy body formation is an indication for the development of Parkinson's disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    Resting-state theta oscillations and reward sensitivity in risk taking

    Females demonstrate greater risk aversion than males on a variety of tasks, but the underlying neurobiological basis is still unclear. We studied how theta (4-7 Hz) oscillations at rest related to three different measures of risk taking. Thirty-five participants (15 females) completed the Bomb Risk Elicitation Task (BRET), which allowed us to measure risk taking during an economic game. The Domain-Specific Risk-Taking Scale (DOSPERT) was used to measure self-assessed risk attitudes as well as reward and punishment sensitivities. In addition, the Barratt Impulsiveness Scale (BIS11) was included to quantify impulsiveness. To obtain measures of frontal theta asymmetry and frontal theta power, we used magnetoencephalography (MEG) acquired prior to task completion, while participants were at rest. Frontal theta asymmetry correlated with average risk taking during the game but only in the female sample. By contrast, frontal theta power correlated with risk taking as well as with measures of reward and punishment sensitivity in the joint sample. Importantly, we showed that reward sensitivity mediated a correlation between risk taking and the power of theta oscillations localized to the anterior cingulate cortex. In addition, we observed significant sex differences in source- and sensor-space theta power, risk taking during the game, and reward sensitivity. Our findings suggest that sensitivity to rewards, associated with resting-state theta oscillations in the anterior cingulate cortex, is a trait that potentially contributes to sex differences in risk taking.

    in bioRxiv: Neuroscience on February 23, 2021 12:00 AM.

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    Correction to Supporting Information for Senior et al., Global associations between macronutrient supply and age-specific mortality [SI Correction]

    POPULATION BIOLOGY Correction to Supporting Information for “Global associations between macronutrient supply and age-specific mortality,” by Alistair M. Senior, Shinichi Nakagawa, David Raubenheimer, and Stephen J. Simpson, which first published November 16, 2020; 10.1073/pnas.2015058117 (Proc. Natl. Acad. Sci. U.S.A. 117, 30824–30835). The authors note that Fig. S2 in the SI...

    in PNAS on February 22, 2021 08:04 PM.

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    Correction for Alam et al., Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha [Corrections]

    PHARMACOLOGY Correction for “Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha,” by Camille Alam, Susanne Aufreiter, Constantine J. Georgiou, Md. Tozammel Hoque, Richard H. Finnell, Deborah L. O’Connor, I. David Goldman, and Reina Bendayan, which first published August 12, 2019;...

    in PNAS on February 22, 2021 08:04 PM.

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    Correction to Supporting Information for Chibaya et al., Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis [SI Correction]

    CELL BIOLOGY Correction to Supporting Information for “Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis,” by Loretah Chibaya, Baktiar Karim, Hong Zhang, and Stephen N. Jones, which first published January 19, 2021; 10.1073/pnas.2003193118 (Proc. Natl. Acad. Sci. U.S.A. 118, e2003193118). The...

    in PNAS on February 22, 2021 08:04 PM.

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    Computational reproductions of external force field adaption without assuming desired trajectories

    Publication date: Available online 21 February 2021

    Source: Neural Networks

    Author(s): Hiroyuki Kambara, Atsushi Takagi, Haruka Shimizu, Toshihiro Kawase, Natsue Yoshimura, Nicolas Schweighofer, Yasuharu Koike

    in Neural Networks on February 22, 2021 02:00 PM.

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    Computational modeling of the gut microbiota reveals putative metabolic mechanisms of recurrent <i>Clostridioides difficile</i> infection

    by Michael A. Henson

    Approximately 30% of patients who have Clostridioides difficile infection (CDI) will suffer at least one incident of reinfection. While the underlying causes of CDI recurrence are poorly understood, interactions between C. difficile and commensal gut bacteria are thought to play an important role. In this study, an in silico pipeline was used to process 16S rRNA gene amplicon sequence data of 225 stool samples from 93 CDI patients into sample-specific models of bacterial community metabolism. Clustered metabolite production rates generated from post-diagnosis samples generated a high Enterobacteriaceae abundance cluster containing disproportionately large numbers of recurrent samples and patients. This cluster was predicted to have significantly reduced capabilities for secondary bile acid synthesis but elevated capabilities for aromatic amino acid catabolism. When applied to 16S sequence data of 40 samples from fecal microbiota transplantation (FMT) patients suffering from recurrent CDI and their stool donors, the community modeling method generated a high Enterobacteriaceae abundance cluster with a disproportionate large number of pre-FMT samples. This cluster also was predicted to exhibit reduced secondary bile acid synthesis and elevated aromatic amino acid catabolism. Collectively, these in silico predictions suggest that Enterobacteriaceae may create a gut environment favorable for C. difficile spore germination and/or toxin synthesis.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Calcium-vesicles perform active diffusion in the sea urchin embryo during larval biomineralization

    by Mark R. Winter, Miri Morgulis, Tsvia Gildor, Andrew R. Cohen, Smadar Ben-Tabou de-Leon

    Biomineralization is the process by which organisms use minerals to harden their tissues and provide them with physical support. Biomineralizing cells concentrate the mineral in vesicles that they secret into a dedicated compartment where crystallization occurs. The dynamics of vesicle motion and the molecular mechanisms that control it, are not well understood. Sea urchin larval skeletogenesis provides an excellent platform for investigating the kinetics of mineral-bearing vesicles. Here we used lattice light-sheet microscopy to study the three-dimensional (3D) dynamics of calcium-bearing vesicles in the cells of normal sea urchin embryos and of embryos where skeletogenesis is blocked through the inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR). We developed computational tools for displaying 3D-volumetric movies and for automatically quantifying vesicle dynamics. Our findings imply that calcium vesicles perform an active diffusion motion in both, calcifying (skeletogenic) and non-calcifying (ectodermal) cells of the embryo. The diffusion coefficient and vesicle speed are larger in the mesenchymal skeletogenic cells compared to the epithelial ectodermal cells. These differences are possibly due to the distinct mechanical properties of the two tissues, demonstrated by the enhanced f-actin accumulation and myosinII activity in the ectodermal cells compared to the skeletogenic cells. Vesicle motion is not directed toward the biomineralization compartment, but the vesicles slow down when they approach it, and probably bind for mineral deposition. VEGFR inhibition leads to an increase of vesicle volume but hardly changes vesicle kinetics and doesn’t affect f-actin accumulation and myosinII activity. Thus, calcium vesicles perform an active diffusion motion in the cell of the sea urchin embryo, with diffusion length and speed that inversely correlate with the strength of the actomyosin network. Overall, our studies provide an unprecedented view of calcium vesicle 3D-dynamics and point toward cytoskeleton remodeling as an important effector of the motion of mineral-bearing vesicles.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Nonlinear effects of intrinsic dynamics on temporal encoding in a model of avian auditory cortex

    by Christof Fehrman, Tyler D. Robbins, C. Daniel Meliza

    Neurons exhibit diverse intrinsic dynamics, which govern how they integrate synaptic inputs to produce spikes. Intrinsic dynamics are often plastic during development and learning, but the effects of these changes on stimulus encoding properties are not well known. To examine this relationship, we simulated auditory responses to zebra finch song using a linear-dynamical cascade model, which combines a linear spectrotemporal receptive field with a dynamical, conductance-based neuron model, then used generalized linear models to estimate encoding properties from the resulting spike trains. We focused on the effects of a low-threshold potassium current (KLT) that is present in a subset of cells in the zebra finch caudal mesopallium and is affected by early auditory experience. We found that KLT affects both spike adaptation and the temporal filtering properties of the receptive field. The direction of the effects depended on the temporal modulation tuning of the linear (input) stage of the cascade model, indicating a strongly nonlinear relationship. These results suggest that small changes in intrinsic dynamics in tandem with differences in synaptic connectivity can have dramatic effects on the tuning of auditory neurons.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Rapid 3D phenotypic analysis of neurons and organoids using data-driven cell segmentation-free machine learning

    by Philipp Mergenthaler, Santosh Hariharan, James M. Pemberton, Corey Lourenco, Linda Z. Penn, David W. Andrews

    Phenotypic profiling of large three-dimensional microscopy data sets has not been widely adopted due to the challenges posed by cell segmentation and feature selection. The computational demands of automated processing further limit analysis of hard-to-segment images such as of neurons and organoids. Here we describe a comprehensive shallow-learning framework for automated quantitative phenotyping of three-dimensional (3D) image data; using unsupervised data-driven voxel-based feature learning, which enables computationally facile classification, clustering and advanced data visualization. We demonstrate the analysis potential on complex 3D images by investigating the phenotypic alterations of: neurons in response to apoptosis-inducing treatments and morphogenesis for oncogene-expressing human mammary gland acinar organoids. Our novel implementation of image analysis algorithms called Phindr3D allowed rapid implementation of data-driven voxel-based feature learning into 3D high content analysis (HCA) operations and constitutes a major practical advance as the computed assignments represent the biology while preserving the heterogeneity of the underlying data. Phindr3D is provided as Matlab code and as a stand-alone program (https://github.com/DWALab/Phindr3D).

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    A mathematical model of the role of aggregation in sonic hedgehog signalling

    by Daniel J. A. Derrick, Kathryn Wolton, Richard A. Currie, Marcus John Tindall

    Effective regulation of the sonic hedgehog (Shh) signalling pathway is essential for normal development in a wide variety of species. Correct Shh signalling requires the formation of Shh aggregates on the surface of producing cells. Shh aggregates subsequently diffuse away and are recognised in receiving cells located elsewhere in the developing embryo. Various mechanisms have been postulated regarding how these aggregates form and what their precise role is in the overall signalling process. To understand the role of these mechanisms in the overall signalling process, we formulate and analyse a mathematical model of Shh aggregation using nonlinear ordinary differential equations. We consider Shh aggregate formation to comprise of multimerisation, association with heparan sulfate proteoglycans (HSPG) and binding with lipoproteins. We show that the size distribution of the Shh aggregates formed on the producing cell surface resembles an exponential distribution, a result in agreement with experimental data. A detailed sensitivity analysis of our model reveals that this exponential distribution is robust to parameter changes, and subsequently, also to variations in the processes by which Shh is recruited by HSPGs and lipoproteins. The work demonstrates the time taken for different sized Shh aggregates to form and the important role this likely plays in Shh diffusion.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Spectrally specific temporal analyses of spike-train responses to complex sounds: A unifying framework

    by Satyabrata Parida, Hari Bharadwaj, Michael G. Heinz

    Significant scientific and translational questions remain in auditory neuroscience surrounding the neural correlates of perception. Relating perceptual and neural data collected from humans can be useful; however, human-based neural data are typically limited to evoked far-field responses, which lack anatomical and physiological specificity. Laboratory-controlled preclinical animal models offer the advantage of comparing single-unit and evoked responses from the same animals. This ability provides opportunities to develop invaluable insight into proper interpretations of evoked responses, which benefits both basic-science studies of neural mechanisms and translational applications, e.g., diagnostic development. However, these comparisons have been limited by a disconnect between the types of spectrotemporal analyses used with single-unit spike trains and evoked responses, which results because these response types are fundamentally different (point-process versus continuous-valued signals) even though the responses themselves are related. Here, we describe a unifying framework to study temporal coding of complex sounds that allows spike-train and evoked-response data to be analyzed and compared using the same advanced signal-processing techniques. The framework uses a set of peristimulus-time histograms computed from single-unit spike trains in response to polarity-alternating stimuli to allow advanced spectral analyses of both slow (envelope) and rapid (temporal fine structure) response components. Demonstrated benefits include: (1) novel spectrally specific temporal-coding measures that are less confounded by distortions due to hair-cell transduction, synaptic rectification, and neural stochasticity compared to previous metrics, e.g., the correlogram peak-height, (2) spectrally specific analyses of spike-train modulation coding (magnitude and phase), which can be directly compared to modern perceptually based models of speech intelligibility (e.g., that depend on modulation filter banks), and (3) superior spectral resolution in analyzing the neural representation of nonstationary sounds, such as speech and music. This unifying framework significantly expands the potential of preclinical animal models to advance our understanding of the physiological correlates of perceptual deficits in real-world listening following sensorineural hearing loss.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Quantitative profiling of protease specificity

    by Boris I. Ratnikov, Piotr Cieplak, Albert G. Remacle, Elise Nguyen, Jeffrey W. Smith

    Proteases are an important class of enzymes, whose activity is central to many physiologic and pathologic processes. Detailed knowledge of protease specificity is key to understanding their function. Although many methods have been developed to profile specificities of proteases, few have the diversity and quantitative grasp necessary to fully define specificity of a protease, both in terms of substrate numbers and their catalytic efficiencies. We have developed a concept of “selectome”; the set of substrate amino acid sequences that uniquely represent the specificity of a protease. We applied it to two closely related members of the Matrixin family–MMP-2 and MMP-9 by using substrate phage display coupled with Next Generation Sequencing and information theory-based data analysis. We have also derived a quantitative measure of substrate specificity, which accounts for both the number of substrates and their relative catalytic efficiencies. Using these advances greatly facilitates elucidation of substrate selectivity between closely related members of a protease family. The study also provides insight into the degree to which the catalytic cleft defines substrate recognition, thus providing basis for overcoming two of the major challenges in the field of proteolysis: 1) development of highly selective activity probes for studying proteases with overlapping specificities, and 2) distinguishing targeted proteolysis from bystander proteolytic events.

    in PLoS Computational Biology on February 22, 2021 02:00 PM.

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    Age‐Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin

    Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine‐adenine‐guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far‐reaching implications for future gene‐therapy treatment strategies. ANN NEUROL 2021

    in Annals of Neurology on February 22, 2021 12:29 PM.

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    Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease

    Objectives Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis. Methods We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations. Results After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1‐SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07–1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C‐reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1‐SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01–1.18, p = 0.02). Interpretation We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021

    in Annals of Neurology on February 22, 2021 12:24 PM.

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    Impact of Global Health Electives on Neurology Trainees

    We surveyed neurologists who completed a global health experience as residents or fellows to assess the impact of the experience. A total of 100% (n = 72) would recommend the experience to others. Most reported improved clinical (86%) and examination (82%) skills. All gained an understanding of different health care systems, and 83% reported deeper commitment to underserved populations. A total of 41 participants (57%) reported more judicious use of resources upon return to the United States. Global health electives had a positive impact on neurology trainees. More attention to the host country perspective and predeparture training may help inform program structure and participant expectations in the future. ANN NEUROL 2021

    in Annals of Neurology on February 22, 2021 11:28 AM.

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    Physical principles of morphogenesis in mushrooms

    Author(s): X. Chen, P. Ciarletta, and H.-H. Dai

    Mushroom species display distinctive morphogenetic features. For example, Amanita muscaria and Mycena chlorophos grow in a similar manner, their caps expanding outward quickly and then turning upward. However, only the latter finally develops a central depression in the cap. Here we use a mathematic...


    [Phys. Rev. E 103, 022412] Published Mon Feb 22, 2021

    in Physical Review E: Biological physics on February 22, 2021 10:00 AM.

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    Morphoelasticity of large bending deformations of cell sheets during development

    Author(s): Pierre A. Haas and Raymond E. Goldstein

    During development, plant and animal tissues undergo large bending deformations that are outside the validity of frequently used thin-shell theories. This work uses asymptotic expansion of a three-dimensional system to develop a theory of incompressible shells that is valid for large bending transformations and improves on the classical thin-shell theories. The theory is applied to the green alga Volvox, which has a spherical embryonic cell sheet that turns itself inside out during development.


    [Phys. Rev. E 103, 022411] Published Mon Feb 22, 2021

    in Physical Review E: Biological physics on February 22, 2021 10:00 AM.

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    Long-term maturation of human cortical organoids matches key early postnatal transitions

    Nature Neuroscience, Published online: 22 February 2021; doi:10.1038/s41593-021-00802-y

    Gordon et al. use genome-wide unbiased approaches to show that human cerebral cortical organoids, when cultured for many months, start to resemble stages of postnatal brain development, with a timeline that parallels in vivo development.

    in Nature Neuroscience on February 22, 2021 12:00 AM.

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    Independent generation of sequence elements by motor cortex

    Nature Neuroscience, Published online: 22 February 2021; doi:10.1038/s41593-021-00798-5

    Examination of neural activity reveals that performing a rapid sequence of actions depends not upon fusing those actions into a holistic unit, but upon the ability of motor cortex to swiftly prepare the next action while the present unfolds.

    in Nature Neuroscience on February 22, 2021 12:00 AM.

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    Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex

    Nature Neuroscience, Published online: 22 February 2021; doi:10.1038/s41593-021-00797-6

    Spikes of deep-layer ID2+Nkx2.1+ cortical neurons are anticorrelated with spiking of all principal cells and interneurons, prominently during down states of sleep, and shape the sequential firing of neurons at down–up transitions.

    in Nature Neuroscience on February 22, 2021 12:00 AM.

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    Genome-scale deconvolution of RNA structure ensembles

    Nature Methods, Published online: 22 February 2021; doi:10.1038/s41592-021-01075-w

    The DRACO algorithm deconvolutes coexisting RNA structures from mutational profiling experiments, and can be applied to bacterial regulatory structures and elements from the SARS-CoV-2 genome.

    in Nature Methods on February 22, 2021 12:00 AM.

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    Stressed out decision making

    Nature Reviews Neuroscience, Published online: 22 February 2021; doi:10.1038/s41583-021-00442-y

    Stressful experience increases erroneous choices in a reward-based learning task by weakening excitatory synapses in the lateral habenula via a reduction in AMPA-receptor-mediated synaptic transmission.

    in Nature Reviews on February 22, 2021 12:00 AM.

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    Author Correction: Simulating the ghost: quantum dynamics of the solvated electron

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21706-2

    Author Correction: Simulating the ghost: quantum dynamics of the solvated electron

    in Nature Communications on February 22, 2021 12:00 AM.

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    Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21471-2

    Learning-activated engram neurons play a critical role in memory recall but the role of these neurons in offline memory consolidation is unclear. The authors show that sleep-associated reactivation of learning-activated sensory neurons is necessary for memory consolidation.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Land, lava, and disaster create a social dilemma after the 2018 eruption of Kīlauea volcano

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21455-2

    The unprecedented cost of the 2018 eruption in Hawai’i reflects an intersection of disparate physical and social phenomena: widely spaced, highly destructive eruptions, and atypically high population growth. These were linked and the former indirectly drove the latter with unavoidable consequences.

    in Nature Communications on February 22, 2021 12:00 AM.

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    RING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21443-6

    The mechanism by which RING E3-anchored ubiquitin chains are formed is not well understood. Here, the authors solve a crystal structure of the RING E3 enzyme TRIM21 trapped in the process of self-anchored chain elongation and provide biochemical and cellular insights into the mechanism of ubiquitin conjugation.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Reconfigurable all-dielectric metalens with diffraction-limited performance

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21440-9

    Here, the authors report an active all-dielectric metasurface platform based on phase change materials, combining phase tuning in the full 2π range, and demonstrate aberration-free and multi-depth imaging with a non-mechanical tunable metalens.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21410-1

    Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Coupled nitrification and N2 gas production as a cryptic process in oxic riverbeds

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21400-3

    The N cycle involves complex, microbially-mediated shuttling between ammonium, nitrite and nitrate, with climatically important greenhouse gas byproducts. Here the authors use isotope labeling experiments in river sediments and find a cryptic new step in the N cycle between nitrification and the removal of fixed N through N2 gas production.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Uniform genomic data analysis in the NCI Genomic Data Commons

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21254-9

    The Genomic Data Commons repository contains genomic, epigenomic, proteomic and clinical data from the TCGA and TARGET datasets. Here, the authors describe the analysis methods for how these divergent datasets were integrated together.

    in Nature Communications on February 22, 2021 12:00 AM.

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    Reply to ‘Oxic methanogenesis is only a minor source of lake-wide diffusive CH4 emissions from lakes’

    Nature Communications, Published online: 22 February 2021; doi:10.1038/s41467-021-21216-1

    Reply to ‘Oxic methanogenesis is only a minor source of lake-wide diffusive CH4 emissions from lakes’

    in Nature Communications on February 22, 2021 12:00 AM.

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    Assessing Uncertainty and Reliability of Connective Field Estimations From Resting State fMRI Activity at 3T

    Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modeling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data. This is important since 3T scanners are much more abundant and more often used in clinical research compared to 7T scanners. Therefore in this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans, which were separated by the acquisition of visual field mapping data in 12 healthy participants. Our results show good agreement between RS- and visual field (VF)- based maps using either the standard or Bayesian CF approach. In addition to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter, beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. Moreover, observations obtained using 3T scanners were qualitatively similar to those reported for 7T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 22, 2021 12:00 AM.

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    Using EEG Alpha States to Understand Learning During Alpha Neurofeedback Training for Chronic Pain

    Objective

    Alpha-neurofeedback (α-NFB) is a novel therapy which trains individuals to volitionally increase their alpha power to improve pain. Learning during NFB is commonly measured using static parameters such as mean alpha power. Considering the biphasic nature of alpha rhythm (high and low alpha), dynamic parameters describing the time spent by individuals in high alpha state and the pattern of transitioning between states might be more useful. Here, we quantify the changes during α-NFB for chronic pain in terms of dynamic changes in alpha states.

    Methods

    Four chronic pain and four healthy participants received five NFB sessions designed to increase frontal alpha power. Changes in pain resilience were measured using visual analogue scale (VAS) during repeated cold-pressor tests (CPT). Changes in alpha state static and dynamic parameters such as fractional occupancy (time in high alpha state), dwell time (length of high alpha state) and transition probability (probability of moving from low to high alpha state) were analyzed using Friedman’s Test and correlated with changes in pain scores using Pearson’s correlation.

    Results

    There was no significant change in mean frontal alpha power during NFB. There was a trend of an increase in fractional occupancy, mean dwell duration and transition probability of high alpha state over the five sessions in chronic pain patients only. Significant correlations were observed between change in pain scores and fractional occupancy (r = −0.45, p = 0.03), mean dwell time (r = -0.48, p = 0.04) and transition probability from a low to high state (r = -0.47, p = 0.03) in chronic pain patients but not in healthy participants.

    Conclusion

    There is a differential effect between patients and healthy participants in terms of correlation between change in pain scores and alpha state parameters. Parameters providing a more precise description of the alpha power dynamics than the mean may help understand the therapeutic effect of neurofeedback on chronic pain.

    in Frontiers in Neuroscience: Neural Technology on February 22, 2021 12:00 AM.

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    Optimal Model Mapping for Intravoxel Incoherent Motion MRI

    In general, only one diffusion model would be applied to whole field-of-view voxels in the intravoxel incoherent motion-magnetic resonance imaging (IVIM-MRI) study. However, the choice of the applied diffusion model can significantly influence the estimated diffusion parameters. The quality of the diffusion analysis can influence the reliability of the perfusion analysis. This study proposed an optimal model mapping method to improve the reliability of the perfusion parameter estimation in the IVIM study. Six healthy volunteers (five males and one female; average age of 38.3 ± 7.5 years). Volunteers were examined using a 3.0 Tesla scanner. IVIM-MRI of the brain was applied at 17 b-values ranging from 0 to 2,500 s/mm2. The Gaussian model, the Kurtosis model, and the Gamma model were found to be optimal for the CSF, white matter (WM), and gray matter (GM), respectively. In the mean perfusion fraction (fp) analysis, the GM/WM ratios were 1.16 (Gaussian model), 1.80 (Kurtosis model), 1.94 (Gamma model), and 1.54 (Optimal model mapping); in the mean pseudo diffusion coefficient (D*) analysis, the GM/WM ratios were 1.18 (Gaussian model), 1.19 (Kurtosis model), 1.56 (Gamma model), and 1.24 (Optimal model mapping). With the optimal model mapping method, the estimated fp and D* were reliable compared with the conventional methods. In addition, the optimal model maps, the associated products of this method, may provide additional information for clinical diagnosis.

    in Frontiers in Human Neuroscience on February 22, 2021 12:00 AM.

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    The Association Between Metabolic Disturbance and Cognitive Impairments in Early-Stage Schizophrenia

    Background: Cognitive impairment is one of the core symptoms of schizophrenia, which is considered to be significantly correlated to prognosis. In recent years, many studies have suggested that metabolic disorders could be related to a higher risk of cognitive defects in a general setting. However, there has been limited evidence on the association between metabolism and cognitive function in patients with early-stage schizophrenia.

    Methods: In this study, we recruited 172 patients with early-stage schizophrenia. Relevant metabolic parameters were examined and cognitive function was evaluated by using the MATRICS Consensus Cognitive Battery (MCCB) to investigate the relationship between metabolic disorder and cognitive impairment.

    Results: Generally, the prevalence of cognitive impairment among patients in our study was 84.7% (144/170), which was much higher than that in the general population. Compared with the general Chinese setting, the study population presented a higher proportion of metabolic disturbance. Patients who had metabolic disturbance showed no significant differences on cognitive function compared with the other patients. Correlation analysis showed that metabolic status was significantly correlated with cognitive function as assessed by the cognitive domain scores (p < 0.05), while such association was not found in further multiple regression analysis.

    Conclusions: Therefore, there may be no association between metabolic disorder and cognitive impairment in patients with early-stage schizophrenia.

    Trial Registration: Clinicaltrials.gov, NCT03451734. Registered March 2, 2018 (retrospectively registered).

    in Frontiers in Human Neuroscience on February 22, 2021 12:00 AM.

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    Semantic Relatedness Emerges in Deep Convolutional Neural Networks Designed for Object Recognition

    Human not only can effortlessly recognize objects, but also characterize object categories into semantic concepts with a nested hierarchical structure. One dominant view is that top-down conceptual guidance is necessary to form such hierarchy. Here we challenged this idea by examining whether deep convolutional neural networks (DCNNs) could learn relations among objects purely based on bottom-up perceptual experience of objects through training for object categorization. Specifically, we explored representational similarity among objects in a typical DCNN (e.g., AlexNet), and found that representations of object categories were organized in a hierarchical fashion, suggesting that the relatedness among objects emerged automatically when learning to recognize them. Critically, the emerged relatedness of objects in the DCNN was highly similar to the WordNet in human, implying that top-down conceptual guidance may not be a prerequisite for human learning the relatedness among objects. In addition, the developmental trajectory of the relatedness among objects during training revealed that the hierarchical structure was constructed in a coarse-to-fine fashion, and evolved into maturity before the establishment of object recognition ability. Finally, the fineness of the relatedness was greatly shaped by the demand of tasks that the DCNN performed, as the higher superordinate level of object classification was, the coarser the hierarchical structure of the relatedness emerged. Taken together, our study provides the first empirical evidence that semantic relatedness of objects emerged as a by-product of object recognition in DCNNs, implying that human may acquire semantic knowledge on objects without explicit top-down conceptual guidance.

    in Frontiers in Computational Neuroscience on February 22, 2021 12:00 AM.

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    The Absence of the Transient Receptor Potential Vanilloid 1 Directly Impacts on the Expression and Localization of the Endocannabinoid System in the Mouse Hippocampus

    The transient receptor potential vanilloid 1 (TRPV1) is a non-selective ligand-gated cation channel involved in synaptic transmission, plasticity, and brain pathology. In the hippocampal dentate gyrus, TRPV1 localizes to dendritic spines and dendrites postsynaptic to excitatory synapses in the molecular layer (ML). At these same synapses, the cannabinoid CB1 receptor (CB1R) activated by exogenous and endogenous cannabinoids localizes to the presynaptic terminals. Hence, as both receptors are activated by endogenous anandamide, co-localize, and mediate long-term depression of the excitatory synaptic transmission at the medial perforant path (MPP) excitatory synapses though by different mechanisms, it is plausible that they might be exerting a reciprocal influence from their opposite synaptic sites. In this anatomical scenario, we tested whether the absence of TRPV1 affects the endocannabinoid system. The results obtained using biochemical techniques and immunoelectron microscopy in a mouse with the genetic deletion of TRPV1 show that the expression and localization of components of the endocannabinoid system, included CB1R, change upon the constitutive absence of TRPV1. Thus, the expression of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) drastically increased in TRPV1−/− whole homogenates. Furthermore, CB1R and MAGL decreased and the cannabinoid receptor interacting protein 1a (CRIP1a) increased in TRPV1−/− synaptosomes. Also, CB1R positive excitatory terminals increased, the number of excitatory terminals decreased, and CB1R particles dropped significantly in inhibitory terminals in the dentate ML of TRPV1−/− mice. In the outer 2/3 ML of the TRPV1−/− mutants, the proportion of CB1R particles decreased in dendrites, and increased in excitatory terminals and astrocytes. In the inner 1/3 ML, the proportion of labeling increased in excitatory terminals, neuronal mitochondria, and dendrites. Altogether, these observations indicate the existence of compensatory changes in the endocannabinoid system upon TRPV1 removal, and endorse the importance of the potential functional adaptations derived from the lack of TRPV1 in the mouse brain.

    in Frontiers in Neuroanatomy on February 22, 2021 12:00 AM.

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    The Neurocognitive Effects of Bacopa monnieri and Cognitive Training on Markers of Brain Microstructure in Healthy Older Adults

    Bacopa monnieri (BM) is a herbal supplement that increases signaling molecules implicated in synaptogenesis. Combined with cognitive stimulation, it may be a viable supplement to enhance long-term potentiation (LTP) and improve cognitive health in older adults. This randomized, double-blind, placebo-controlled trial asked 28 healthy adults aged over 55 years to complete cognitive training (CT) 3 hours weekly for 12 weeks. Fifteen consumed a standardized extract of BM and 13 consumed a placebo daily. Cognitive tasks, life-satisfaction, memory complaints and mood were assessed, and bloods analyzed for serum brain-derived neurotrophic factor (BDNF) before and after 12-weeks of the intervention. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in gray (GM) and white matter (WM) were also analyzed. Results demonstrated slower reaction time in an image discrimination task in the BM group and faster reaction time in a spatial working memory task (SWM-O RT) in the placebo group. Mean accuracy was higher in the BM group for these tasks, suggesting a change in the speed accuracy trade-off. Exploratory neuroimaging analysis showed increased WM mean diffusivity (MD) and GM dispersion of neurites (orientation dispersion index, ODI) and decreased WM fractional anisotropy (FA) and GM neurite density (ND) in the BM group. No other outcomes reached statistical significance. An increase in ODI with a decrease in MD and ND in the BM group may indicate an increase in network complexity (through higher dendritic branching) accompanied by dendritic pruning to enhance network efficiency. These neuroimaging outcomes conflict with the behavioral results, which showed poorer reaction time in the BM group. Given the exploratory outcomes and inconsistent findings between the behavioral and neuroimaging data, a larger study is needed to confirm the synaptogenic mechanisms of BM.

    in Frontiers in Ageing Neuroscience on February 22, 2021 12:00 AM.

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    Structural Network Efficiency Predicts Resilience to Cognitive Decline in Elderly at Risk for Alzheimer’s Disease

    Introduction: Functional imaging studies have demonstrated the recruitment of additional neural resources as a possible mechanism to compensate for age and Alzheimer’s disease (AD)-related cerebral pathology, the efficacy of which is potentially modulated by underlying structural network connectivity. Additionally, structural network efficiency (SNE) is associated with intelligence across the lifespan, which is a known factor for resilience to cognitive decline. We hypothesized that SNE may be a surrogate of the physiological basis of resilience to cognitive decline in elderly persons without dementia and with age- and AD-related cerebral pathology.Methods: We included 85 cognitively normal elderly subjects or mild cognitive impairment (MCI) patients submitted to baseline diffusion imaging, liquor specimens, amyloid-PET and longitudinal cognitive assessments. SNE was calculated from baseline MRI scans using fiber tractography and graph theory. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher SNE and the modulation of this association by increased cerebral amyloid, liquor tau or WMHV. Results: For the majority of cognitive outcome measures, higher SNE was associated with higher resilience to cognitive decline (p-values: 0.011–0.039). Additionally, subjects with higher SNE showed more resilience to cognitive decline at higher cerebral amyloid burden (p-values: <0.001–0.036) and lower tau levels (p-values: 0.002–0.015).Conclusion: These results suggest that SNE to some extent may quantify the physiological basis of resilience to cognitive decline most effective at the earliest stages of AD, namely at increased amyloid burden and before increased tauopathy.

    in Frontiers in Ageing Neuroscience on February 22, 2021 12:00 AM.

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    Resilience and Psychobiological Response to Stress in Older People: The Mediating Role of Coping Strategies

    Resilience, the ability to overcome adversity and face stressful demands and experiences, has been strongly associated with successful aging, a low risk of diseases and high mental and physical functioning. This relationship could be based on adaptive coping behaviors, but more research is needed to gain knowledge about the strategies employed to confront social stress. Thus, we aimed to investigate the role of the use of active or passive coping strategies by resilient people in dealing with stressful situations. For this purpose, we measured resilience, coping strategies, and perceived stress in 66 healthy older adults (31 men and 35 women) between 56 and 75 years old who were exposed to stress (Trier Social Stress Test, TSST) or a control situation. The stress response was analyzed at endocrine (cortisol) and psychological (anxiety) levels. In the stress condition, moderated mediation analysis showed a conditional indirect effect of resilience on cortisol reactivity through active coping. However, passive coping strategies did not mediate the resilience-cortisol relationship. In addition, neither active nor passive coping mediated the relationship between resilience and the anxiety response. These results suggest that resilience is associated with active coping strategies, which in turn could explain, at least in part, individual differences in the cortisol response to a psychosocial laboratory stressor. These factors may prevent the development of stress-related pathologies associated with aging and facilitate healthy and satisfactory aging.

    in Frontiers in Ageing Neuroscience on February 22, 2021 12:00 AM.

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    Altered Regional Cerebral Blood Flow and Brain Function Across the Alzheimer's Disease Spectrum: A Potential Biomarker

    Objective: To investigate variation in the characteristics of regional cerebral blood flow (rCBF), brain activity, and intrinsic functional connectivity (FC) across the Alzheimer's disease spectrum (ADS).

    Methods: The study recruited 20 individuals in each of the following categories: Alzheimer's disease (AD), mild cognitive impairment (MCI), subjective cognitive decline (SCD), and healthy control (HC). All participants completed the 3.0T resting-state functional MRI (rs-fMRI) and arterial spin labeling scans in addition to neuropsychological tests. Additionally, the normalized CBF, regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) of individual subjects were compared in the ADS. Moreover, the changes in intrinsic FC were investigated across the ADS using the abnormal rCBF regions as seeds and behavioral correlations. Finally, a support-vector classifier model of machine learning was used to distinguish individuals with ADS from HC.

    Results: Compared to the HC subjects, patients with AD showed the poorest level of rCBF in the left precuneus (LPCUN) and right middle frontal gyrus (RMFG) among all participants. In addition, there was a significant decrease in the ALFF in the bilateral posterior cingulate cortex (PCC) and ReHo in the right PCC. Moreover, RMFG- and LPCUN-based FC analysis revealed that the altered FCs were primarily located in the posterior brain regions. Finally, a combination of altered rCBF, ALFF, and ReHo in posterior cingulate cortex/precuneus (PCC/PCUN) showed a better ability to differentiate ADS from HC, AD from SCD and MCI, but not MCI from SCD.

    Conclusions: The study demonstrated the significance of an altered rCBF and brain activity in the early stages of ADS. These findings, therefore, present a potential diagnostic neuroimaging-based biomarker in ADS. Additionally, the study provides a better understanding of the pathophysiology of AD.

    in Frontiers in Ageing Neuroscience on February 22, 2021 12:00 AM.

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    Machine Learning Profiling of Alzheimer's Disease Patients Based on Current Cerebrospinal Fluid Markers and Iron Content in Biofluids

    Alzheimer's disease (AD) is the most common form of dementia, characterized by a complex etiology that makes therapeutic strategies still not effective. A true understanding of key pathological mechanisms and new biomarkers are needed, to identify alternative disease-modifying therapies counteracting the disease progression. Iron is an essential element for brain metabolism and its imbalance is implicated in neurodegeneration, due to its potential neurotoxic effect. However, the role of iron in different stages of dementia is not clearly established. This study aimed to investigate the potential impact of iron both in cerebrospinal fluid (CSF) and in serum to improve early diagnosis and the related therapeutic possibility. In addition to standard clinical method to detect iron in serum, a precise quantification of total iron in CSF was performed using graphite-furnace atomic absorption spectrometry in patients affected by AD, mild cognitive impairment, frontotemporal dementia, and non-demented neurological controls. The application of machine learning techniques, such as clustering analysis and multiclassification algorithms, showed a new potential stratification of patients exploiting iron-related data. The results support the involvement of iron dysregulation and its potential interaction with biomarkers (Tau protein and Amyloid-beta) in the pathophysiology and progression of dementia.

    in Frontiers in Ageing Neuroscience on February 22, 2021 12:00 AM.

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    DDK regulates replication initiation by controlling the multiplicity of Cdc45-GINS binding to Mcm2-7

    The committed step of eukaryotic DNA replication occurs when the pairs of Mcm2-7 replicative helicases that license each replication origin are activated. Helicase activation requires the recruitment of Cdc45 and GINS to Mcm2-7, forming Cdc45-Mcm2-7-GINS complexes (CMGs). Using single-molecule biochemical assays to monitor CMG formation, we found that Cdc45 and GINS are recruited to loaded Mcm2-7 in two stages. Initially, Cdc45, GINS, and likely additional proteins are recruited to unstructured Mcm2-7 N-terminal tails in a Dbf4-dependent kinase (DDK)-dependent manner, forming Cdc45-tail-GINS intermediates (CtGs). DDK phosphorylation of multiple phosphorylation sites on the Mcm2‑7 tails modulates the number of CtGs formed per Mcm2-7. In a second, inefficient event, a subset of CtGs transfer their Cdc45 and GINS components to form CMGs. Importantly, higher CtG multiplicity increases the frequency of CMG formation. Our findings reveal molecular mechanisms sensitizing helicase activation to DDK levels with implications for control of replication origin efficiency and timing.

    in eLife on February 22, 2021 12:00 AM.

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    March Mammal Madness and the power of narrative in science outreach

    March Mammal Madness is a science outreach project that, over the course of several weeks in March, reaches hundreds of thousands of people in the United States every year. We combine four approaches to science outreach – gamification, social media platforms, community event(s), and creative products – to run a simulated tournament in which 64 animals compete to become the tournament champion. While the encounters between the animals are hypothetical, the outcomes rely on empirical evidence from the scientific literature. Players select their favored combatants beforehand, and during the tournament scientists translate the academic literature into gripping “play-by-play” narration on social media. To date ~1100 scholarly works, covering almost 400 taxa, have been transformed into science stories. March Mammal Madness is most typically used by high-school educators teaching life sciences, and we estimate that our materials reached ~1% of high-school students in the United States in 2019. Here we document the intentional design, public engagement, and magnitude of reach of the project. We further explain how human psychological and cognitive adaptations for shared experiences, social learning, narrative, and imagery contribute to the widespread use of March Mammal Madness.

    in eLife on February 22, 2021 12:00 AM.

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    Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

    Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subjected to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial tricarboxylic acid (TCA) energetics, and redox balance are significantly reprogrammed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcriptomic analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate that sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.

    in eLife on February 22, 2021 12:00 AM.

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    Evolutionary shifts in taste coding in the fruit pest Drosophila suzukii

    Although most Drosophila species lay eggs in overripe fruit, the agricultural pest Drosophila suzukii lays eggs in ripe fruit. We found that changes in bitter taste perception have accompanied this adaptation. We show that bitter-sensing mutants of Drosophila melanogaster undergo a shift in egg laying preference toward ripe fruit. D. suzukii has lost 20% of the bitter-sensing sensilla from the labellum, the major taste organ of the head. Physiological responses to various bitter compounds are lost. Responses to strawberry purées are lost from two classes of taste sensilla. Egg laying is not deterred by bitter compounds that deter other species. Profiling of labellar transcriptomes reveals reduced expression of several bitter Gr genes (gustatory receptors). These findings support a model in which bitter compounds in early ripening stages deter egg laying in most Drosophila species, but a loss of bitter response contributes to the adaptation of D. suzukii to ripe fruit.

    in eLife on February 22, 2021 12:00 AM.

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    Dynamic interactions between the RNA chaperone Hfq, small regulatory RNAs and mRNAs in live bacterial cells

    RNA-binding proteins play myriad roles in regulating RNAs and RNA-mediated functions. In bacteria, the RNA chaperone Hfq is an important post-transcriptional gene regulator. Using live-cell super-resolution imaging, we can distinguish Hfq binding to different sizes of cellular RNAs. We demonstrate that under normal growth conditions, Hfq exhibits widespread mRNA-binding activity, with the distal face of Hfq contributing mostly to the mRNA binding in vivo. In addition, sRNAs can either co-occupy Hfq with the mRNA as a ternary complex, or displace the mRNA from Hfq in a binding face-dependent manner, suggesting mechanisms through which sRNAs rapidly access Hfq to induce sRNA-mediated gene regulation. Finally, our data suggest that binding of Hfq to certain mRNAs through its distal face can recruit RNase E to promote turnover of these mRNAs in an sRNA-independent manner, and such regulatory function of Hfq can be decoyed by sRNA competitors that bind strongly at the distal face.

    in eLife on February 22, 2021 12:00 AM.

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    Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

    Synapses of glutamatergic mossy fibers onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC's large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

    in eLife on February 22, 2021 12:00 AM.

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    Investigation of Drosophila fruitless neurons that express Dpr/DIP cell adhesion molecules

    Drosophila reproductive behaviors are directed by fruitless neurons. A reanalysis of genomic studies shows that genes encoding dpr and DIP Immunoglobulin superfamily (IgSF) members are expressed in fru P1 neurons. We find that each fru P1 and dpr/DIP (fru P1dpr/DIP) overlapping expression pattern is similar in both sexes, but there are dimorphisms in neuronal morphology and cell number. Behavioral studies of fru P1dpr/DIP perturbation genotypes indicates that the mushroom body functions together with the lateral protocerebral complex to direct courtship behavior. A single-cell RNA-seq analysis of fru P1 neurons shows that many DIPs have high expression in a small set of neurons, whereas the dprs are often expressed in a larger set of neurons at intermediate levels, with a myriad of dpr/DIP expression combinations. Functionally, we find that perturbations of sex hierarchy genes and of DIP-ε change the sex-specific morphologies of fru P1DIP-α neurons.

    in eLife on February 22, 2021 12:00 AM.

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    Accelerating with FlyBrainLab the discovery of the functional logic of the Drosophila brain in the connectomic era

    In recent years, a wealth of Drosophila neuroscience data have become available including cell type, connectome/synaptome datasets for both the larva and adult fly. To facilitate integration across data modalities and to accelerate the understanding of the functional logic of the fly brain, we have developed FlyBrainLab, a unique open-source computing platform that integrates 3D exploration and visualization of diverse datasets with interactive exploration of the functional logic of modeled executable brain circuits. FlyBrainLab's User Interface, Utilities Libraries and Circuit Libraries bring together neuroanatomical, neurogenetic and electrophysiological datasets with computational models of different researchers for validation and comparison within the same platform. Seeking to transcend the limitations of the connectome/synaptome, FlyBrainLab also provides libraries for molecular transduction arising in sensory coding in vision/olfaction. Together with sensory neuron activity data, these libraries serve as entry points for the exploration, analysis, comparison and evaluation of circuit functions of the fruit fly brain.

    in eLife on February 22, 2021 12:00 AM.

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    Identifying molecular features that are associated with biological function of intrinsically disordered protein regions

    In previous work, we showed that intrinsically disordered regions (IDRs) of proteins contain sequence-distributed molecular features that are conserved over evolution, despite little sequence similarity that can be detected in alignments (Zarin et al. 2019). Here, we aim to use these molecular features to predict specific biological functions for individual IDRs and identify the molecular features within them that are associated with these functions. We find that the predictable functions are diverse. Examining the associated molecular features, we note some that are consistent with previous reports, and identify others that were previously unknown. We experimentally confirm that elevated isoelectric point and hydrophobicity, features that are positively associated with mitochondrial localization, are necessary for mitochondrial targeting function. Remarkably, increasing isoelectric point in a synthetic IDR restores weak mitochondrial targeting. We believe feature analysis represents a new systematic approach to understand how biological functions of IDRs are specified by their protein sequences.

    in eLife on February 22, 2021 12:00 AM.

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    Functional reallocation of sensory processing resources caused by long-term neural adaptation to altered optics

    The eye's optics are a major determinant of visual perception. Elucidating how long-term exposure to optical defects affects visual processing is key for understanding the capacity for, and limits of, sensory plasticity. Here, we show evidence of functional reallocation of sensory processing resources following long-term exposure to poor optical quality. Using adaptive optics to bypass all optical defects, we assessed visual processing in neurotypically-developed adults with healthy eyes and with keratoconus—a corneal disease causing severe optical aberrations. Under fully-corrected optical conditions, keratoconus patients showed altered contrast sensitivity, with impaired sensitivity for fine spatial details and better-than-typical sensitivity for coarse details. Both gains and losses in sensitivity were more pronounced in patients experiencing poorer optical quality in their daily life, and mediated by changes in signal enhancement mechanisms. These findings show that adult neural processing adapts to better match the changes in sensory inputs caused by long-term exposure to altered optics.

    in eLife on February 22, 2021 12:00 AM.

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    Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy

    Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.

    in eLife on February 22, 2021 12:00 AM.

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    A generative adversarial network approach to (ensemble) weather prediction

    Publication date: Available online 21 February 2021

    Source: Neural Networks

    Author(s): Alex Bihlo

    in Neural Networks on February 21, 2021 07:00 PM.

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    Extracellular microvesicles promote microglia‐mediated pro‐inflammatory responses to ethanol

    Ethanol causes the secretion of pro‐inflammatory microvesicles (MVs) from brain tissue. Ethanol‐induced MVs reproduce the pro‐inflammatory gene induction and microglial activation seen with ethanol alone, and inhibition of their secretion blocks ethanol‐induced neuroinflammation. Microglia are required for the generation of pro‐inflammatory MVs, with MV secretion involving activation of microglial PI3K. Abstract Alcohol use disorder (AUD) pathology features pro‐inflammatory gene induction and microglial activation. The underlying cellular processes that promote this activation remain unclear. Previously considered cellular debris, extracellular vesicles (EVs) have emerged as mediators of inflammatory signaling in several disease states. We investigated the role of microvesicles (MVs, 50 nm–100 µm diameter EVs) in pro‐inflammatory and microglial functional gene expression using primary organotypic brain slice culture (OBSC). Ethanol caused a unique immune gene signature that featured: temporal induction of pro‐inflammatory TNF‐α and IL‐1β, reduction of homeostatic microglia state gene Tmem119, progressive increases in purinergic receptor P2RY12 and the microglial inhibitory fractalkine receptor CX3CR1, an increase in the microglial presynaptic gene C1q, and a reduction in the phagocytic gene TREM2. MV signaling was implicated in this response as reduction of MV secretion by imipramine blocked pro‐inflammatory TNF‐α and IL‐1β induction by ethanol, and ethanol‐conditioned MVs (EtOH‐MVs) reproduced the ethanol‐associated immune gene signature in naïve OBSC slices. Depletion of microglia prior to ethanol treatment prevented pro‐inflammatory activity of EtOH‐MVs, as did incubation of EtOH‐MVs with the HMGB1 inhibitor glycyrrhizin. Ethanol caused HMGB1 secretion from cultured BV2 microglia in MVs through activation of PI3 kinase. In summary, these studies find MVs modulate pro‐inflammatory gene induction and microglial activation changes associated with ethanol. Thus, MVs may represent a novel therapeutic target to reduce neuroinflammation in the setting of alcohol abuse or other diseases that feature a neuroimmune component.

    in Journal of Neuroscience Research on February 21, 2021 03:24 AM.

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    Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency

    In a transient systemic hypoxic‐ischemic model of placental insufficiency, erythropoietin is found to have lasting, mitigating effects on the diminished cognitive flexibility and increased perseveration which are associated with encephalopathy of prematurity. Highly translatable testing, including novel object recognition and touchscreen‐based visual discrimination and reversal learning, reveal significant differences post‐treatment. Abstract Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

    in Journal of Neuroscience Research on February 21, 2021 03:18 AM.

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    The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats

    The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have...

    in Behavioural and Brain Functions on February 21, 2021 12:00 AM.

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    Sex differences in the social brain and in social cognition

    Abstract Many studies have reported sex differences in empathy and social skills. In this review, several lines of empirical evidences about sex differences in functions and anatomy of social brain are discussed. The most relevant differences involve face processing, facial expression recognition, response to baby schema, the ability to see faces in things, the processing of social interactions, the response to the others’ pain, interest in social information, processing of gestures and actions, biological motion, erotic, and affective stimuli. Sex differences in oxytocin‐based parental response are also reported. In conclusion, the female and male brains show several neuro‐functional differences in various aspects of social cognition, and especially in emotional coding, face processing, and response to baby schema. An interpretation of this sexual dimorphism is provided in the view of evolutionary psychobiology.

    in Journal of Neuroscience Research on February 20, 2021 09:41 AM.

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    Noradrenaline‐induced l‐lactate production requires d‐glucose entry and transit through the glycogen shunt in single‐cultured rat astrocytes

    d‐glucose uptake in astrocytes is an essential source for the noradrenaline‐induced increase in intracellular L‐lactate. We found that intracellular l‐lactate arises exclusively from the glycogen—a temporary energy store in the brain. The glycolytic pathway intermediates also support oxidative phosphorylation in mitochondria. At rest, a large proportion of d‐glucose is metabolized in the Krebs cycle, since the resting l‐lactate concentration is low. This is increased when the Krebs cycle is blocked or when cells are stimulated with noradrenaline. Abstract During cognitive efforts mediated by local neuronal networks, approximately 20% of additional energy is required; this is mediated by chemical messengers such as noradrenaline (NA). NA targets astroglial aerobic glycolysis, the hallmark of which is the end product l‐lactate, a fuel for neurons. Biochemical studies have revealed that astrocytes exhibit a prominent glycogen shunt, in which a portion of d‐glucose molecules entering the cytoplasm is transiently incorporated into glycogen, a buffer and source of d‐glucose during increased energy demand. Here, we studied single astrocytes by measuring cytosolic L‐lactate ([lac]i) with the FRET nanosensor Laconic. We examined whether NA‐induced increase in [lac]i is influenced by: (a) 2‐deoxy‐d‐glucose (2‐DG, 3 mM), a molecule that enters the cytosol and inhibits the glycolytic pathway; (b) 1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB, 300 µM), a potent inhibitor of glycogen phosphorylase and glycogen degradation; and (c) 3‐nitropropionic acid (3‐NPA, 1 mM), an inhibitor of the Krebs cycle. The results of these pharmacological experiments revealed that d‐glucose uptake is essential for the NA‐induced increase in [lac]i, and that this exclusively arises from glycogen degradation, indicating that most, if not all, d‐glucose molecules in NA‐stimulated cells transit the glycogen shunt during glycolysis. Moreover, under the defined transmembrane d‐glucose gradient, the glycolytic intermediates were not only used to produce l‐lactate, but also to significantly support oxidative phosphorylation, as demonstrated by an elevation in [lac]i when Krebs cycle was inhibited. We conclude that l‐lactate production via aerobic glycolysis is an essential energy pathway in NA‐stimulated astrocytes; however, oxidative metabolism is important at rest.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein

    The protein α‐synuclein is central to Parkinson's disease. For the first time, we report that α‐synuclein from Parkinson's patients brain samples caused signaling deficits in brain cells, and novel drug candidates known to block the sigma‐2 receptor complex reversed these deficits. Abstract α‐Synuclein oligomers are thought to have a pivotal role in sporadic and familial Parkinson's disease (PD) and related α‐synucleinopathies, causing dysregulation of protein trafficking, autophagy/lysosomal function, and protein clearance, as well as synaptic function impairment underlying motor and cognitive symptoms of PD. Moreover, trans‐synaptic spread of α‐synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block α‐synuclein oligomer‐induced pathogenesis are urgently needed. Here, we show for the first time that α‐synuclein species isolated from human PD patient brain and recombinant α‐synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while α‐synuclein species isolated from non‐PD human control brain samples did not. Recombinant α‐synuclein oligomers also increased neuronal expression of lysosomal‐associated membrane protein‐2A (LAMP‐2A), the lysosomal receptor that has a critical role in chaperone‐mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma‐2 receptor antagonists as the most effective at blocking α‐synuclein oligomer‐induced trafficking deficits and LAMP‐2A upregulation in a dose‐dependent manner. These results indicate that antagonists of the sigma‐2 receptor complex may alleviate α‐synuclein oligomer‐induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related α‐synucleinopathies.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Mitochondrial dysfunction, mitophagy, and role of dynamin‐related protein 1 in Alzheimer's disease

    Oxidative stress implicates mitochondrial damage and effects on mitochondrial function, production of ATP, mitochondrial dynamics and biogenesis. The mitochondrial dysfunction eventually demonstrates its lethal behaviour on Aβ clearance and mitochondrial fission, especially on the protein Drp1. In AD pathogenesis, Drp1 can play an important regulatory role in mitophagy and autophagy. The miR‐499 causes suppression of calcineurin‐mediated dephosphorylation of Drp1, whereas miR‐30a inhibits mitochondrial fission by suppressing p53 and subsequent Drp‐1 downstream signaling. Mitochondrial targeted antioxidant (MTA) molecules such as Mdivi1, SS31 and Dynasore can reduce excessive mitochondrial fission activity of Drp1 and restore normal mitochondrial functions, fusion‐fission activities, mitophagy and autophagy functions in clearing dead mitochondria for normal synaptic functions. Abstract Alzheimer's disease (AD) is the most common type of dementia and progressive neurodegenerative disease. The presence of β‐amyloid (Aβ) plaques and phosphorylated Tau tangles are considered to be the two main hallmarks of AD. Recent findings have shown that different changes in the structure and dynamics of mitochondria play an important role in AD pathology progression. Mitochondrial changes in AD are expressed as enhanced mitochondrial fragmentation, altered mitochondrial dynamics, and changes in the expression of mitochondrial biogenesis genes in vitro and in vivo models. Therefore, targeting mitochondria and associated mitochondrial proteins seems to be a promising alternative instead of targeting Aβ and Tau in the prevention of Alzheimer's disease. The dynamin‐related protein (Drp1) is one such protein that plays an important role in the regulation of mitochondrial division and maintenance of mitochondrial structures. Few researchers have shown that inhibition of Drp1 GTPase activity in neuronal cells rescues excessive mitochondrial fragmentation. In addition, the growing evidence revealed that Drp1 can interact with both Aβ and Tau protein in human brain tissues and mouse models. In this review, we would like to update existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Select neurotrophins promote oligodendrocyte progenitor cell process outgrowth in the presence of chondroitin sulfate proteoglycans

    Oligodendrocyte progenitor cells cannot extend cellular process in the presence of Chondroitin Sulfate Proteoglycans. Treatment of OPCs with different neurotrophic factors (BDNF, GDNF, and NT‐3) allows OPCs to overcome the inhibitory effects of CSPGs, allowing for OPC process outgrowth which is a critical step in the differentiation of OPCs. Abstract Axonal damage and the subsequent interruption of intact neuronal pathways in the spinal cord are largely responsible for the loss of motor function after injury. Further exacerbating this loss is the demyelination of neighboring uninjured axons. The post‐injury environment is hostile to repair, with inflammation, a high expression of chondroitin sulfate proteoglycans (CSPGs) around the glial scar, and myelin breakdown. Numerous studies have demonstrated that treatment with the enzyme chondroitinase ABC (cABC) creates a permissive environment around a spinal lesion that permits axonal regeneration. Neurotrophic factors like brain‐derived neurotrophic factor (BDNF), glial cell line‐derived neurotrophic factor (GDNF), neurotrophic factor‐3 (NT‐3), and ciliary neurotrophic factor (CNTF) have been used to promote neuronal survival and stimulate axonal growth. CSPGs expressed near a lesion also inhibit migration and differentiation of endogenous oligodendrocyte progenitor cells (OPCs) in the spinal cord, and cABC treatment can neutralize this inhibition. This study examined the neurotrophins commonly used to stimulate axonal regeneration after injury and their potential effects on OPCs cultured in the presence of CSPGs. The results reveal differential effects on OPCs, with BDNF and GDNF promoting process outgrowth and NT‐3 stimulating differentiation of OPCs, while CNTF appears to have no observable effect. This finding suggests that certain neurotrophic agents commonly utilized to stimulate axonal regeneration after a spinal injury may also have a beneficial effect on the endogenous oligodendroglial cells as well.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Extra‐striatal dopamine in Parkinson's disease with rapid eye movement sleep behavior disorder

    This PET study characterized D2 receptor (D2R) availability within extra‐striatal regions in Parkinson's disease (PD) patients with (+) and without (−) REM sleep behavior disorder (RBD). With disease progression, only PD‐RBD+ patients showed steep decline in D2R availability within the left uncus parahippocampus. Beyond the striatum, extra‐striatal dopaminergic system may also contribute to PD‐RBD in advanced stages. Abstract Rapid eye movement sleep behavior disorder (RBD) is a common condition found in more than 50% of the patients with Parkinson's disease (PD). Molecular imaging shows that PD with RBD (PD‐RBD+) have lower striatal dopamine transporter activity within the caudate and putamen relative to PD without RBD (PD‐RBD−). However, the characterization of the extra‐striatal dopamine within the mesocortical and mesolimbic pathways remains unknown. We aim to elucidate this with PET imaging in 15 PD‐RBD+ and 15 PD‐RBD− patients, while having 15 age‐matched healthy controls (HC). Each participant underwent a single PET scan with [11C]FLB‐457 to detect the D2 receptor availability within the extra‐striatal regions of interest (ROI), including the prefrontal, temporal, and limbic areas. [11C]FLB‐457 retention was expressed as the nondisplaceable binding potential. Our results reveal that relative to HC, PD‐RBD+ and PD‐RBD− patients have lower levels of D2 receptor availability within the uncus parahippocampus, superior, lateral, and inferior temporal cortex. PD‐RBD+ showed steep decline in D2 receptors within the left uncus parahippocampus with increasing disease severity, but this was not observed for PD‐RBD− patients. Findings imply that extra‐striatal dopaminergic system may play a role in contributing to symptomatic progress in PD patients with RBD. However, validation with more advanced PD patients are needed.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Social isolation is closely linked to a marked reduction in physical activity in male mice

    By observing the behavior of mice in their home cage environment, using the powerful PhenoTyper tracking system, we demonstrate that mice display dramatic reductions in movement and exploration when isolated from their cage mates, an instantaneous effect that escalates over the next 5 days, which is reversible upon re‐pairing. Abstract The effects of social isolation on an individual's behavior is an important field of research, especially as public health officials encourage social distancing to prevent the spread of pandemic disease. In this study we evaluate the effects of social isolation on physical activity in mice. Utilizing a pixel‐based tracking system, we continuously monitored the movement of isolated mice compared with paired cage mates in the home cage environment. We demonstrate that mice that are socially isolated dramatically decrease their movement when separated from their cage mate, and especially in the dark cycle, when mice are normally most active. When isolated mice are re‐paired with their original cage mate, this effect is reversed, and mice return to their prior levels of activity. These findings suggest a close link between social isolation and physical activity, and are of particular interest in the wake of coronavirus disease 2019, when many are forced into isolation. Social isolation may affect an individual's overall activity levels in humans too, which may have unintended effects on health that deserve further consideration.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events

    Abstract Photodynamic therapy (PDT) has recently gained attention as an alternative treatment of malignant gliomas. Glioblastoma (GBM) is the most prevalent within tumors of the central nervous system (CNS). Conventional treatments for this CNS tumor include surgery, radiation, and chemotherapy. Surgery is still being considered as the treatment of choice. Even so, the poor prognosis and/or recurrence of the disease after applying any of these treatments highlight the urgency of exploring new therapies and/or improving existing ones to achieve the definitive eradication of tumor masses and remaining cells. PDT is a therapeutic modality that involves the destruction of tumor cells by reactive oxygen species induced by light, which were previously treated with a photosensitizing agent. However, in recent years, its experimental application has expanded to other effects that could improve overall performance against GBM. In the current review, we revisit the main advances of PDT for GBM management and also, the recent mechanistic insights about cellular and molecular aspects related to tumoral resistance to PDT of GBM.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Gpr37l1/prosaposin receptor regulates Ptch1 trafficking, Shh production, and cell proliferation in cerebellar primary astrocytes

    Genetic ablation of G protein‐coupled receptor 37‐like 1 results in increased patched 1 expression and internalization. This leads to the intracellular accumulation of cholesterol, with concomitant stimulation of sonic hedgehog (Shh) production and activation of Shh‐induced proliferative signaling. Abstract Mammalian cerebellar astrocytes critically regulate the differentiation and maturation of neuronal Purkinje cells and granule precursors. The G protein‐coupled receptor 37‐like 1 (Gpr37l1) is expressed by Bergmann astrocytes and interacts with patched 1 (Ptch1) at peri‐ciliary membranes. Cerebellar primary astrocyte cultures from wild‐type and Gpr37l1 null mutant mouse pups were established and studied. Primary cilia were produced by cultures of both genotypes, as well as Ptch1 and smoothened (Smo) components of the sonic hedgehog (Shh) mitogenic pathway. Compared to wild‐type cells, Gpr37l1−/− astrocytes displayed striking increases in proliferative activity, Ptch1 protein expression and internalization, intracellular cholesterol content, ciliary localization of Smo, as well as a marked production of active Shh. Similar effects were reproduced by treating wild‐type astrocytes with a putative prosaptide ligand of Gpr37l1. These findings indicate that Gpr37l1–Ptch1 interactions specifically regulate Ptch1 internalization and trafficking, with consequent stimulation of Shh production and activation of proliferative signaling.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Intersectional targeting of defined neural circuits by adeno‐associated virus vectors

    Abstract The mammalian nervous system is a complex network of interconnected cells. We review emerging techniques that use the axonal transport of adeno‐associated virus (AAV) vectors to dissect neural circuits. These intersectional approaches specifically target AAV‐mediated gene expression to discrete neuron populations based on their axonal connectivity, including: (a) neurons with one defined output, (b) neurons with one defined input, (c) neurons with one defined input and one defined output, and (d) neurons with two defined inputs or outputs. The number of labeled neurons can be directly controlled to trace axonal projections and examine cellular morphology. These approaches can precisely target the expression of fluorescent reporters, optogenetic ion channels, chemogenetic receptors, disease‐associated proteins, and other factors to defined neural circuits in mammals ranging from mice to macaques, and thereby provide a powerful new means to understand the structure and function of the nervous system.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease‐specific changes in sleep and incongruous peripheral inflammation

    In similarly aged individuals, traumatic brain injury (TBI) induced more profound sleep alterations than Alzheimer's disease (AD), with incongruous inflammation. Altered sleep may be associated with deleterious pathological processes and unique pathological sleep pathways may exist in older individuals that incur TBI compared with similarly aged individuals that have AD. Abstract Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16‐month‐old wild‐type (WT Aged) and 3xTg‐AD mice, as well as a 2‐month‐old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre‐ and post‐TBI) and 3xTg‐AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed‐effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre‐TBI and compared with AD mice. However, differences between WT Aged and 3xTg‐AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease‐specific treatments in clinical settings.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Detection of functional connectivity in the brain during visuo‐guided grip force tracking tasks: A functional near‐infrared spectroscopy study

    The brain activity of the four brain regions during visuo‐guided grip force tracking tasks were detected by functional near‐infrared spectroscopy. Pearson's correlation method, partial correlation method, and a pairwise maximum entropy model were used to get a more comprehensive and accurate functional connectivity for precise grip force control. Abstract The functional connectivity (FC) between multiple brain regions during tasks is currently gradually being explored with functional near‐infrared spectroscopy (fNIRS). However, the FC present during grip force tracking tasks performed under visual feedback remains unclear. In the present study, we used fNIRS to measure brain activity during resting states and grip force tracking tasks at 25%, 50%, and 75% of maximum voluntary contraction (MVC) in 11 healthy subjects, and the activity was measured from four target brain regions: the left prefrontal cortex (lPFC), right prefrontal cortex (rPFC), left sensorimotor cortex (lSMC), and right sensorimotor cortex (rSMC). We determined the FC between these regions utilizing three different methods: Pearson's correlation method, partial correlation method, and a pairwise maximum entropy model (MEM). The results showed that the FC of lSMC‐rSMC and lPFC‐rPFC (interhemispheric homologous pairs) were significantly stronger than those of other brain region pairs. Moreover, FC of lPFC‐rPFC was strengthened during the 75% MVC task compared to the other task states and the resting states. The FC of lSMC‐lPFC and rSMC‐rPFC (intrahemispheric region pairs) strengthened with a higher task load. The results provided new insights into the FC between brain regions during visuo‐guided grip force tracking tasks.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

    Glial cell line‐derived neurotrophic factor derived from glioma cells upregulate matrix metallopeptidase 9 and 14 expression on microglia, which in turn promote glioma progression. Abstract Glial cell line‐derived neurotrophic factor (GDNF) is released by glioma cells and promotes tumor growth. We have previously found that GDNF released from the tumor cells is a chemoattractant for microglial cells, the immune cells of the central nervous system. Here we show that GDNF increases matrix metalloproteinase (MMP) 9 and MMP14 expression in cultured microglial cells from mixed sexes of neonatal mice. The GDNF‐induced microglial MMP9 and MMP14 upregulation is mediated by GDNF family receptor alpha 1 receptors and dependent on p38 mitogen‐activated protein kinase signaling. In organotypic brain slices, GDNF promotes the growth of glioma and this effect depends on the presence of microglia. We also previously found that MMP9 and MMP14 upregulation can be mediated by Toll‐like receptor (TLR) 2 signaling and here we demonstrate that GDNF increases the expression of TLR1 and TLR2. In conclusion, GDNF promotes the pro‐tumorigenic phenotype of microglia.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

    The potential approaches to treating neonatal H‐I injury are as follows: 1. Inhibiting M1 microglia to secrete pro‐inflammatory cytokines or to promote microglia M2 polarization. 2. Targeting OPCs and oligodendrocytes and promoting their differentiation and maturation to maintain axonal integrity and conductivity and restoring axonal functions through remyelination. Abstract Neonatal hypoxic–ischemic (H‐I) injury, which mainly causes neuronal damage and white matter injury (WMI), is among the predominant causes of infant morbidity (cerebral palsy, cognitive and persistent motor disabilities) and mortality. Disruptions to the oxygen and blood supply in the perinatal brain affect the cerebral microenvironment and may affect microglial activation, excitotoxicity, and oxidative stress. Microglia are significantly associated with axonal damage and myelinating oligodendrocytes, which are major pathological components of WMI. However, the effects of H‐I injury on microglial functions and underlying transformation mechanisms remain poorly understood. The historical perception that these cells are major risk factors for ischemic stroke has been questioned due to our improved understanding of the diversity of microglial phenotypes and their alterable functions, which exacerbate or attenuate injuries in different regions in response to environmental instability. Unfortunately, although therapeutic hypothermia is an efficient treatment, death and disability remain the prognosis for a large proportion of neonates with H‐I injury. Hence, novel neuroprotective therapies to treat WMI following H‐I injury are urgently needed. Here, we review microglial mechanisms that might occur in the developing brain due to neonatal H‐I injury and discuss whether microglia function as a double‐edged sword in WMI. Then, we emphasize microglial heterogeneity, notably at the single‐cell level, and sex‐specific effects on the etiology of neurological diseases. Finally, we discuss current knowledge of strategies aiming to improve microglia modulation and remyelination following neonatal H‐I injury. Overall, microglia‐targeted therapy might provide novel and valuable insights into the treatment of neonatal H‐I insult.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Issue Information

    Journal of Neuroscience Research, Volume 99, Issue 4, Page 979-980, April 2021.

    in Journal of Neuroscience Research on February 20, 2021 08:57 AM.

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    Development of parvalbumin neurons and perineuronal nets in the visual cortex of normal and dark‐exposed cats

    At the peak of the critical period, immersion into complete darkness for 10 days significantly reduces the number of perineuronal nets (PNN) in the primary visual cortex of cats but does not alter the number of parvalbumin (PV) cells that they usually surround. Darkness also reduces the size of PV cells even if they are surrounded by a PNN, indicating that PNNs do not inhibit all forms of neural plasticity. Abstract During development, the visual system maintains a high capacity for modification by expressing characteristics permissive for plasticity, enabling neural circuits to be refined by visual experience to achieve their mature form. This period is followed by the emergence of characteristics that stabilize the brain to consolidate for lifetime connections that were informed by experience. Attenuation of plasticity potential is thought to derive from an accumulation of plasticity‐inhibiting characteristics that appear at ages beyond the peak of plasticity. Perineuronal nets (PNNs) are molecular aggregations that primarily surround fast‐spiking inhibitory neurons called parvalbumin (PV) cells, which exhibit properties congruent with a plasticity inhibitor. In this study, we examined the development of PNNs and PV cells in the primary visual cortex of a highly visual mammal, and assessed the impact that 10 days of darkness had on both characteristics. Here, we show that labeling for PV expression emerges earlier and reaches adult levels sooner than PNNs. We also demonstrate that darkness, a condition known to enhance plasticity, significantly reduces the density of PNNs and the size of PV cell somata but does not alter the number of PV cells in the visual cortex. The darkness‐induced reduction of PV cell size occurred irrespective of whether neurons were surrounded by a PNN, suggesting that PNNs have a restricted capacity to inhibit plasticity. Finally, we show that PV cells surrounded by a PNN were significantly larger than those without one, supporting the view that PNNs may mediate trophic support to the cells they surround.

    in Journal of Comparative Neurology on February 20, 2021 08:50 AM.

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    Rodent mnemonic similarity task performance requires the prefrontal cortex

    Abstract Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex. Impairments on this task are known to manifest with advancing age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests that other brain structures support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, rats were trained on a LEGO object‐based mnemonic similarity task adapted for rodents, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity‐dependent immediate‐early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50–90% feature overlap with the target. Thus, in contrast hippocampal infusions, PFC inactivation impaired target‐lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus.

    in Hippocampus on February 19, 2021 03:15 PM.

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    Resilience, pain, and the brain: Relationships differ by sociodemographics

    Higher resilience associates with lower pain severity and pain disability in those with chronic pain. Additionally, relationships between resilience and pain‐related brain structure were indicated in the right amygdala, bilateral thalamus, and postcentral gyrus which differed by sex and ethnicity/race. Considering sociodemographic factors in pain and resilience investigations are important. Abstract Chronic musculoskeletal (MSK) pain is disabling to individuals and burdensome to society. A relationship between telomere length and resilience was reported in individuals with consideration for chronic pain intensity. While chronic pain associates with brain changes, little is known regarding the neurobiological interface of resilience. In a group of individuals with chronic MSK pain, we examined the relationships between a previously investigated resilience index, clinical pain and functioning measures, and pain‐related brain structures, with consideration for sex and ethnicity/race. A cross‐sectional analysis of 166 non‐Hispanic Black and non‐Hispanic White adults, 45–85 years of age with pain ≥ 1 body site (s) over the past 3 months was completed. Measures of clinical pain and functioning, biobehavioral and psychosocial resilience, and structural MRI were completed. Our findings indicate higher levels of resilience associate with lower levels of clinical pain and functional limitations. Significant associations between resilience, ethnicity/race, and/or sex, and pain‐related brain gray matter structure were demonstrated in the right amygdaloid complex, bilateral thalamus, and postcentral gyrus. Our findings provide compelling evidence that in order to decipher the neurobiological code of chronic pain and related protective factors, it will be important to improve how chronic pain is phenotyped; to include an equal representation of females in studies including analyses stratifying by sex, and to consider other sociodemographic factors.

    in Journal of Neuroscience Research on February 19, 2021 03:07 PM.

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    Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure

    After a single, binge‐level exposure to ethanol in development, we found subtle effects on glia in the mouse somatosensory cortex and hippocampus. Ethanol treatment reduced colocalization between two astrocytic markers, GFAP and Aldh1L1; induced region‐specific changes in microglia volume, process morphology, and density; and had no effect on glial interactions. Abstract Fetal alcohol spectrum disorders (FASD) are the most common cause of nonheritable, preventable mental disability and are characterized by cognitive, behavioral, and physical impairments. FASD occurs in almost 5% of births in the United States, but despite this prevalence there is no known cure, largely because the biological mechanisms that translate alcohol exposure to neuropathology are not well understood. While the effects of early ethanol exposure on neuronal survival and circuitry have received more attention, glia, the cells most closely tied to initiating and propagating inflammatory events, could be an important target for alcohol in the developing brain. Inflammation is known to alter developmental trajectories, but it has recently been shown that even small changes in both astrocytes and microglia in the absence of full‐blown inflammatory signaling can alter brain function long‐term. Here, we studied the acute response of astrocytes and microglia to a single exposure to ethanol in development across sexes in a mouse model of human third trimester exposure, in order to understand how these cells may transition from their normal developmental path to a different program that leads to FASD neuropathology. We found that although a single ethanol exposure delivered subcutaneously on postnatal day 4 did not cause large changes in microglial morphology or the expression of AldH1L1 and GFAP in the cortex and hippocampus, subtle effects were observed. These findings suggest that even a single, early ethanol exposure can induce mild acute alterations in glia that could contribute to developmental deficits.

    in Journal of Neuroscience Research on February 19, 2021 02:45 PM.

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    Margination and adhesion dynamics of tumor cells in a real microvascular network

    by Sitong Wang, Ting Ye, Guansheng Li, Xuejiao Zhang, Huixin Shi

    In tumor metastasis, the margination and adhesion of tumor cells are two critical and closely related steps, which may determine the destination where the tumor cells extravasate to. We performed a direct three-dimensional simulation on the behaviors of the tumor cells in a real microvascular network, by a hybrid method of the smoothed dissipative particle dynamics and immersed boundary method (SDPD-IBM). The tumor cells are found to adhere at the microvascular bifurcations more frequently, and there is a positive correlation between the adhesion of the tumor cells and the wall-directed force from the surrounding red blood cells (RBCs). The larger the wall-directed force is, the closer the tumor cells are marginated towards the wall, and the higher the probability of adhesion behavior happen is. A relatively low or high hematocrit can help to prevent the adhesion of tumor cells, and similarly, increasing the shear rate of blood flow can serve the same purpose. These results suggest that the tumor cells may be more likely to extravasate at the microvascular bifurcations if the blood flow is slow and the hematocrit is moderate.

    in PLoS Computational Biology on February 19, 2021 02:00 PM.

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    An antigenic diversification threshold for falciparum malaria transmission at high endemicity

    by Qixin He, Mercedes Pascual

    In malaria and several other important infectious diseases, high prevalence occurs concomitantly with incomplete immunity. This apparent paradox poses major challenges to malaria elimination in highly endemic regions, where asymptomatic Plasmodium falciparum infections are present across all age classes creating a large reservoir that maintains transmission. This reservoir is in turn enabled by extreme antigenic diversity of the parasite and turnover of new variants. We present here the concept of a threshold in local pathogen diversification that defines a sharp transition in transmission intensity below which new antigen-encoding genes generated by either recombination or migration cannot establish. Transmission still occurs below this threshold, but diversity of these genes can neither accumulate nor recover from interventions that further reduce it. An analytical expectation for this threshold is derived and compared to numerical results from a stochastic individual-based model of malaria transmission that incorporates the major antigen-encoding multigene family known as var. This threshold corresponds to an “innovation” number we call Rdiv; it is different from, and complementary to, the one defined by the classic basic reproductive number of infectious diseases, R0, which does not easily apply under large and dynamic strain diversity. This new threshold concept can be exploited for effective malaria control and applied more broadly to other pathogens with large multilocus antigenic diversity.

    in PLoS Computational Biology on February 19, 2021 02:00 PM.

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    Efficient and flexible Integration of variant characteristics in rare variant association studies using integrated nested Laplace approximation

    by Hana Susak, Laura Serra-Saurina, German Demidov, Raquel Rabionet, Laura Domènech, Mattia Bosio, Francesc Muyas, Xavier Estivill, Geòrgia Escaramís, Stephan Ossowski

    Rare variants are thought to play an important role in the etiology of complex diseases and may explain a significant fraction of the missing heritability in genetic disease studies. Next-generation sequencing facilitates the association of rare variants in coding or regulatory regions with complex diseases in large cohorts at genome-wide scale. However, rare variant association studies (RVAS) still lack power when cohorts are small to medium-sized and if genetic variation explains a small fraction of phenotypic variance. Here we present a novel Bayesian rare variant Association Test using Integrated Nested Laplace Approximation (BATI). Unlike existing RVAS tests, BATI allows integration of individual or variant-specific features as covariates, while efficiently performing inference based on full model estimation. We demonstrate that BATI outperforms established RVAS methods on realistic, semi-synthetic whole-exome sequencing cohorts, especially when using meaningful biological context, such as functional annotation. We show that BATI achieves power above 70% in scenarios in which competing tests fail to identify risk genes, e.g. when risk variants in sum explain less than 0.5% of phenotypic variance. We have integrated BATI, together with five existing RVAS tests in the ‘Rare Variant Genome Wide Association Study’ (rvGWAS) framework for data analyzed by whole-exome or whole genome sequencing. rvGWAS supports rare variant association for genes or any other biological unit such as promoters, while allowing the analysis of essential functionalities like quality control or filtering. Applying rvGWAS to a Chronic Lymphocytic Leukemia study we identified eight candidate predisposition genes, including EHMT2 and COPS7A.

    in PLoS Computational Biology on February 19, 2021 02:00 PM.

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    Ecological rules for the assembly of microbiome communities

    by Katharine Z. Coyte, Chitong Rao, Seth Rakoff-Nahoum, Kevin R. Foster

    Humans and many other hosts establish a diverse community of beneficial microbes anew each generation. The order and identity of incoming symbionts is critical for health, but what determines the success of the assembly process remains poorly understood. Here we develop ecological theory to identify factors important for microbial community assembly. Our method maps out all feasible pathways for the assembly of a given microbiome—with analogies to the mutational maps underlying fitness landscapes in evolutionary biology. Building these “assembly maps” reveals a tradeoff at the heart of the assembly process. Ecological dependencies between members of the microbiota make assembly predictable—and can provide metabolic benefits to the host—but these dependencies may also create barriers to assembly. This effect occurs because interdependent species can fail to establish when each relies on the other to colonize first. We support our predictions with published data from the assembly of the preterm infant microbiota, where we find that ecological dependence is associated with a predictable order of arrival. Our models also suggest that hosts can overcome barriers to assembly via mechanisms that either promote the uptake of multiple symbiont species in one step or feed early colonizers. This predicted importance of host feeding is supported by published data on the impacts of breast milk in the assembly of the human microbiome. We conclude that both microbe–microbe and host–microbe interactions are important for the trajectory of microbiome assembly.

    in PLoS Biology on February 19, 2021 02:00 PM.

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    Olfactory ensheathing cells: Unique glial cells promising for treatments of spinal cord injury

    Schematic drawing of the olfactory system. Olfactory mucosa contains olfactory receptor neurons (yellow), extending from the olfactory epithelia to the olfactory bulb (OB). Olfactory ensheathing cells (OECs) ensheath axons of olfactory receptor neurons until they reach glomeruli. Two subtypes of OECs residing within olfactory mucosa (OM) and OB and named accordingly as OM‐OECs (purple) and OB‐OECs (blue), respectively. Two subtypes of OECs with their secretions, affecting neuronal repair on spinal cord injuries (SCI) differently. OM‐OECs secrete molecules related to extracellular matrix remodeling such as laminin, fibronectin, matrix metalloproteases (MMPs), vascular endothelial growth factor (VEGF), neural cell adhesion molecule (NCAM), and transforming growth factor‐β3 (TGF‐β3). Meanwhile, OB‐OECs secrete molecules promoting neuronal proliferation and axonal growth such as NGF, GDNF, BDNF neuregulin, and other neurotrophins Abstract Spinal cord injury (SCI) is generally the consequence of physical damage, which may result in devastating consequences such as paraplegia or paralysis. Some certain candidates for SCI repair are olfactory ensheathing cells (OECs), which are unique glial cells located in the transition region of the peripheral nervous system and central nervous system and perform neuron regeneration in the olfactory system throughout life. Culture studies have clarified many properties of OECs, but their mechanisms of actions are not fully understood. Successful results achieved in animal models showcased that SCI treatment with OEC transplants is suitable for clinical trials. However, clinical trials are limited by difficulties like cell acquisition for autograft transplantation. Despite the improvements in both animal and clinical studies so far, there is still insufficient information about the mechanism of actions, adverse effects, proper application methods, effective subtypes, and sources of cells. This review summarizes pre‐clinical and clinical literature focused on the cellular characterization of both OECs in vitro and post‐transplantation. We highlight the roles and effects of OECs on (a) the injury‐induced glial milieu, (b) neuronal growth/regeneration, and (c) functional recovery after injury. Due to the shown benefits of OECs with in vitro and animal studies and a limited number of clinical trials, where safety and effectivity were shown, it is necessary to conduct more studies on OECs to obtain effective and feasible treatment methods.

    in Journal of Neuroscience Research on February 19, 2021 10:26 AM.

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    Estimating integrated information in bidirectional neuron-astrocyte communication

    Author(s): Luis Abrego, Susanna Gordleeva, Oleg Kanakov, Mikhail Krivonosov, and Alexey Zaikin

    There is growing evidence that suggests the importance of astrocytes as elements for neural information processing through the modulation of synaptic transmission. A key aspect of this problem is understanding the impact of astrocytes in the information carried by compound events in neurons across t...


    [Phys. Rev. E 103, 022410] Published Fri Feb 19, 2021

    in Physical Review E: Biological physics on February 19, 2021 10:00 AM.

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    Optimal transition paths of phenotypic switching in a non-Markovian self-regulation gene expression

    Author(s): Hongwei Yin, Shuqin Liu, and Xiaoqing Wen

    Gene expression is a complex biochemical process involving multiple reaction steps, creating molecular memory because the probability of waiting time between consecutive reaction steps no longer follows exponential distributions. What effect the molecular memory has on metastable states in gene expr...


    [Phys. Rev. E 103, 022409] Published Fri Feb 19, 2021

    in Physical Review E: Biological physics on February 19, 2021 10:00 AM.

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    Astrocyte‐induced synapse formation and ischemic stroke

    Abstract Astrocytes are closely associated with the regulation of synapse formation and function. In addition, astrocytes have been shown to block certain brain impairments, including synaptic damage from stroke and other diseases of the central nervous system (CNS). Although astrocytes do not completely prevent synaptic damage, they appear to be protective and to restore synaptic function following damage. The purpose of this study is to discuss the role of astrocytes in synaptogenesis and synaptic damage in ischemic stroke. I detail the mechanism of action of the multiple factors secreted by astrocytes that are involved in synapse formation. In particular, I describe the characteristics and role in synapse formation of each secreted molecule related to synaptic structure and function. Furthermore, I discuss the effect of astrocytes on synaptogenesis and repair in ischemic stroke and in other CNS diseases. Astrocytes release molecules such as thrombospondin, hevin, secreted protein acidic rich in cysteine, etc., due to activation by ischemia to induce synaptic structure and function, an effect associated with protection of the brain from synaptic damage in ischemic stroke. In conclusion, I show that astrocytes may regulate synaptic transmission while having the potential to block and repair synaptic dysfunction in stroke‐associated brain damage.

    in Journal of Neuroscience Research on February 19, 2021 05:03 AM.

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    Postictal death is associated with tonic phase apnea in a mouse model of SUDEP

    Objective Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. Methods We performed cardiorespiratory monitoring of seizure‐induced death in mice carrying either an p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele – mutations identified from patients that died from SUDEP – and by seizure‐induced death of pentylenetetrazole‐treated wild type mice. Results The primary cause of seizure‐induced death for all mice was apnea, as 1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and 2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p,Leu257Val) revealed similarities to those of the mice; an extended tonic phase that was accompanied by apnea. Interpretation We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure‐induced death in Scn8a mutant mice. This article is protected by copyright. All rights reserved.

    in Annals of Neurology on February 19, 2021 02:33 AM.

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    The molecular biology of FMRP: new insights into fragile X syndrome

    Nature Reviews Neuroscience, Published online: 19 February 2021; doi:10.1038/s41583-021-00432-0

    Inactivation of the gene encoding fragile X mental retardation protein (FMRP) drives the impairments in brain development and function that underlie fragile X syndrome. Richter and Zhao illustrate how innovative genetic and molecular biology tools have enhanced our understanding of both FMRP’s function and the causes of fragile X syndrome pathophysiology.

    in Nature Reviews on February 19, 2021 12:00 AM.

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    In memory of Arthur Ashkin

    Nature Photonics, Published online: 19 February 2021; doi:10.1038/s41566-021-00768-0

    Radiation pressure exerted by light was a lifelong passion for Arthur Ashkin. He foresaw that light pressure could do useful work and invented the optical tweezers that can trap microscopic objects, from small ‘living things’ down to individual atoms.

    in Nature Photomics on February 19, 2021 12:00 AM.

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    Estimating Fisher discriminant error in a linear integrator model of neural population activity

    Decoding approaches provide a useful means of estimating the information contained in neuronal circuits. In this work, we analyze the expected classification error of a decoder based on Fisher linear discrimin...

    in The Journal of Mathematical Neuroscience on February 19, 2021 12:00 AM.

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    Phenotypic Characterization and Brain Structure Analysis of Calcium Channel Subunit α2δ-2 Mutant (Ducky) and α2δ Double Knockout Mice

    Auxiliary α2δ subunits of voltage-gated calcium channels modulate channel trafficking, current properties, and synapse formation. Three of the four isoforms (α2δ-1, α2δ-2, and α2δ-3) are abundantly expressed in the brain; however, of the available knockout models, only α2δ-2 knockout or mutant mice display an obvious abnormal neurological phenotype. Thus, we hypothesize that the neuronal α2δ isoforms may have partially specific as well as redundant functions. To address this, we generated three distinct α2δ double knockout mouse models by crossbreeding single knockout (α2δ-1 and -3) or mutant (α2δ-2/ducky) mice. Here, we provide a first phenotypic description and brain structure analysis. We found that genotypic distribution of neonatal litters in distinct α2δ-1/-2, α2δ-1/-3, and α2δ-2/-3 breeding combinations did not conform to Mendel’s law, suggesting premature lethality of single and double knockout mice. Notably, high occurrences of infant mortality correlated with the absence of specific α2δ isoforms (α2Δ-2 > α2δ-1 > α2δ-3), and was particularly observed in cages with behaviorally abnormal parenting animals of α2δ-2/-3 cross-breedings. Juvenile α2δ-1/-2 and α2δ-2/-3 double knockout mice displayed a waddling gate similar to ducky mice. However, in contrast to ducky and α2δ-1/-3 double knockout animals, α2δ-1/-2 and α2δ-2/-3 double knockout mice showed a more severe disease progression and highly impaired development. The observed phenotypes within the individual mouse lines may be linked to differences in the volume of specific brain regions. Reduced cortical volume in ducky mice, for example, was associated with a progressively decreased space between neurons, suggesting a reduction of total synaptic connections. Taken together, our findings show that α2δ subunits differentially regulate premature survival, postnatal growth, brain development, and behavior, suggesting specific neuronal functions in health and disease.

    in Frontiers in Synaptic Neuroscience on February 19, 2021 12:00 AM.

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    Dosimetry Analysis in Non-brain Tissues During TMS Exposure of Broca’s and M1 Areas

    For human protection, the internal electric field is used as a dosimetric quantity for electromagnetic fields lower than 5–10 MHz. According to international standards, in this frequency range, electrostimulation is the main adverse effect against which protection is needed. One of the topics to be investigated is the quantification of the internal electric field threshold levels of perception and pain. Pain has been reported as a side effect during transcranial magnetic stimulation (TMS), especially during stimulation of the Broca’s (speech) area of the brain. In this study, we designed an experiment to conduct a dosimetry analysis to quantify the internal electric field corresponding to perception and pain thresholds when targeting the Broca’s and M1 areas from magnetic stimulator exposure. Dosimetry analysis was conducted using a multi-scale analysis in an individualized head model to investigate electrostimulation in an axonal model. The main finding is that the stimulation on the primary motor cortex has higher perception and pain thresholds when compared to Broca’s area. Also, TMS-induced electric field applied to Broca’s area exhibited dependence on the coil orientation at lower electric field threshold which was found to be related to the location and thickness of pain fibers. The derived dosimetry quantities provide a scientific rationale for the development of human protection guidelines and the estimation of possible side effects of magnetic stimulation in clinical applications.

    in Frontiers in Neuroscience: Neural Technology on February 19, 2021 12:00 AM.

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    Incidental Brain Magnetic Resonance Imaging Findings and the Cognitive and Motor Performance in the Elderly: The Shanghai Changfeng Study

    Background

    The frequently discovered incidental findings (IFs) from imaging observations are increasing. The IFs show the potential clues of structural abnormalities underlying cognitive decline in elders. Detecting brain IFs and their relationship with cognitive and behavioral functions helps provide the information for clinical strategies.

    Methods

    Five hundred and seventy-nine participants were recruited in the Shanghai Changfeng Study. All participants performed the demographic, biochemical, and cognitive functions and gait speed assessment and underwent the high-resolution multimodal magnetic resonance imaging scans. We calculated the detection rate of brain IFs. The association between cardiovascular risk factors and IFs and the associations between IFs and cognitive and motor functions were assessed using regression models. The relationships among gray matter volume, cognitive function, and gait speed were assessed with/without adjusting the IFs to evaluate the effects of potential IFs confounders.

    Results

    IFs were found in a total of 578 subjects with a detection rate of 99.8%. Age and blood pressure were the most significant cardiovascular risk factors correlated with IFs. IFs were found to be negatively associated with Montreal Cognitive Assessment, Mini-Mental State Examination, and gait speed. The gray matter volume was found to be positively correlated with the cognitive function without adjusting the white matter hyperintensity but not if adjusted.

    Conclusion

    IFs are commonly found in the elderly population and related to brain functions. The adequate intervention of IFs related cardiovascular risk factors that may slow down the progression of brain function decline. We also suggest that IFs should be considered as confounding factors that may affect cognitive issues on the structural neuroimaging researches in aging or diseases.

    in Frontiers in Neuroscience: Neurodegeneration on February 19, 2021 12:00 AM.

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    Morphometric and Functional Brain Connectivity Differentiates Chess Masters From Amateur Players

    A common task in brain image analysis includes diagnosis of a certain medical condition wherein groups of healthy controls and diseased subjects are analyzed and compared. On the other hand, for two groups of healthy participants with different proficiency in a certain skill, a distinctive analysis of the brain function remains a challenging problem. In this study, we develop new computational tools to explore the functional and anatomical differences that could exist between the brain of healthy individuals identified on the basis of different levels of task experience/proficiency. Toward this end, we look at a dataset of amateur and professional chess players, where we utilize resting-state functional magnetic resonance images to generate functional connectivity (FC) information. In addition, we utilize T1-weighted magnetic resonance imaging to estimate morphometric connectivity (MC) information. We combine functional and anatomical features into a new connectivity matrix, which we term as the functional morphometric similarity connectome (FMSC). Since, both the FC and MC information is susceptible to redundancy, the size of this information is reduced using statistical feature selection. We employ off-the-shelf machine learning classifier, support vector machine, for both single- and multi-modality classifications. From our experiments, we establish that the saliency and ventral attention network of the brain is functionally and anatomically different between two groups of healthy subjects (chess players). We argue that, since chess involves many aspects of higher order cognition such as systematic thinking and spatial reasoning and the identified network is task-positive to cognition tasks requiring a response, our results are valid and supporting the feasibility of the proposed computational pipeline. Moreover, we quantitatively validate an existing neuroscience hypothesis that learning a certain skill could cause a change in the brain (functional connectivity and anatomy) and this can be tested via our novel FMSC algorithm.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 19, 2021 12:00 AM.

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    Neuroimage Biomarker Identification of the Conversion of Mild Cognitive Impairment to Alzheimer’s Disease

    An efficient method to identify whether mild cognitive impairment (MCI) has progressed to Alzheimer’s disease (AD) will be beneficial to patient care. Previous studies have shown that magnetic resonance imaging (MRI) has enabled the assessment of AD progression based on imaging findings. The present work aimed to establish an algorithm based on three features, namely, volume, surface area, and surface curvature within the hippocampal subfields, to model variations, including atrophy and structural changes to the cortical surface. In this study, a new biomarker, the ratio of principal curvatures (RPC), was proposed to characterize the folding patterns of the cortical gyrus and sulcus. Along with volumes and surface areas, these morphological features associated with the hippocampal subfields were assessed in terms of their sensitivity to the changes in cognitive capacity by two different feature selection methods. Either the extracted features were statistically significantly different, or the features were selected through a random forest model. The identified subfields and their structural indices that are sensitive to the changes characteristic of the progression from MCI to AD were further assessed with a multilayer perceptron classifier to help facilitate the diagnosis. The accuracy of the classification based on the proposed method to distinguish whether a MCI patient enters the AD stage amounted to 79.95%, solely using the information from the features selected by a logical feature selection method.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 19, 2021 12:00 AM.

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    X-Vectors: New Quantitative Biomarkers for Early Parkinson's Disease Detection From Speech

    Many articles have used voice analysis to detect Parkinson's disease (PD), but few have focused on the early stages of the disease and the gender effect. In this article, we have adapted the latest speaker recognition system, called x-vectors, in order to detect PD at an early stage using voice analysis. X-vectors are embeddings extracted from Deep Neural Networks (DNNs), which provide robust speaker representations and improve speaker recognition when large amounts of training data are used. Our goal was to assess whether, in the context of early PD detection, this technique would outperform the more standard classifier MFCC-GMM (Mel-Frequency Cepstral Coefficients—Gaussian Mixture Model) and, if so, under which conditions. We recorded 221 French speakers (recently diagnosed PD subjects and healthy controls) with a high-quality microphone and via the telephone network. Men and women were analyzed separately in order to have more precise models and to assess a possible gender effect. Several experimental and methodological aspects were tested in order to analyze their impacts on classification performance. We assessed the impact of the audio segment durations, data augmentation, type of dataset used for the neural network training, kind of speech tasks, and back-end analyses. X-vectors technique provided better classification performances than MFCC-GMM for the text-independent tasks, and seemed to be particularly suited for the early detection of PD in women (7–15% improvement). This result was observed for both recording types (high-quality microphone and telephone).

    in Frontiers in Neuroinformatics on February 19, 2021 12:00 AM.

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    MindLink-Eumpy: An Open-Source Python Toolbox for Multimodal Emotion Recognition

    Emotion recognition plays an important role in intelligent human–computer interaction, but the related research still faces the problems of low accuracy and subject dependence. In this paper, an open-source software toolbox called MindLink-Eumpy is developed to recognize emotions by integrating electroencephalogram (EEG) and facial expression information. MindLink-Eumpy first applies a series of tools to automatically obtain physiological data from subjects and then analyzes the obtained facial expression data and EEG data, respectively, and finally fuses the two different signals at a decision level. In the detection of facial expressions, the algorithm used by MindLink-Eumpy is a multitask convolutional neural network (CNN) based on transfer learning technique. In the detection of EEG, MindLink-Eumpy provides two algorithms, including a subject-dependent model based on support vector machine (SVM) and a subject-independent model based on long short-term memory network (LSTM). In the decision-level fusion, weight enumerator and AdaBoost technique are applied to combine the predictions of SVM and CNN. We conducted two offline experiments on the Database for Emotion Analysis Using Physiological Signals (DEAP) dataset and the Multimodal Database for Affect Recognition and Implicit Tagging (MAHNOB-HCI) dataset, respectively, and conducted an online experiment on 15 healthy subjects. The results show that multimodal methods outperform single-modal methods in both offline and online experiments. In the subject-dependent condition, the multimodal method achieved an accuracy of 71.00% in the valence dimension and an accuracy of 72.14% in the arousal dimension. In the subject-independent condition, the LSTM-based method achieved an accuracy of 78.56% in the valence dimension and an accuracy of 77.22% in the arousal dimension. The feasibility and efficiency of MindLink-Eumpy for emotion recognition is thus demonstrated.

    in Frontiers in Human Neuroscience on February 19, 2021 12:00 AM.

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    Automatic Detection of Focal Cortical Dysplasia Type II in MRI: Is the Application of Surface-Based Morphometry and Machine Learning Promising?

    Background and Objectives

    Focal cortical dysplasia (FCD) is a type of malformations of cortical development and one of the leading causes of drug-resistant epilepsy. Postoperative results improve the diagnosis of lesions on structural MRIs. Advances in quantitative algorithms have increased the identification of FCD lesions. However, due to significant differences in size, shape, and location of the lesion in different patients and a big deal of time for the objective diagnosis of lesion as well as the dependence of individual interpretation, sensitive approaches are required to address the challenge of lesion diagnosis. In this research, a FCD computer-aided diagnostic system to improve existing methods is presented.

    Methods

    Magnetic resonance imaging (MRI) data were collected from 58 participants (30 with histologically confirmed FCD type II and 28 without a record of any neurological prognosis). Morphological and intensity-based features were calculated for each cortical surface and inserted into an artificial neural network. Statistical examinations evaluated classifier efficiency.

    Results

    Neural network evaluation metrics—sensitivity, specificity, and accuracy—were 96.7, 100, and 98.6%, respectively. Furthermore, the accuracy of the classifier for the detection of the lobe and hemisphere of the brain, where the FCD lesion is located, was 84.2 and 77.3%, respectively.

    Conclusion

    Analyzing surface-based features by automated machine learning can give a quantitative and objective diagnosis of FCD lesions in presurgical assessment and improve postsurgical outcomes.

    in Frontiers in Human Neuroscience on February 19, 2021 12:00 AM.

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    Transfer of Learning in the Convolutional Neural Networks on Classifying Geometric Shapes Based on Local or Global Invariants

    The convolutional neural networks (CNNs) are a powerful tool of image classification that has been widely adopted in applications of automated scene segmentation and identification. However, the mechanisms underlying CNN image classification remain to be elucidated. In this study, we developed a new approach to address this issue by investigating transfer of learning in representative CNNs (AlexNet, VGG, ResNet-101, and Inception-ResNet-v2) on classifying geometric shapes based on local/global features or invariants. While the local features are based on simple components, such as orientation of line segment or whether two lines are parallel, the global features are based on the whole object such as whether an object has a hole or whether an object is inside of another object. Six experiments were conducted to test two hypotheses on CNN shape classification. The first hypothesis is that transfer of learning based on local features is higher than transfer of learning based on global features. The second hypothesis is that the CNNs with more layers and advanced architectures have higher transfer of learning based global features. The first two experiments examined how the CNNs transferred learning of discriminating local features (square, rectangle, trapezoid, and parallelogram). The other four experiments examined how the CNNs transferred learning of discriminating global features (presence of a hole, connectivity, and inside/outside relationship). While the CNNs exhibited robust learning on classifying shapes, transfer of learning varied from task to task, and model to model. The results rejected both hypotheses. First, some CNNs exhibited lower transfer of learning based on local features than that based on global features. Second the advanced CNNs exhibited lower transfer of learning on global features than that of the earlier models. Among the tested geometric features, we found that learning of discriminating inside/outside relationship was the most difficult to be transferred, indicating an effective benchmark to develop future CNNs. In contrast to the “ImageNet” approach that employs natural images to train and analyze the CNNs, the results show proof of concept for the “ShapeNet” approach that employs well-defined geometric shapes to elucidate the strengths and limitations of the computation in CNN image classification. This “ShapeNet” approach will also provide insights into understanding visual information processing the primate visual systems.

    in Frontiers in Computational Neuroscience on February 19, 2021 12:00 AM.

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    The Neurophysiological Impact of Experimentally-Induced Pain on Direct Muscle Spindle Afferent Response: A Scoping Review

    Background: Musculoskeletal pain disorders are among the leading causes of years lived with disability worldwide representing a significant burden to society. Studies investigating a “nociceptive-fusimotor” relationship using experimentally-induced pain/noxious stimuli and muscle spindle afferent (MSA) response have been published over several decades. The purpose of this scoping review was to systematically identify and summarize research findings related to the impact of experimentally-induced pain or noxious stimulation on direct MSA discharge/response.

    Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane and Embase were searched from database inception to August 2020. Eligible studies were: (a) published in English; (b) clinical or pre-clinical studies; (c) original data studies; (d) included the investigation of MSA response to experimentally-induced pain or noxious stimulation; (e) included quantification of at least one direct physiological measure associated with MSA activity/response. Two-phase screening procedures were conducted by a pair of independent reviewers and data extracted from eligible studies.

    Results: The literature search resulted in 195 articles of which 23 met inclusion criteria. Six studies (26%) were classified as clinical and 17 (74%) as pre-clinical. Two clinical studies investigated the effects of sacral dermatome pin-pricking on MSA response, while the remaining 4 studies investigated the effects of tonic muscle and/or skin pain induced by injection/infusion of hypertonic saline into the tibialis anterior muscle or subdermal tissues. In pre-clinical studies, muscle pain was induced by injection of noxious substances or the surgical removal of the meniscus at the knee joint.

    Conclusion: Clinical studies in awake humans reported that experimentally-induced pain did not affect, or else slightly decreased MSA spontaneous discharge and/or response during weak dorsiflexor muscle contraction, thus failing to support an excitatory nociceptive-fusimotor relationship. However, a majority of pre-clinical studies indicated that ipsilateral and contralateral muscle injection of noxious substances altered MSA resting discharge and/or response to stretch predominately through static fusimotor reflex mechanisms. Methodological differences (use of anesthesia, stretch methodology, etc.) may ultimately be responsible for the discrepancies between clinical and pre-clinical findings. Additional investigative efforts are needed to reconcile these discrepancies and to clearly establish or refute the existence of nociceptive-fusimotor relationship in muscular pain.

    in Frontiers in Cellular Neuroscience on February 19, 2021 12:00 AM.

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    Repeated Low-Level Blast Acutely Alters Brain Cytokines, Neurovascular Proteins, Mechanotransduction, and Neurodegenerative Markers in a Rat Model

    Exposure to the repeated low-level blast overpressure (BOP) periodically experienced by military personnel in operational and training environments can lead to deficits in behavior and cognition. While these low-intensity blasts do not cause overt changes acutely, repeated exposures may lead to cumulative effects in the brain that include acute inflammation, vascular disruption, and other molecular changes, which may eventually contribute to neurodegenerative processes. To identify these acute changes in the brain following repeated BOP, an advanced blast simulator was used to expose rats to 8.5 or 10 psi BOP once per day for 14 days. At 24 h after the final BOP, brain tissue was collected and analyzed for inflammatory markers, astrogliosis (GFAP), tight junction proteins (claudin-5 and occludin), and neurodegeneration-related proteins (Aβ40/42, pTau, TDP-43). After repeated exposure to 8.5 psi BOP, the change in cytokine profile was relatively modest compared to the changes observed following 10 psi BOP, which included a significant reduction in several inflammatory markers. Reduction in the tight junction protein occludin was observed in both groups when compared to controls, suggesting cerebrovascular disruption. While repeated exposure to 8.5 psi BOP led to a reduction in the Alzheimer’s disease (AD)-related proteins amyloid-β (Aβ)40 and Aβ42, these changes were not observed in the 10 psi group, which had a significant reduction in phosphorylated tau. Finally, repeated 10 psi BOP exposures led to an increase in GFAP, indicating alterations in astrocytes, and an increase in the mechanosensitive ion channel receptor protein, Piezo2, which may increase brain sensitivity to injury from pressure changes from BOP exposure. Overall, cumulative effects of repeated low-level BOP may increase the vulnerability to injury of the brain by disrupting neurovascular architecture, which may lead to downstream deleterious effects on behavior and cognition.

    in Frontiers in Cellular Neuroscience on February 19, 2021 12:00 AM.

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    Indolaminergic System in Adult Rat Testes: Evidence for a Local Serotonin System

    Serotonin (5-HT) is member of a family of indolamine molecules that participate in a wide variety of biological processes. Despite its important role in the regulation of local blood systems, little is known about the physiological function of 5-HT in reproductive organs, its functional implications, and its role in the reproduction of mammals. In the present work, we evaluated the localization and distribution of 5-HT (using histochemical analysis of indolamines) and different components of the serotoninergic system in rat testes. We detected local synthesis and degradation through immunofluorescence and western blot analyses against the TPH1, MAOA, 5-HTT, and VMAT1 serotonin transporters. We also identified the localization and distribution of the 5-HT1B, 5-HT2A, and 5-HT3A receptors. RT-PCR results showed the presence of the Tph1, Maoa, Slc6a4, and Htr3a genes in testes and in the brain stem (Tph1 was used as a negative control). High-performance liquid chromatography was used to determine the presence of 5-HT and the activity of tryptophan hydroxylase in testes homogenates in vitro. Our observations suggest that TPH1 activity and local 5-HT synthesis befall in rat testes. We propose that 5-HT could participate in the regulation of testosterone synthesis and in the spermatogenesis process via local serotoninergic system. However, more studies are needed before concluding that rat testes, or those of other mammals, contain an active form of tryptophan hydroxylase and produce 5-HT.

    in Frontiers in Neuroanatomy on February 19, 2021 12:00 AM.

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    Plasma Neurofilament Light Chain as a Predictive Biomarker for Post-stroke Cognitive Impairment: A Prospective Cohort Study

    Background

    Plasma neurofilaments light chain (pNfL) is a marker of axonal injury. The purpose of this study was to examine the role of pNfL as a predictive biomarker for post-stroke cognitive impairment (PSCI).

    Methods

    A prospective single-center observational cohort study was conducted at the General Hospital of Western Theater Command between July 1, 2017 and December 31, 2019. Consecutive patients ≥18 years with first-ever acute ischemic stroke (AIS) of anterior circulation within 24 h of symptom onset were included. PSCI was defined by the Montreal Cognitive Assessment (MOCA) (MOCA < 26) at 90 days after stroke onset.

    Results

    A total of 1,694 patients [male, 893 (52.70%); median age, 64 (16) years] were enrolled in the cohort analysis, and 1,029 (60.70%) were diagnosed with PSCI. Patients with PSCI had significantly higher pNfL [median (IQR), 55.96 (36.13) vs. 35.73 (17.57) pg/ml; P < 0.001] than Non-PSCI. pNfL was valuable for the prediction of PSCI (OR 1.044, 95% CI 1.038–1.049, P < 0.001) after a logistic regression analysis, even after adjusting for conventional risk factors including age, sex, education level, NIHSS, TOAST classification, and infarction volume (OR 1.041, 95% CI 1.034–1.047, P < 0.001). The optimal cutoff value of the pNfL concentration was 46.12 pg/ml, which yielded a sensitivity of 71.0% and a specificity of 81.5%, with the area under the curve (AUC) at 0.785 (95% CI 0.762–0.808, P < 0.001).

    Conclusion

    This prospective cohort study showed that the pNfL concentration within 48 h of onset was an independent risk factor for PSCI 90 days after an anterior circulation stroke, even after being adjusted for potential influencing factors regarded as clinically relevant.

    Clinical Trial Registration

    www.chictr.org.cn, identifier ChiCTR1800020330.

    in Frontiers in Ageing Neuroscience on February 19, 2021 12:00 AM.

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    Cerebral Small Vessel Disease Load Predicts Functional Outcome and Stroke Recurrence After Intracerebral Hemorrhage: A Median Follow-Up of 5 Years

    Background: Uncertainty exists over the long-term prognostic significance of cerebral small vessel disease (CSVD) in primary intracerebral hemorrhage (ICH).

    Methods: We performed a longitudinal analysis of CSVD and clinical outcomes in consecutive patients with primary ICH who had MRI. Baseline CSVD load (including white matter hyperintensities [WMH], cerebral microbleeds [CMBs], lacunes, and enlarged perivascular spaces [EPVS]) was evaluated. The cumulative CSVD score was calculated by combining the presence of each CSVD marker (range 0–4). We followed participants for poor functional outcome [modified Rankin scale [mRS] ≥ 4], stroke recurrence, and time-varying survival during a median follow-up of 4.9 [interquartile range [IQR] 3.1–6.0] years. Parsimonious and fuller multivariable logistic regression analysis and Cox-regression analysis were performed to estimate the association of CSVD markers, individually and collectively, with each outcome.

    Results: A total of 153 patients were included in the analyses. CMBs ≥ 10 [adjusted OR [adOR] 3.252, 95% CI 1.181–8.956, p = 0.023] and periventricular WMH (PWMH) (adOR 2.053, 95% CI 1.220–3.456, p = 0.007) were significantly associated with poor functional outcome. PWMH (adOR 2.908, 95% CI 1.230–6.878, p = 0.015) and lobar CMB severity (adOR 1.811, 95% CI 1.039–3.157, p = 0.036) were associated with stroke recurrence. The cumulative CSVD score was associated with poor functional outcome (adOR 1.460, 95% CI 1.017–2.096) and stroke recurrence (adOR 2.258, 95% CI 1.080–4.723). Death occurred in 36.1% (13/36) of patients with CMBs ≥ 10 compared with 18.8% (22/117) in those with CMB < 10 (adjusted HR 2.669, 95% CI 1.248–5.707, p = 0.011). In addition, the cumulative CSVD score ≥ 2 was associated with a decreased survival rate (adjusted HR 3.140, 95% CI 1.066–9.250, p = 0.038).

    Conclusions: Severe PWMH, CMB, or cumulative CSVD burden exert important influences on the long-term outcome of ICH.

    in Frontiers in Ageing Neuroscience on February 19, 2021 12:00 AM.

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    Gauging Working Memory Capacity From Differential Resting Brain Oscillations in Older Individuals With A Wearable Device

    Working memory is a core cognitive function and its deficits is one of the most common cognitive impairments. Reduced working memory capacity manifests as reduced accuracy in memory recall and prolonged speed of memory retrieval in older adults. Currently, the relationship between healthy older individuals’ age-related changes in resting brain oscillations and their working memory capacity is not clear. Eyes-closed resting electroencephalogram (rEEG) is gaining momentum as a potential neuromarker of mild cognitive impairments. Wearable and wireless EEG headset measuring key electrophysiological brain signals during rest and a working memory task was utilized. This research’s central hypothesis is that rEEG (e.g., eyes closed for 90 s) frequency and network features are surrogate markers for working memory capacity in healthy older adults. Forty-three older adults’ memory performance (accuracy and reaction times), brain oscillations during rest, and inter-channel magnitude-squared coherence during rest were analyzed. We report that individuals with a lower memory retrieval accuracy showed significantly increased alpha and beta oscillations over the right parietal site. Yet, faster working memory retrieval was significantly correlated with increased delta and theta band powers over the left parietal sites. In addition, significantly increased coherence between the left parietal site and the right frontal area is correlated with the faster speed in memory retrieval. The frontal and parietal dynamics of resting EEG is associated with the “accuracy and speed trade-off” during working memory in healthy older adults. Our results suggest that rEEG brain oscillations at local and distant neural circuits are surrogates of working memory retrieval’s accuracy and processing speed. Our current findings further indicate that rEEG frequency and coherence features recorded by wearable headsets and a brief resting and task protocol are potential biomarkers for working memory capacity. Additionally, wearable headsets are useful for fast screening of cognitive impairment risk.

    in Frontiers in Ageing Neuroscience on February 19, 2021 12:00 AM.

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    Extracellular Vesicles From 3xTg-AD Mouse and Alzheimer’s Disease Patient Astrocytes Impair Neuroglial and Vascular Components

    Astrocytes are specialized glial cells that are essential components of the neurovascular unit (NVU) and are involved in neurodevelopment, brain maintenance and repair, and neurodegeneration. Astrocytes mediate these processes by releasing cellular mediators such as extracellular vesicles (EVs). EVs are vehicles of cell-cell communication and have been proposed as mediators of damage in AD. However, the transcellular mechanism by which Alzheimer disease (AD) astrocytes impair the function of NVU components is poorly understood. Therefore, we evaluated the effects of adult PS1-KI and 3xTg-AD astrocyte conditioned media (CM) and EVs on NVU components (neuroglia and endothelium) in vitro. Additionally, SAD and FAD astrocyte-derived EVs (A-EVs) were characterized, and we evaluated their effects on NVU in cocultured cells in vitro and on intrahippocampal CA1 cells in vivo. Surprisingly, cultured 3xTg-AD astrocytes showed increased glial fibrillary acidic protein (GFAP) reactivity compared to PS1-KI astrocytes, which denotes astrocytic hyperreactivity. CM from adult mice 3xTg-AD astrocytes increased cell-cell gaps between endothelial cells, filopodia-like dendritic protrusions in neurons and neuronal and endothelial cell death. 3xTg-AD A-EVs induced neurotoxicity and increased astrocyte GFAP reactivity. Cultured human postmortem astrocytes from AD patients also increased GFAP reactivity and EVs release. No differences in the size or number of A-EVs were detected between AD and control samples; however, both SAD and FAD A-EVs showed increased expression of the surface marker aquaporin 4. A-EVs induced cytotoxicity and astrocyte hyperactivation: specifically, FAD A-EVs induced neuroglial cytotoxicity and increased gaps between the endothelium, while SAD A-EVs mainly altered the endothelium. Similarly, both AD A-EVs increased astrocyte GS reactivity and vascular deterioration in vivo. We associated this finding with perivascular reactive astrocytes and vascular deterioration in the human AD brain. In summary, these results suggest that AD A-EVs impair neuroglial and vascular components.

    in Frontiers in Ageing Neuroscience on February 19, 2021 12:00 AM.

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    Redox controls RecA protein activity via reversible oxidation of its methionine residues

    Reactive oxygen species (ROS) cause damage to DNA and proteins. Here we report that the RecA recombinase is itself oxidized by ROS. Genetic and biochemical analyses revealed that oxidation of RecA altered its DNA repair and DNA recombination activities. Mass spectrometry analysis showed that exposure to ROS converted 4 out of 9 Met residues of RecA to methionine sulfoxide. Mimicking oxidation of Met35 by changing it for Gln caused complete loss of function whereas mimicking oxidation of Met164 resulted in constitutive SOS activation and loss of recombination activity. Yet, all ROS-induced alterations of RecA activity were suppressed by methionine sulfoxide reductases MsrA and MsrB. These findings indicate that under oxidative stress, MsrA/B is needed for RecA homeostasis control. The implication is that, besides damaging DNA structure directly, ROS prevent repair of DNA damage by hampering RecA activity.

    in eLife on February 19, 2021 12:00 AM.

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    Recurrent neural network with noise rejection for cyclic motion generation of robotic manipulators

    Publication date: Available online 17 February 2021

    Source: Neural Networks

    Author(s): Mei Liu, Li He, Bin Hu, Shuai Li

    in Neural Networks on February 18, 2021 07:00 PM.

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    Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

    Abstract Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long‐range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre‐dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2‐Cre) and calcitonin receptor‐like receptor (Crlr‐Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long‐range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal–ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal–ventral differences in DG function.

    in Hippocampus on February 18, 2021 04:13 PM.

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    Deep6mA: A deep learning framework for exploring similar patterns in DNA N6-methyladenine sites across different species

    by Zutan Li, Hangjin Jiang, Lingpeng Kong, Yuanyuan Chen, Kun Lang, Xiaodan Fan, Liangyun Zhang, Cong Pian

    N6-methyladenine (6mA) is an important DNA modification form associated with a wide range of biological processes. Identifying accurately 6mA sites on a genomic scale is crucial for under-standing of 6mA’s biological functions. However, the existing experimental techniques for detecting 6mA sites are cost-ineffective, which implies the great need of developing new computational methods for this problem. In this paper, we developed, without requiring any prior knowledge of 6mA and manually crafted sequence features, a deep learning framework named Deep6mA to identify DNA 6mA sites, and its performance is superior to other DNA 6mA prediction tools. Specifically, the 5-fold cross-validation on a benchmark dataset of rice gives the sensitivity and specificity of Deep6mA as 92.96% and 95.06%, respectively, and the overall prediction accuracy is 94%. Importantly, we find that the sequences with 6mA sites share similar patterns across different species. The model trained with rice data predicts well the 6mA sites of other three species: Arabidopsis thaliana, Fragaria vesca and Rosa chinensis with a prediction accuracy over 90%. In addition, we find that (1) 6mA tends to occur at GAGG motifs, which means the sequence near the 6mA site may be conservative; (2) 6mA is enriched in the TATA box of the promoter, which may be the main source of its regulating downstream gene expression.

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Cholinergic neuromodulation of inhibitory interneurons facilitates functional integration in whole-brain models

    by Carlos Coronel-Oliveros, Rodrigo Cofré, Patricio Orio

    Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although whole-brain computational models have reproduced this neuromodulatory effect, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, we introduce a local inhibitory feedback as a plausible biophysical mechanism that enables the integration of whole-brain activity, and that interacts with the other neuromodulatory influences to facilitate the transition between different functional segregation/integration regimes in the brain.

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Positive interactions within and between populations decrease the likelihood of evolutionary rescue

    by Yaron Goldberg, Jonathan Friedman

    Positive interactions, including intraspecies cooperation and interspecies mutualisms, play crucial roles in shaping the structure and function of many ecosystems, ranging from plant communities to the human microbiome. While the evolutionary forces that form and maintain positive interactions have been investigated extensively, the influence of positive interactions on the ability of species to adapt to new environments is still poorly understood. Here, we use numerical simulations and theoretical analyses to study how positive interactions impact the likelihood that populations survive after an environment deteriorates, such that survival in the new environment requires quick adaptation via the rise of new mutants—a scenario known as evolutionary rescue. We find that the probability of evolutionary rescue in populations engaged in positive interactions is reduced significantly. In cooperating populations, this reduction is largely due to the fact that survival may require at least a minimal number of individuals, meaning that adapted mutants must arise and spread before the population declines below this threshold. In mutualistic populations, the rescue probability is decreased further due to two additional effects—the need for both mutualistic partners to adapt to the new environment, and competition between the two species. Finally, we show that the presence of cheaters reduces the likelihood of evolutionary rescue even further, making it extremely unlikely. These results indicate that while positive interactions may be beneficial in stable environments, they can hinder adaptation to changing environments and thereby elevate the risk of population collapse. Furthermore, these results may hint at the selective pressures that drove co-dependent unicellular species to form more adaptable organisms able to differentiate into multiple phenotypes, including multicellular life.

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Sensing ecosystem dynamics via audio source separation: A case study of marine soundscapes off northeastern Taiwan

    by Tzu-Hao Lin, Tomonari Akamatsu, Yu Tsao

    Remote acquisition of information on ecosystem dynamics is essential for conservation management, especially for the deep ocean. Soundscape offers unique opportunities to study the behavior of soniferous marine animals and their interactions with various noise-generating activities at a fine temporal resolution. However, the retrieval of soundscape information remains challenging owing to limitations in audio analysis techniques that are effective in the face of highly variable interfering sources. This study investigated the application of a seafloor acoustic observatory as a long-term platform for observing marine ecosystem dynamics through audio source separation. A source separation model based on the assumption of source-specific periodicity was used to factorize time-frequency representations of long-duration underwater recordings. With minimal supervision, the model learned to discriminate source-specific spectral features and prove to be effective in the separation of sounds made by cetaceans, soniferous fish, and abiotic sources from the deep-water soundscapes off northeastern Taiwan. Results revealed phenological differences among the sound sources and identified diurnal and seasonal interactions between cetaceans and soniferous fish. The application of clustering to source separation results generated a database featuring the diversity of soundscapes and revealed a compositional shift in clusters of cetacean vocalizations and fish choruses during diurnal and seasonal cycles. The source separation model enables the transformation of single-channel audio into multiple channels encoding the dynamics of biophony, geophony, and anthropophony, which are essential for characterizing the community of soniferous animals, quality of acoustic habitat, and their interactions. Our results demonstrated the application of source separation could facilitate acoustic diversity assessment, which is a crucial task in soundscape-based ecosystem monitoring. Future implementation of soundscape information retrieval in long-term marine observation networks will lead to the use of soundscapes as a new tool for conservation management in an increasingly noisy ocean.

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Ten simple rules for getting started with command-line bioinformatics

    by Parice A. Brandies, Carolyn J. Hogg

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Ten simple rules for starting (and sustaining) an academic data science initiative

    by Micaela S. Parker, Arlyn E. Burgess, Philip E. Bourne

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Ten simple rules for running and managing virtual internships

    by Johannes Werner, Debora Jeske

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Brain-inspired model for early vocal learning and correspondence matching using free-energy optimization

    by Alexandre Pitti, Mathias Quoy, Sofiane Boucenna, Catherine Lavandier

    We propose a developmental model inspired by the cortico-basal system (CX-BG) for vocal learning in babies and for solving the correspondence mismatch problem they face when they hear unfamiliar voices, with different tones and pitches. This model is based on the neural architecture INFERNO standing for Iterative Free-Energy Optimization of Recurrent Neural Networks. Free-energy minimization is used for rapidly exploring, selecting and learning the optimal choices of actions to perform (eg sound production) in order to reproduce and control as accurately as possible the spike trains representing desired perceptions (eg sound categories). We detail in this paper the CX-BG system responsible for linking causally the sound and motor primitives at the order of a few milliseconds. Two experiments performed with a small and a large audio database show the capabilities of exploration, generalization and robustness to noise of our neural architecture in retrieving audio primitives during vocal learning and during acoustic matching with unheared voices (different genders and tones).

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Ten simple rules for navigating the computational aspect of an interdisciplinary PhD

    by Sabrina Islam, Christine A. Wells

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    Bayesian parameter estimation for automatic annotation of gene functions using observational data and phylogenetic trees

    by George G. Vega Yon, Duncan C. Thomas, John Morrison, Huaiyu Mi, Paul D. Thomas, Paul Marjoram

    Gene function annotation is important for a variety of downstream analyses of genetic data. But experimental characterization of function remains costly and slow, making computational prediction an important endeavor. Phylogenetic approaches to prediction have been developed, but implementation of a practical Bayesian framework for parameter estimation remains an outstanding challenge. We have developed a computationally efficient model of evolution of gene annotations using phylogenies based on a Bayesian framework using Markov Chain Monte Carlo for parameter estimation. Unlike previous approaches, our method is able to estimate parameters over many different phylogenetic trees and functions. The resulting parameters agree with biological intuition, such as the increased probability of function change following gene duplication. The method performs well on leave-one-out cross-validation, and we further validated some of the predictions in the experimental scientific literature.

    in PLoS Computational Biology on February 18, 2021 02:00 PM.

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    The plant metabolome guides fitness-relevant foraging decisions of a specialist herbivore

    by Ricardo A. R. Machado, Vanitha Theepan, Christelle A. M. Robert, Tobias Züst, Lingfei Hu, Qi Su, Bernardus C. J. Schimmel, Matthias Erb

    Plants produce complex mixtures of primary and secondary metabolites. Herbivores use these metabolites as behavioral cues to increase their fitness. However, how herbivores combine and integrate different metabolite classes into fitness-relevant foraging decisions in planta is poorly understood. We developed a molecular manipulative approach to modulate the availability of sugars and benzoxazinoid secondary metabolites as foraging cues for a specialist maize herbivore, the western corn rootworm. By disrupting sugar perception in the western corn rootworm and benzoxazinoid production in maize, we show that sugars and benzoxazinoids act as distinct and dynamically combined mediators of short-distance host finding and acceptance. While sugars improve the capacity of rootworm larvae to find a host plant and to distinguish postembryonic from less nutritious embryonic roots, benzoxazinoids are specifically required for the latter. Host acceptance in the form of root damage is increased by benzoxazinoids and sugars in an additive manner. This pattern is driven by increasing damage to postembryonic roots in the presence of benzoxazinoids and sugars. Benzoxazinoid- and sugar-mediated foraging directly improves western corn rootworm growth and survival. Interestingly, western corn rootworm larvae retain a substantial fraction of their capacity to feed and survive on maize plants even when both classes of chemical cues are almost completely absent. This study unravels fine-grained differentiation and combination of primary and secondary metabolites into herbivore foraging and documents how the capacity to compensate for the lack of important chemical cues enables a specialist herbivore to survive within unpredictable metabolic landscapes.

    in PLoS Biology on February 18, 2021 02:00 PM.

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    Regular spiking in high-conductance states: The essential role of inhibition

    Author(s): Tomas Barta and Lubomir Kostal

    Strong inhibitory input to neurons, which occurs in balanced states of neural networks, increases synaptic current fluctuations. This has led to the assumption that inhibition contributes to the high spike-firing irregularity observed in vivo. We used single compartment neuronal models with time-cor...


    [Phys. Rev. E 103, 022408] Published Thu Feb 18, 2021

    in Physical Review E: Biological physics on February 18, 2021 10:00 AM.

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    Macaque Monkey Trigeminal Blink Reflex Circuits Targeting Orbicularis Oculi Motoneurons

    The blink reflex is critical for protecting the eyes and spreading the tear film, and is a commonly used learning model. We demonstrate monosynaptic trigeminal (shown here) and disynaptic reticular formation pathways connecting the principal and the spinal trigeminal nucleus (pars caudalis) with orbicularis oculi motoneurons in the macaque monkey. ABSTRACT The trigeminal blink reflex plays an important role in protecting the corneal surface from damage and preserving visual function in an unpredictable environment. The closing phase of the reflex, produced by activation of the orbicularis oculi muscles, consists of an initial, small, ipsilateral R1 component, followed by a larger, bilateral R2 component. We investigated the circuitry that underlies this reflex in macaque (Macaca fascicularis and mulatta) monkeys by use of single and dual tracer methods. Injection of retrograde tracer into the facial nucleus labeled neurons in the principal trigeminal nucleus, and in the spinal nucleus pars oralis and interpolaris, bilaterally, and in pars caudalis, ipsilaterally. Injection of anterograde tracer into the principal trigeminal nucleus labeled axons that directly terminated on orbicularis oculi motoneurons, with an ipsilateral predominance. Injection of anterograde tracer into pars caudalis of the spinal trigeminal nucleus labeled axons that directly terminated on ipsilateral orbicularis oculi motoneurons. The observed pattern of labeling indicates that the reticular formation ventromedial to the principal and spinal nuclei also contributes extensive bilateral input to orbicularis oculi motoneurons. Thus, much of the trigeminal sensory complex is in a position to supply monosynaptic drive for lid closure, and the adjacent reticular formation can supply a disynaptic drive. These findings indicate that assignment of the R1 and R2 components of the blink reflex to different parts of trigeminal sensory complex cannot be exclusively based on subdivision connectional relationships with facial motoneurons. The characteristics of the R2 component may be due, instead, to other circuit properties. This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on February 18, 2021 09:07 AM.

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    Early predictors of 9‐year disability in pediatric multiple sclerosis

    Objectives To assess early predictors of 9‐year disability in pediatric multiple sclerosis patients. Methods Clinical and MRI assessments of 123 pediatric multiple sclerosis patients were obtained at disease onset and after 1 and 2 years. A 9‐year clinical follow‐up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9‐year outcomes. Results Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR]=2.10, p=0.02) and high‐efficacy treatment exposure (HR=0.31, p=0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (β=‐0.15, p<0.001), cervical cord lesions (β=0.16, p=0.003) and high‐efficacy treatment exposure (β=‐0.14, p=0.01); considering also 1‐year variables, number of relapses (β=0.14, p=0.002) and the previous baseline predictors; considering 2‐year variables, time to first relapse (2‐year: β=‐0.12, p=0.01) entered, while high‐efficacy treatment exposure exit from the model. Predictors of 9‐year disability worsening were: at baseline, presence of optic nerve lesions [odds ratio (OR)=6.45, p=0.01]; considering 1‐ and 2‐year variables, Expanded Disability Status Scale (EDSS) changes (1‐year: OR=26.05, p<0.001; 2‐year: OR=16.38, p=0.02) and ≥2 new T2‐lesions in 2 years (2‐year: OR=4.91, p=0.02). Predictors of higher 9‐year EDSS score were: at baseline, EDSS score (β=0.58, p<0.001), presence of brainstem (β=0.31, p=0.04) and number of cervical cord lesions (β=0.22, p=0.05); considering 1‐ and 2‐year variables, EDSS changes (1‐year: β=0.79, p<0.001; 2‐year: β=0.55, p<0.001), and ≥2 new T2‐lesions (1‐year: β=0.28, p=0.03; 2‐year: β=0.35, p=0.01). Interpretation A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9‐year prognosis in pediatric multiple sclerosis. This article is protected by copyright. All rights reserved.

    in Annals of Neurology on February 18, 2021 07:15 AM.

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    Publisher Correction: Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

    Nature Neuroscience, Published online: 18 February 2021; doi:10.1038/s41593-021-00817-5

    Publisher Correction: Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

    in Nature Neuroscience on February 18, 2021 12:00 AM.

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    Integrating new memories into the hippocampal network activity space

    Nature Neuroscience, Published online: 18 February 2021; doi:10.1038/s41593-021-00804-w

    Gava et al. explore the organization of neuronal co-activity in hippocampus from a graph theoretical perspective to report how new associative memories integrate into the network and restructure the neural patterns representing prior memories.

    in Nature Neuroscience on February 18, 2021 12:00 AM.

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    Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia

    Nature Neuroscience, Published online: 18 February 2021; doi:10.1038/s41593-021-00801-z

    Oxidized phosphatidylcholines found in MS lesions are not just markers of oxidative stress but are also promoters of demyelination and axon injury. Microglia suppress oxidized-phosphatidylcholine-mediated neurodegeneration by phagocytosis through TREM2.

    in Nature Neuroscience on February 18, 2021 12:00 AM.

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    Brain capillary pericytes exert a substantial but slow influence on blood flow

    Nature Neuroscience, Published online: 18 February 2021; doi:10.1038/s41593-020-00793-2

    Vast networks of capillaries feed the brain. Hartmann et al. show that pericyte contractility is critical for maintenance of enduring capillary tone, which sets an optimized rate and distribution of blood flow through brain capillary networks.

    in Nature Neuroscience on February 18, 2021 12:00 AM.

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    Increasing the statistical power of animal experiments with historical control data

    Nature Neuroscience, Published online: 18 February 2021; doi:10.1038/s41593-020-00792-3

    Bonapersona and colleagues describe how historical control data can be used to improve statistical power while reducing the number of animals required in experiments. They present an open-source tool, RePAIR, that can be used to apply this approach.

    in Nature Neuroscience on February 18, 2021 12:00 AM.

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    Tunable van Hove singularities and correlated states in twisted monolayer–bilayer graphene

    Nature Physics, Published online: 18 February 2021; doi:10.1038/s41567-021-01172-9

    A structure of monolayer and bilayer graphene with a small twist between them shows correlated insulating states that can be tuned by changing the twist angle or applying an electric field.

    in Nature Physics on February 18, 2021 12:00 AM.

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    Topological limits to the parallel processing capability of network architectures

    Nature Physics, Published online: 18 February 2021; doi:10.1038/s41567-021-01170-x

    The ability to perform multiple tasks simultaneously is a key characteristic of parallel architectures. Using methods from statistical physics, this study provides analytical results that quantify the limitations of processing capacity for different types of tasks in neural networks.

    in Nature Physics on February 18, 2021 12:00 AM.

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    Proton–electron mass ratio by high-resolution optical spectroscopy of ion ensembles in the resolved-carrier regime

    Nature Physics, Published online: 18 February 2021; doi:10.1038/s41567-020-01150-7

    Laser spectroscopy can resolve vibrational transitions of molecular hydrogen ions without Doppler broadening when these are trapped within a cluster of laser-cooled atomic ions.

    in Nature Physics on February 18, 2021 12:00 AM.

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    Editorial: Dendritic Spines: From Biophysics to Neuropathology

    in Frontiers in Synaptic Neuroscience on February 18, 2021 12:00 AM.

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    Editorial: Cognitive Dysfunctions in Psychiatric Disorders: Brain-Immune Interaction Mechanisms and Integrative Therapeutic Approaches

    in Frontiers in Integrative Neuroscience on February 18, 2021 12:00 AM.

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    Repetitive Peripheral Magnetic Stimulation of Wrist Extensors Enhances Cortical Excitability and Motor Performance in Healthy Individuals

    Repetitive peripheral magnetic stimulation (rPMS) may improve motor function following central nervous system lesions, but the optimal parameters of rPMS to induce neural plasticity and mechanisms underlying its action remain unclear. We examined the effects of rPMS over wrist extensor muscles on neural plasticity and motor performance in 26 healthy volunteers. In separate experiments, the effects of rPMS on motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), direct motor response (M-wave), Hoffmann-reflex, and ballistic wrist extension movements were assessed before and after rPMS. First, to examine the effects of stimulus frequency, rPMS was applied at 50, 25, and 10 Hz by setting a fixed total number of stimuli. A significant increase in MEPs of wrist extensors was observed following 50 and 25 Hz rPMS, but not 10 Hz rPMS. Next, we examined the time required to induce plasticity by increasing the number of stimuli, and found that at least 15 min of 50 and 25 Hz rPMS was required. Based on these parameters, lasting effects were evaluated following 15 min of 50 or 25 Hz rPMS. A significant increase in MEP was observed up to 60 min following 50 and 25 Hz rPMS; similarly, an attenuation of SICI and enhancement of ICF were also observed. The maximal M-wave and Hoffmann-reflex did not change, suggesting that the increase in MEP was due to plastic changes at the motor cortex. This was accompanied by increasing force and electromyograms during wrist ballistic extension movements following 50 and 25 Hz rPMS. These findings suggest that 15 min of rPMS with 25 Hz or more induces an increase in cortical excitability of the relevant area rather than altering the excitability of spinal circuits, and has the potential to improve motor output.

    in Frontiers in Neuroscience: Neural Technology on February 18, 2021 12:00 AM.

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    Systematic Review: Quantitative Susceptibility Mapping (QSM) of Brain Iron Profile in Neurodegenerative Diseases

    Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration.

    in Frontiers in Neuroscience: Neurodegeneration on February 18, 2021 12:00 AM.

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    Optimal Approach for Signal Detection in Steady-State Visual Evoked Potentials in Humans Using Single-Channel EEG and Stereoscopic Stimuli

    In EEG studies, one of the most common ways to detect a weak periodic signal in the steady-state visual evoked potential (SSVEP) is spectral evaluation, a process that detects peaks of power present at notable temporal frequencies. However, the presence of noise decreases the signal-to-noise ratio (SNR), which in turn lowers the probability of successful detection of these spectral peaks. In this paper, using a single EEG channel, we compare the detection performance of four different metrics to analyse the SSVEP: two metrics that use spectral power density, and two other metrics that use phase coherency. We employ these metrics find weak signals with a known temporal frequency hidden in the SSVEP, using both simulation and real data from a stereoscopic apparent depth movement perception task. We demonstrate that out of these metrics, the phase coherency analysis is the most sensitive way to find weak signals in the SSVEP, provided that the phase information of the stimulus eliciting the SSVEP is preserved.

    in Frontiers in Neuroscience: Brain Imaging Methods on February 18, 2021 12:00 AM.

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    A Novel SOD1 Intermediate Oligomer, Role of Free Thiols and Disulfide Exchange

    Wild-type human SOD1 forms a highly conserved intra-molecular disulfide bond between C57-C146, and in its native state is greatly stabilized by binding one copper and one zinc atom per monomer rendering the protein dimeric. Loss of copper extinguishes dismutase activity and destabilizes the protein, increasing accessibility of the disulfide with monomerization accompanying disulfide reduction. A further pair of free thiols exist at C6 and C111 distant from metal binding sites, raising the question of their function. Here we investigate their role in misfolding of SOD1 along a pathway that leads to formation of amyloid fibrils. We present the seeding reaction of a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1) to exclude variables caused by these free cysteines. Completely reduced fibril seeds decreasing the kinetic barrier to cleave the highly conserved intramolecular disulfide bond, and accelerating SOD1 reduction and initiation of fibrillation. Presence or absence of the pair of free thiols affects kinetics of fibrillation. Previously, we showed full maturation with both Cu and Zn prevents this behavior while lack of Cu renders sensitivity to fibrillation, with presence of the native disulfide bond modulating this propensity much more strongly than presence of Zn or dimerization. Here we further investigate the role of reduction of the native C57-C146 disulfide bond in fibrillation of wild-type hSOD1, firstly through removal of free thiols by paired mutations C6A, C111S (AS-SOD1), and secondly in seeded fibrillation reactions modulated by reductant tris (2-carboxyethyl) phosphine (TCEP). Fibrillation of AS-SOD1 was dependent upon disulfide reduction and showed classic lag and exponential growth phases compared with wild-type hSOD1 whose fibrillation trajectories were typically somewhat perturbed. Electron microscopy showed that AS-SOD1 formed classic fibrils while wild-type fibrillation reactions showed the presence of smaller “sausage-like” oligomers in addition to fibrils, highlighting the potential for mixed disulfides involving C6/C111 to disrupt efficient fibrillation. Seeding by addition of sonicated fibrils lowered the TCEP concentration needed for fibrillation in both wild-type and AS-SOD1 providing evidence for template-driven structural disturbance that elevated susceptibility to reduction and thus propensity to fibrillate.

    in Frontiers in Neuroscience: Neurodegeneration on February 18, 2021 12:00 AM.

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    Constructing Brain Connectivity Model Using Causal Network Reconstruction Approach

    Studying brain function is a challenging task. In the past, we could only study brain anatomical structures post-mortem, or infer brain functions from clinical data of patients with a brain injury. Nowadays technology, such as functional magnetic resonance imaging (fMRI), enable non-invasive brain activity observation. Several approaches have been proposed to interpret brain activity data. The brain connectivity model is a graphical tool that represents the interaction between brain regions, during certain states. It depicts how a brain region cause changes to other parts of the brain, which can be implied as information flow. This model can be used to help interpret how the brain works. There are several mathematical frameworks that can be used to infer the connectivity model from brain activity signals. Granger causality is one such approach and is one of the first that has been applied to brain activity data. However, due to the concept of the framework, such as the use of pairwise correlation, combined with the limitation of brain activity data such as low temporal resolution in case of fMRI signal, makes the interpretation of the connectivity difficult. We therefore propose the application of the Tigramite causal discovery framework on fMRI data. The Tigramite framework uses measures such as causal effect to analyze causal relations in the system. This enables the framework to identify both direct and indirect pathways or connectivities. In this paper, we applied the framework to the Human Connectome Project motor task-fMRI dataset. We then present the results and discuss how the framework improves interpretability of the connectivity model. We hope that this framework will help us understand more complex brain functions such as memory, consciousness, or the resting-state of the brain, in the future.

    in Frontiers in Neuroinformatics on February 18, 2021 12:00 AM.

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    Comparing the Electrophysiology and Morphology of Human and Mouse Layer 2/3 Pyramidal Neurons With Bayesian Networks

    Pyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and dendritic morphology. We found that, among other differences, human pyramidal neurons had a higher action potential threshold voltage, a lower input resistance, and larger dendritic arbors. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. In human cells, electrophysiological variables were correlated even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Cortical depth was correlated with both electrophysiological and morphological variables in both species, and its effect on electrophysiology could not be explained in terms of the morphological variables. For some variables, the effect of cortical depth was opposite in the two species. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons.

    in Frontiers in Neuroinformatics on February 18, 2021 12:00 AM.

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    Intraoperative Brain Mapping by Cortico-Cortical Evoked Potential

    To preserve postoperative brain function, it is important for neurosurgeons to fully understand the brain's structure, vasculature, and function. Intraoperative high-frequency electrical stimulation during awake craniotomy is the gold standard for mapping the function of the cortices and white matter; however, this method can only map the “focal” functions and cannot monitor large-scale cortical networks in real-time. Recently, an in vivo electrophysiological method using cortico-cortical evoked potentials (CCEPs) induced by single-pulse electrical cortical stimulation has been developed in an extraoperative setting. By using the CCEP connectivity pattern intraoperatively, mapping and real-time monitoring of the dorsal language pathway is available. This intraoperative CCEP method also allows for mapping of the frontal aslant tract, another language pathway, and detection of connectivity between the primary and supplementary motor areas in the frontal lobe network. Intraoperative CCEP mapping has also demonstrated connectivity between the frontal and temporal lobes, likely via the ventral language pathway. Establishing intraoperative electrophysiological monitoring is clinically useful for preserving brain function, even under general anesthesia. This CCEP technique demonstrates potential clinical applications for mapping and monitoring large-scale cortical networks.

    in Frontiers in Human Neuroscience on February 18, 2021 12:00 AM.

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    Neural Signatures of Performance Feedback in the Paced Auditory Serial Addition Task (PASAT): An ERP Study

    Research on cognitive control has sparked increasing interest in recent years, as it is an important prerequisite for goal oriented human behavior. The paced auditory serial addition task (PASAT) has been used to test and train cognitive control functions. This adaptive, challenging task includes continuous performance feedback. Therefore, additional cognitive control capacities are required to process this information along with the already high task-load. The underlying neural mechanisms, however, are still unclear. To explore the neural signatures of the PASAT and particularly the processing of distractive feedback information, feedback locked event-related potentials were derived from 24 healthy participants during an adaptive 2-back version of the PASAT. Larger neural activation after negative feedback was found for feedback related negativity (FRN), P300, and late positive potential (LPP). In early stages of feedback processing (i.e., FRN), a larger difference between positive and negative feedback responses was associated with poorer overall performance. This association was inverted in later stages (i.e., P300 and LPP). Together, our findings indicate stage-dependent associations between neural activation after negative information and cognitive functioning. Conceivably, increased early responses to negative feedback signify distraction, whereas higher activity at later stages reflects cognitive control processes to preserve ongoing performance.

    in Frontiers in Human Neuroscience on February 18, 2021 12:00 AM.

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    Characterizing the Action-Observation Network Through Functional Near-Infrared Spectroscopy: A Review

    Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that has undergone tremendous growth over the last decade due to methodological advantages over other measures of brain activation. The action-observation network (AON), a system of brain structures proposed to have “mirroring” abilities (e.g., active when an individual completes an action or when they observe another complete that action), has been studied in humans through neural measures such as fMRI and electroencephalogram (EEG); however, limitations of these methods are problematic for AON paradigms. For this reason, fNIRS is proposed as a solution to investigating the AON in humans. The present review article briefly summarizes previous neural findings in the AON and examines the state of AON research using fNIRS in adults. A total of 14 fNIRS articles are discussed, paying particular attention to methodological choices and considerations while summarizing the general findings to aid in developing better protocols to study the AON through fNIRS. Additionally, future directions of this work are discussed, specifically in relation to researching AON development and potential multimodal imaging applications.

    in Frontiers in Human Neuroscience on February 18, 2021 12:00 AM.

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    Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury

    This study investigated the neuromodulatory effects of transspinal stimulation on soleus H-reflex excitability and electromyographic (EMG) activity during stepping in humans with and without spinal cord injury (SCI). Thirteen able-bodied adults and 5 individuals with SCI participated in the study. EMG activity from both legs was determined for steps without, during, and after a single-pulse or pulse train transspinal stimulation delivered during stepping randomly at different phases of the step cycle. The soleus H-reflex was recorded in both subject groups under control conditions and following single-pulse transspinal stimulation at an individualized exactly similar positive and negative conditioning-test interval. The EMG activity was decreased in both subject groups at the steps during transspinal stimulation, while intralimb and interlimb coordination were altered only in SCI subjects. At the steps immediately after transspinal stimulation, the physiological phase-dependent EMG modulation pattern remained unaffected in able-bodied subjects. The conditioned soleus H-reflex was depressed throughout the step cycle in both subject groups. Transspinal stimulation modulated depolarization of motoneurons over multiple segments, limb coordination, and soleus H-reflex excitability during assisted stepping. The soleus H-reflex depression may be the result of complex spinal inhibitory interneuronal circuits activated by transspinal stimulation and collision between orthodromic and antidromic volleys in the peripheral mixed nerve. The soleus H-reflex depression by transspinal stimulation suggests a potential application for normalization of spinal reflex excitability after SCI.

    in Frontiers in Human Neuroscience on February 18, 2021 12:00 AM.

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    Asymmetries in Accessing Vowel Representations Are Driven by Phonological and Acoustic Properties: Neural and Behavioral Evidence From Natural German Minimal Pairs

    In vowel discrimination, commonly found discrimination patterns are directional asymmetries where discrimination is faster (or easier) if differing vowels are presented in a certain sequence compared to the reversed sequence. Different models of speech sound processing try to account for these asymmetries based on either phonetic or phonological properties. In this study, we tested and compared two of those often-discussed models, namely the Featurally Underspecified Lexicon (FUL) model (Lahiri and Reetz, 2002) and the Natural Referent Vowel (NRV) framework (Polka and Bohn, 2011). While most studies presented isolated vowels, we investigated a large stimulus set of German vowels in a more naturalistic setting within minimal pairs. We conducted an mismatch negativity (MMN) study in a passive and a reaction time study in an active oddball paradigm. In both data sets, we found directional asymmetries that can be explained by either phonological or phonetic theories. While behaviorally, the vowel discrimination was based on phonological properties, both tested models failed to explain the found neural patterns comprehensively. Therefore, we additionally examined the influence of a variety of articulatory, acoustical, and lexical factors (e.g., formant structure, intensity, duration, and frequency of occurrence) but also the influence of factors beyond the well-known (perceived loudness of vowels, degree of openness) in depth via multiple regression analyses. The analyses revealed that the perceptual factor of perceived loudness has a greater impact than considered in the literature and should be taken stronger into consideration when analyzing preattentive natural vowel processing.

    in Frontiers in Human Neuroscience on February 18, 2021 12:00 AM.

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    A Neuromechanical Model of Multiple Network Rhythmic Pattern Generators for Forward Locomotion in C. elegans

    Multiple mechanisms contribute to the generation, propagation, and coordination of the rhythmic patterns necessary for locomotion in Caenorhabditis elegans. Current experiments have focused on two possibilities: pacemaker neurons and stretch-receptor feedback. Here, we focus on whether it is possible that a chain of multiple network rhythmic pattern generators in the ventral nerve cord also contribute to locomotion. We use a simulation model to search for parameters of the anatomically constrained ventral nerve cord circuit that, when embodied and situated, can drive forward locomotion on agar, in the absence of pacemaker neurons or stretch-receptor feedback. Systematic exploration of the space of possible solutions reveals that there are multiple configurations that result in locomotion that is consistent with certain aspects of the kinematics of worm locomotion on agar. Analysis of the best solutions reveals that gap junctions between different classes of motorneurons in the ventral nerve cord can play key roles in coordinating the multiple rhythmic pattern generators.

    in Frontiers in Computational Neuroscience on February 18, 2021 12:00 AM.

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    Nicotine Enhances Amplitude and Consistency of Timing of Responses to Acoustic Trains in A1

    Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2–40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5–10 Hz and complete at 20–40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2–10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20–40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2–10 Hz range.

    in Frontiers in Neural Circuits on February 18, 2021 12:00 AM.

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    Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic

    Coronavirus disease 2019 (COVID-19) is marked by cardio-respiratory alterations, with increasing reports also indicating neurological and psychiatric symptoms in infected individuals. During COVID-19 pathology, the central nervous system (CNS) is possibly affected by direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion, exaggerated systemic inflammatory responses, or hypoxia. Psychosocial stress imposed by the pandemic further affects the CNS of COVID-19 patients, but also the non-infected population, potentially contributing to the emergence or exacerbation of various neurological or mental health disorders. Microglia are central players of the CNS homeostasis maintenance and inflammatory response that exert their crucial functions in coordination with other CNS cells. During homeostatic challenges to the brain parenchyma, microglia modify their density, morphology, and molecular signature, resulting in the adjustment of their functions. In this review, we discuss how microglia may be involved in the neuroprotective and neurotoxic responses against CNS insults deriving from COVID-19. We examine how these responses may explain, at least partially, the neurological and psychiatric manifestations reported in COVID-19 patients and the general population. Furthermore, we consider how microglia might contribute to increased CNS vulnerability in certain groups, such as aged individuals and people with pre-existing conditions.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation

    Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (LRP1) on astrocytic maturation within the hippocampus was analyzed during development. Previous studies mostly focused on the involvement of LRP1 in the neuronal compartment, where the deletion caused hyperactivity and motor dysfunctions in knockout animals. However, the influence of LRP1 on glia cells is less intensively investigated. Therefore, we used a newly generated mouse model, where LRP1 is specifically deleted from GLAST-positive astrocytes co-localized with the expression of the reporter tdTomato to visualize recombination and knockout events in vivo. The influence of LRP1 on the maturation of hippocampal astrocytes was assessed with immunohistochemical stainings against stage-specific markers as well as on mRNA level with RT-PCR analysis. The examination revealed that the knockout induction caused a significantly decreased number of mature astrocytes at an early developmental timepoint compared to control animals. Additionally, the delayed maturation of astrocytes also caused a reduced activity of neurons within the hippocampus. As previous studies showed that the glial specification and maturation of astrocytes is dependent on the signaling cascades Ras/Raf/MEK/Erk and PI3K/Akt, the phosphorylation of the signaling molecules Erk1/2 and Akt was analyzed. The hippocampal tissue of LRP1-deficient animals at P21 showed a significantly decreased amount of activated Erk in comparison to control tissue leading to the conclusion that the activation of this signaling cascade is dependent on LRP1 in astrocytes, which in turn is necessary for proper maturation of astrocytes. Our results showed that the deletion of LRP1 at an early developmental timepoint caused a delayed maturation of astrocytes in the hippocampus based on an altered activation of the Ras/Raf/MEK/Erk signaling pathway. However, with ongoing development these effects were compensated and the number of mature astrocytes was comparable as well as the activity of neurons. Therefore, LRP1 acts as an early regulator of the differentiation and maturation of astrocytes within the hippocampus.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Indoleamine-2,3-Dioxygenase 1 Deficiency Suppresses Seizures in Epilepsy

    Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme in the metabolism of tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in the pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear.

    Objective: In this study, we investigated whether IDO1 deficiency could affect epilepsy in a lithium-pilocarpine-induced model.

    Methods: Patients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO, IDO1−/−) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The levels of IDO1 and concentrations of TRP and KYN in patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS), respectively. Then, behavioral phenotypes related to epileptic seizures and neuronal damage were compared between KO and wild-type (WT) mice with lithium-pilocarpine-induced epilepsy. To explore the underlying pathways involved in the effects of IDO1 deficiency, the concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cell activation, the levels of major pro-inflammatory cytokines, and antioxidant enzyme activity were measured by LC-MS, immunohistochemistry, and ELISA.

    Results: In this study, IDO1 levels and the KYN/TRP ratio in the sera and cerebrospinal fluid (CSF) were increased in patients with epilepsy. Also, IDO1 levels, the KYN/TRP ratio, and the levels of pro-inflammatory cytokines in the sera and hippocampi were increased in mice during the acute phase and chronic phase after status epilepticus (SE). Furthermore, IDO1 was localized in microglial cells in epileptic mice. IDO1 deficiency delayed SE onset and attenuated the frequency, duration, and severity of spontaneous recurrent seizures (SRSs). Moreover, IDO1 deficiency improved neuronal survival. Additionally, IDO1−/− epileptic mice showed progressive declines in QUIN production, glial cell activation and pro-inflammatory cytokines levels, and enhanced antioxidant enzyme activity.

    Conclusions: IDO1 deletion suppressed seizures and alleviated neuronal damage by reducing the IDO1-dependent production of neurotoxic metabolites, which finally inhibited glial cell activation and pro-inflammatory cytokine production and improved antioxidant enzyme activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has the potential to be a therapeutic target for epilepsy treatment.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Endothelial Progenitor Cell-Derived Microvesicles Promote Angiogenesis in Rat Brain Microvascular Endothelial Cells In vitro

    Brain microvascular endothelial cells (BMECs) are a major component of the blood-brain barrier that maintains brain homeostasis. Preserving and restoring the normal biological functions of BMECs can reverse or reduce brain injury. Endothelial progenitor cells (EPCs) may promote brain vascular remodeling and restore normal endothelial function. As a novel vehicle for cell-cell communication, microvesicles (MVs) have varied biological functions. The present study investigated the biological effects of EPC-derived MVs (EPC-MVs) on BMECs in vitro. We isolated MVs from the supernatant of EPCs in a serum-depleted medium. BMECs were cultured alone or in the presence of EPC-MVs. BMEC viability and proliferation were evaluated with the Cell Counting Kit-8 and by flow cytometry, and the proangiogenic effect of EPC-MVs on BMECs was assessed with the transwell migration, wound healing, and tube formation assays. Our results showed that EPC-derived MVs labeled with DiI were internalized by cultured BMECs; this enhanced BMEC viability and promoted their proliferation. EPC-MVs also stimulated migration and tube formation in BMECs. These results demonstrate that EPC-derived MVs exert a proangiogenic effect on BMECs, which has potential applications in cell-free therapy for brain injury.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

    The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice

    Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Chronic and Acute Manipulation of Cortical Glutamate Transmission Induces Structural and Synaptic Changes in Co-cultured Striatal Neurons

    In contrast to the prenatal topographic development of sensory cortices, striatal circuit organization is slow and requires the functional maturation of cortical and thalamic excitatory inputs throughout the first postnatal month. While mechanisms regulating synapse development and plasticity are quite well described at excitatory synapses of glutamatergic neurons in the neocortex, comparatively little is known of how this translates to glutamate synapses onto GABAergic neurons in the striatum. Here we investigate excitatory striatal synapse plasticity in an in vitro system, where glutamate can be studied in isolation from dopamine and other neuromodulators. We examined pre-and post-synaptic structural and functional plasticity in GABAergic striatal spiny projection neurons (SPNs), co-cultured with glutamatergic cortical neurons. After synapse formation, medium-term (24 h) TTX silencing increased the density of filopodia, and modestly decreased dendritic spine density, when assayed at 21 days in vitro (DIV). Spine reductions appeared to require residual spontaneous activation of ionotropic glutamate receptors. Conversely, chronic (14 days) TTX silencing markedly reduced spine density without any observed increase in filopodia density. Time-dependent, biphasic changes to the presynaptic marker Synapsin-1 were also observed, independent of residual spontaneous activity. Acute silencing (3 h) did not affect presynaptic markers or postsynaptic structures. To induce rapid, activity-dependent plasticity in striatal neurons, a chemical NMDA receptor-dependent “long-term potentiation (LTP)” paradigm was employed. Within 30 min, this increased spine and GluA1 cluster densities, and the percentage of spines containing GluA1 clusters, without altering the presynaptic signal. The results demonstrate that the growth and pruning of dendritic protrusions is an active process, requiring glutamate receptor activity in striatal projection neurons. Furthermore, NMDA receptor activation is sufficient to drive glutamatergic structural plasticity in SPNs, in the absence of dopamine or other neuromodulators.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Emerging Evidence Highlighting the Importance of Redox Dysregulation in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)

    The cellular redox state, or balance between cellular oxidation and reduction reactions, serves as a vital antioxidant defence system that is linked to all important cellular activities. Redox regulation is therefore a fundamental cellular process for aerobic organisms. Whilst oxidative stress is well described in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), other aspects of redox dysfunction and their contributions to pathophysiology are only just emerging. ALS is a fatal neurodegenerative disease affecting motor neurons, with few useful treatments. Hence there is an urgent need to develop more effective therapeutics in the future. Here, we discuss the increasing evidence for redox dysregulation as an important and primary contributor to ALS pathogenesis, which is associated with multiple disease mechanisms. Understanding the connection between redox homeostasis, proteins that mediate redox regulation, and disease pathophysiology in ALS, may facilitate a better understanding of disease mechanisms, and lead to the design of better therapeutic strategies.

    in Frontiers in Cellular Neuroscience on February 18, 2021 12:00 AM.

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    Immunoreactivity of Vesicular Glutamate Transporter 2 Corresponds to Cytochrome Oxidase-Rich Subcompartments in the Visual Cortex of Squirrel Monkeys

    Cytochrome oxidase (CO) histochemistry has been used to reveal the cytoarchitecture of the primate brain, including blobs/puffs/patches in the striate cortex (V1), and thick, thin and pale stripes in the middle layer of the secondary visual cortex (V2). It has been suggested that CO activity is coupled with the spiking activity of neurons, implying that neurons in these CO-rich subcompartments are more active than surrounding regions. However, we have discussed possibility that CO histochemistry represents the distribution of thalamo-cortical afferent terminals that generally use vesicular glutamate transporter 2 (VGLUT2) as their main glutamate transporter, and not the activity of cortical neurons. In this study, we systematically compared the labeling patterns observed between CO histochemistry and immunohistochemistry (IHC) for VGLUT2 from the system to microarchitecture levels in the visual cortex of squirrel monkeys. The two staining patterns bore striking similarities at all levels of the visual cortex, including the honeycomb structure of V1 layer 3Bβ (Brodmann's layer 4A), the patchy architecture in the deep layers of V1, the superficial blobs of V1, and the V2 stripes. The microarchitecture was more evident in VGLUT2 IHC, as expected. VGLUT2 protein expression that produced specific IHC labeling is thought to originate from the thalamus since the lateral geniculate nucleus (LGN) and the pulvinar complex both show high expression levels of VGLUT2 mRNA, but cortical neurons do not. These observations support our theory that the subcompartments revealed by CO histochemistry represent the distribution of thalamo-cortical afferent terminals in the primate visual cortex.

    in Frontiers in Neuroanatomy on February 18, 2021 12:00 AM.

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    Brain Ischemia as a Prelude to Alzheimer's Disease

    Transient ischemic brain injury causes massive neuronal death in the hippocampus of both humans and animals. This was accompanied by progressive atrophy of the hippocampus, brain cortex, and white matter lesions. Furthermore, it has been noted that neurodegenerative processes after an episode of ischemia-reperfusion in the brain can continue well-beyond the acute stage. Rarefaction of white matter was significantly increased in animals at 2 years following ischemia. Some rats that survived 2 years after ischemia developed severe brain atrophy with dementia. The profile of post-ischemic brain neurodegeneration shares a commonality with neurodegeneration in Alzheimer's disease. Furthermore, post-ischemic brain injury is associated with the deposition of folding proteins, such as amyloid and tau protein, in the intracellular and extracellular space. Recent studies on post-ischemic brain neurodegeneration have revealed the dysregulation of Alzheimer's disease-associated genes such as amyloid protein precursor, α-secretase, β-secretase, presenilin 1, presenilin 2, and tau protein. The latest data demonstrate that Alzheimer's disease-related proteins and their genes play a key role in the development of post-ischemic brain neurodegeneration with full-blown dementia in disease types such as Alzheimer's. Ongoing interest in the study of brain ischemia has provided evidence showing that ischemia may be involved in the development of the genotype and phenotype of Alzheimer's disease, suggesting that brain ischemia can be considered as a useful model for understanding the mechanisms responsible for the initiation of Alzheimer's disease.

    in Frontiers in Ageing Neuroscience on February 18, 2021 12:00 AM.

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    Age-Related EEG Power Reductions Cannot Be Explained by Changes of the Conductivity Distribution in the Head Due to Brain Atrophy

    Electroencephalogram (EEG) power reductions in the aging brain have been described by numerous previous studies. However, the underlying mechanism for the observed brain signal power reduction remains unclear. One possible cause for reduced EEG signals in elderly subjects might be the increased distance from the primary neural electrical currents on the cortex to the scalp electrodes as the result of cortical atrophies. While brain shrinkage itself reflects age-related neurological changes, the effects of changes in the distribution of electrical conductivity are often not distinguished from altered neural activity when interpreting EEG power reductions. To address this ambiguity, we employed EEG forward models to investigate whether brain shrinkage is a major factor for the signal attenuation in the aging brain. We simulated brain shrinkage in spherical and realistic brain models and found that changes in the conductor geometry cannot fully account for the EEG power reductions even when the brain was shrunk to unrealistic sizes. Our results quantify the extent of power reductions from brain shrinkage and pave the way for more accurate inferences about deficient neural activity and circuit integrity based on EEG power reductions in the aging population.

    in Frontiers in Ageing Neuroscience on February 18, 2021 12:00 AM.

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    Neuroimaging, Behavioral, and Gait Correlates of Fall Profile in Older Adults

    Prior research has suggested that measurements of brain functioning and performance on dual tasks (tasks which require simultaneous performance) are promising candidate predictors of fall risk among older adults. However, no prior study has investigated whether brain function measurements during dual task performance could improve prediction of fall risks and whether the type of subtasks used in the dual task paradigm affects the strength of the association between fall characteristics and dual task performance. In this study, 31 cognitively normal, community-dwelling older adults provided a self-reported fall profile (number of falls and fear of falling), completed a gait dual task (spell a word backward while walking on a GaitRite mat), and completed a supine dual task (rhythmic finger tapping with one hand while completing the AX continuous performance task (AX-CPT) with the other hand) during functional magnetic resonance imaging (fMRI). Gait performance, AX-CPT reaction time and accuracy, finger tapping cadence, and brain functioning in finger-tapping-related and AX-CPT-related brain regions all showed declines in the dual task condition compared to the single task condition. Dual-task gait, AX-CPT and finger tapping performance, and brain functioning were all independent predictors of fall profile. No particular measurement domain stood out as being the most strongly associated measure with fall variables. Fall characteristics are determined by multiple factors; brain functioning, motor task, and cognitive task performance in challenging dual-task conditions all contribute to the risk of falling.

    in Frontiers in Ageing Neuroscience on February 18, 2021 12:00 AM.

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    Voxel-Mirrored Homotopic Connectivity Associated With Change of Cognitive Function in Chronic Pontine Stroke

    Recent neuroimaging studies have shown the possibility of cognitive impairment after pontine stroke. In this study, we aimed to use voxel-mirrored homotopic connectivity (VMHC) to investigate changes in the cognitive function in chronic pontine stroke. Functional MRI (fMRI) and behavioral assessments of cognitive function were obtained from 56 patients with chronic pontine ischemic stroke [28 patients with left-sided pontine stroke (LP) and 28 patients with right-sided pontine stroke (RP)] and 35 matched healthy controls (HC). The one-way ANOVA test was performed for the three groups after the VMHC analysis. Results showed that there were significant decreases in the bilateral lingual gyrus (Lingual_L and Lingual_R) and the left precuneus (Precuneus_L) in patients with chronic pontine ischemic stroke compared to HCs. However, in a post-hoc multiple comparison test, this difference remained only between the HC and RP groups. Moreover, we explored the relationship between the decreased z-values in VMHC and the behavior-task scores using a Pearson's correlation test and found that both scores of short-term memory and long-term memory in the Rey Auditory Verbal Learning Test were positively correlated with z-values of the left lingual gyrus (Lingual_L), the right lingual gyrus (Lingual_R), and the left precuneus (Precuneus_L) in VMHC. Besides that, the z-values of Precuneus_L in VMHC were also negatively correlated with the reaction time for correct responses in the Flanker task and the spatial memory task. In conclusion, first, the lingual gyrus played an important role in verbal memory. Second, the precuneus influenced the working memory, both auditory-verbal memory and visual memory. Third, the right-sided stroke played a greater role in the results of this study. This study provides a basis for further elucidation of the characteristics and mechanisms of cognitive impairment after pontine stroke.

    in Frontiers in Ageing Neuroscience on February 18, 2021 12:00 AM.

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    Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

    Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

    in Frontiers in Ageing Neuroscience on February 18, 2021 12:00 AM.

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    Self-augmentation: Generalizing deep networks to unseen classes for few-shot learning

    Publication date: Available online 17 February 2021

    Source: Neural Networks

    Author(s): Jin-Woo Seo, Hong-Gyu Jung, Seong-Whan Lee

    in Neural Networks on February 17, 2021 07:00 PM.

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    Small universal spiking neural P systems with dendritic/axonal delays and dendritic trunk/feedback

    Publication date: Available online 16 February 2021

    Source: Neural Networks

    Author(s): Luis Garcia, Giovanny Sanchez, Eduardo Vazquez, Gerardo Avalos, Esteban Anides, Mariko Nakano, Gabriel Sanchez, Hector Perez

    in Neural Networks on February 17, 2021 07:00 PM.

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    Exponential quasi-synchronization of coupled delayed memristive neural networks via intermittent event-triggered control

    Publication date: Available online 16 February 2021

    Source: Neural Networks

    Author(s): Jiejie Chen, Boshan Chen, Zhigang Zeng

    in Neural Networks on February 17, 2021 07:00 PM.

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    Cover Image, Volume 31, Issue 3

    The cover image is based on the Rapid Communication Multiple coordinated cellular dynamics mediate CA1 map plasticity by Kotaro Mizuta et al., https://doi.org/10.1002/hipo.23300.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Multiple coordinated cellular dynamics mediate CA1 map plasticity

    Abstract In the hippocampus, spatial and nonspatial information are jointly represented as a neural map in which locations associated with salient features are over‐represented by increased densities of relevant place cells. Although we recently demonstrated that experience‐dependent establishment of these disproportionate maps is governed by selective stabilization of salient place cells following their conversion from non‐place cells, the underlying mechanism for pre‐established map reorganization remained to be understood. To this end, we investigated the changes in CA1 functional cellular maps imaged using two‐photon calcium imaging in mice performing a reward‐rearrangement task in virtual reality. Mice were pre‐trained on a virtual linear track with a visual landmark and a reward in two distinct locations. Then, they were re‐trained on the same track with the exception that the location of reward was shifted to match the landmark location. We found that, in contrast to de novo map formation, robust map reorganization occurred through parallel coordination of new place field formation, lateral shifting of existing place fields, and selective stabilization of place fields encoding salient locations. Our findings demonstrate that intricate interplay between multiple forms of cellular dynamics enables rapid updating of information stored in hippocampal maps.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Exercise interventions preserve hippocampal volume: A meta‐analysis

    Abstract Hippocampal volume is a marker of brain health and is reduced with aging and neurological disease. Exercise may be effective at increasing and preserving hippocampal volume, potentially serving as a treatment for conditions associated with hippocampal atrophy (e.g., dementia). This meta‐analysis aimed to identify whether exercise training has a positive effect on hippocampal volume and how population characteristics and exercise parameters moderate this effect. Studies met the following criteria: (a) controlled trials; (b) interventions of physical exercise; (c) included at least one time‐point of hippocampal volume data before the intervention and one after; (d) assessed hippocampal volume using either manual or automated segmentation algorithms. Animal studies, voxel‐based morphometry analyses, and multi‐modal interventions (e.g., cognitive training or meditation) were excluded. The primary analysis in n = 23 interventions from 22 published studies revealed a significant positive effect of exercise on total hippocampal volume. The overall effect was significant in older samples (65 years of age or older) and in interventions that lasted over 24 weeks and had less than 150 min per week of exercise. These findings suggest that moderate amounts of exercise for interventions greater than 6 months have a positive effect on hippocampal volume including in older populations vulnerable to hippocampal atrophy.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction

    Abstract Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short‐term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long‐lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36–44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain‐derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety‐like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba‐1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro‐BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long‐lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal‐dependent learning and memory in adolescence.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Maximal aerobic capacity is associated with hippocampal cognitive reserve in older adults with amnestic mild cognitive impairment

    Abstract Maximal aerobic capacity (MAC) has been associated with preserved neural tissue or brain maintenance (BM) in healthy older adults, including the hippocampus. Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease. While aMCI is characterized by hippocampal deterioration, the MAC‐hippocampal relationship in these patients is not well understood. In contrast to healthy individuals, neurocognitive protective effects in neurodegenerative populations have been associated with mechanisms of cognitive reserve (CR) altering the neuropathology‐cognition relationship. We investigated the MAC‐hippocampal relationship in aMCI (n = 29) from the perspectives of BM and CR mechanistic models with structural MRI and a memory fMRI paradigm using both group‐level (higher‐fit patients vs. lower‐fit patients) and individual level (continuous correlation) approaches. While MAC was associated with smaller hippocampal volume, contradicting the BM model, higher‐fit patients demonstrated statistically significant lower correlation between hippocampal volume and memory performance compared with the lower‐fit patients, supporting the model of CR. In addition, while there was no difference in brain activity between the groups during low cognitive demand (encoding of familiar stimuli), higher MAC level was associated with increased cortical and sub‐cortical activation during increased cognitive demand (encoding of novel stimuli) and also with bilateral hippocampal activity even when controlling for hippocampal volume, suggesting for an independent effect of MAC. Our results suggest that MAC may be associated with hippocampal‐related cognitive reserve in aMCI through altering the relationship between hippocampal‐related structural deterioration and cognitive function. In addition, MAC was found to be associated with increased capacity to recruit neural resources during increased cognitive demands.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Activation of ventral CA1 hippocampal neurons projecting to the lateral septum during feeding

    Abstract A number of studies have reported the involvement of the ventral hippocampus (vHip) and the lateral septum (LS) in negative emotional responses. Besides these well‐documented functions, they are also thought to control feeding behavior. In particular, optogenetic and pharmacogenetic interventions to LS‐projecting vHip neurons have demonstrated that the vHip→LS neural circuit exerts an inhibition on feeding behavior. However, there have been no reports of vHip neuronal activity during feeding. Here, we focused on LS‐projecting vCA1 neurons (vCA1→LS) and monitored their activity during feeding behaviors in mice. vCA1→LS neurons were retrogradely labeled with adeno‐associated virus carrying a ratiometric Ca2+ indicator and measured compound Ca2+ dynamics by fiber photometry. We first examined vCA1→LS activity in random food‐exploring behavior and found that vCA1→LS activation seemed to coincide with food intake; however, our ability to visually confirm this during freely moving behaviors was not sufficiently reliable. We next examined vCA1→LS activity in a goal‐directed, food‐seeking lever‐press task which temporally divided the mouse state into preparatory, effort, and consummatory phases. We observed vCA1→LS activation in the postprandial period during the consummatory phase. Such timing‐ and pathway‐specific activation was not observed from pan‐vCA1 neurons. In contrast, reward omission eliminated this activity, indicating that vCA1→LS activation is contingent on the food reward. Sated mice pressed the lever significantly fewer times but still ate food; however, vCA1→LS neurons were not activated, suggesting that vCA1→LS neurons did not respond to habitual behavior. Combined, these results suggest that gastrointestinal interoception rather than food‐intake motions or external sensations are likely to coincide with vCA1→LS activity. Accordingly, we propose that vCA1→LS neurons discriminate between matched or unmatched predictive bodily states in which incoming food will satisfy an appetite. We also demonstrate that vCA1→LS neurons are activated in aversive/anxious situations in an elevated plus maze and tail suspension test. Future behavioral tests utilizing anxious conflict and food intake may reconcile the multiple functions of vCA1→LS neurons.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Prolactin enhances hippocampal synaptic plasticity in female mice of reproductive age

    Abstract Dynamic signaling between the endocrine system (ES) and the nervous system (NS) is essential for brain and body homeostasis. In particular, reciprocal interaction occurs during pregnancy and motherhood that may involve changes in some brain plasticity processes. Prolactin (PRL), a hormone with pleiotropic effects on the NS, promotes maternal behavior and has been linked to modifications in brain circuits during motherhood; however, it is unclear whether PRL may regulate synaptic plasticity. Therefore, the main aim of the present work was to determine the cellular and molecular mechanisms triggered by PRL that regulate synaptic plasticity in the hippocampus. By analyzing extracellular recordings in CA3‐CA1 synapses of hippocampal slices, we report that PRL modifies short and long‐term synaptic plasticity in female mice of reproductive age, but not in sexually immature females or adult males. This effect is carried out through mechanisms that include participation of GABAA receptors and activation of the JAK2‐mediated signaling pathway. These findings show for the first time how PRL enhances the synaptic strength in hippocampal circuits and that this effect is sexually dimorphic, which would influence complex brain processes in physiological conditions like pregnancy and lactation.

    in Hippocampus on February 17, 2021 04:02 PM.

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    The effects of hippocampal and area parahippocampalis lesions on the processing and retention of serial‐order behavior, autoshaping, and spatial behavior in pigeons

    Abstract We examined the role of the avian hippocampus and area parahippocampalis in serial‐order behavior and a variety of other tasks known to be sensitive to hippocampal damage in mammals. Damage to the hippocampus and area parahippocampalis caused impairments in autoshaping and performance on an analogue of a radial‐arm maze task, but had no effect on acquisition of 2‐item, 3‐item, and 4‐item serial‐order lists. Additionally, the lesions had no effect on the retention of 3‐items lists, or on the ability to perform novel derived lists composed of elements from lists they had previously learned. The impairments in autoshaping and spatial behavior are consistent with the findings in mammals. The absence of impairments on the serial‐order task may also be consistent once one considers that damage to the hippocampus in mammals seems to affect more internally‐organized rather than externally‐organized serial‐order tasks. Together, the findings support the view that the avian hippocampal complex serves a function very similar to the mammalian hippocampus, a finding that is interesting given that the architecture of the avian hippocampus differs dramatically from that of the mammalian hippocampus.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Hippocampal spatial memory representations in mice are heterogeneously stable

    Abstract The population of hippocampal neurons actively coding space continually changes across days as mice repeatedly perform tasks. Many hippocampal place cells become inactive while other previously silent neurons become active, challenging the idea that stable behaviors and memory representations are supported by stable patterns of neural activity. Active cell replacement may disambiguate unique episodes that contain overlapping memory cues, and could contribute to reorganization of memory representations. How active cell replacement affects the evolution of representations of different behaviors within a single task is unknown. We trained mice to perform a delayed nonmatching to place task over multiple weeks, and performed calcium imaging in area CA1 of the dorsal hippocampus using head‐mounted miniature microscopes. Cells active on the central stem of the maze “split” their calcium activity according to the animal's upcoming turn direction (left or right), the current task phase (study or test), or both task dimensions, even while spatial cues remained unchanged. We found that, among reliably active cells, different splitter neuron populations were replaced at unequal rates, resulting in an increasing number of cells modulated by turn direction and a decreasing number of cells with combined modulation by both turn direction and task phase. Despite continual reorganization, the ensemble code stably segregated these task dimensions. These results show that hippocampal memories can heterogeneously reorganize even while behavior is unchanging.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Issue Information ‐ TOC

    Hippocampus, Volume 31, Issue 3, Page C4-C4, March 2021.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Issue Information ‐ Editorial Board

    Hippocampus, Volume 31, Issue 3, Page 233-233, March 2021.

    in Hippocampus on February 17, 2021 04:02 PM.

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    Data-driven method to infer the seizure propagation patterns in an epileptic brain from intracranial electroencephalography

    by Viktor Sip, Meysam Hashemi, Anirudh N. Vattikonda, Marmaduke M. Woodman, Huifang Wang, Julia Scholly, Samuel Medina Villalon, Maxime Guye, Fabrice Bartolomei, Viktor K. Jirsa

    Surgical interventions in epileptic patients aimed at the removal of the epileptogenic zone have success rates at only 60-70%. This failure can be partly attributed to the insufficient spatial sampling by the implanted intracranial electrodes during the clinical evaluation, leading to an incomplete picture of spatio-temporal seizure organization in the regions that are not directly observed. Utilizing the partial observations of the seizure spreading through the brain network, complemented by the assumption that the epileptic seizures spread along the structural connections, we infer if and when are the unobserved regions recruited in the seizure. To this end we introduce a data-driven