• #### Journal of Molecular Neuroscience

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

### Abstract

Inflammation contributes to mitochondrial dysfunction and neuronal apoptosis. The aim of this study was to determine whether insulin-like growth factor-1 (IGF-1) alleviates mitochondrial apoptosis in lipopolysaccharide (LPS)-treated PC-12 cells, and to further explore the mechanism involved. Prepared PC-12 cells were treated with IGF-1, Mdivi-1 (DRP1 blocker), LY294002 (PI3K blocker), betulinic acid (NF-κB activator) or their combinations. Mitochondrial membrane potential and ATP generation were then measured to assess mitochondrial function. The rate of apoptosis was determined using flow cytometry. The expression of several apoptosis proteins (i.e. Bax, cleaved caspase-9 and cleaved caspase-3) and signaling proteins (i.e. p-GSK3β, NF-κB and NLRP3) was measured using western blotting. Compared with the control cells, the LPS-treated cells showed evidence of mitochondrial dysfunction, increased apoptosis and upregulation of apoptosis proteins, which were significantly alleviated by Mdivi-1. These findings indicate that neuronal apoptosis was activated partly through the mitochondrial pathway. IGF-1 treatment inhibited mitochondrial apoptosis in a dose-dependent manner in the LPS-treated cells. The reagent also increased the expression of p-GSK3β and decreased the expression of NF-κB and NLRP3. Both LY294002 and betulinic acid reversed the protective effect of IGF-1. In addition, LY294002 affected the expression of the three signaling proteins, while betulinic acid only affected the expression of NF-κB and NLRP3. These findings indicated a GSK3β/NF-κB/NLRP3 signaling pathway was existed and was involved in the protective mechanism of IGF-1. In conclusion, IGF-1 alleviated mitochondrial apoptosis through GSK3β/NF-κB/NLRP3 signaling pathway in LPS-treated PC-12 cells.

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

### Abstract

The existence of Gram-negative bacteria in the brain, regardless of underlying immune status has been demonstrated by recent studies. The colocalization of lipopolysaccharide (LPS) with Aβ1-40/42 in amyloid plaques supports the hypothesis that brain microbes may be the cause, triggering chronic neuroinflammation, leading to Alzheimer’s disease (AD). To investigate the behavioral changes induced by infectious neuroinflammation, we chose the third ventricle as the site of a single LPS injection (20 μg or 80 μg) in male Wistar rats to avoid mechanical injury to forebrain structures while inducing widespread inflammation throughout the brain. Chronic neuroinflammation induced by LPS resulted in depressive-like behaviors and the impairment of spatial learning; however, there was no evidence of the development of pathological hallmarks (e.g., the phosphorylation of tau) for 10 months following LPS injection. The acceleration of cholesterol metabolism via CYP46A1 and the retardation of cholesterol synthesis via HMGCR were observed in the hippocampus of rats treated with either low-dose or high-dose LPS. The rate-limiting enzymes of cholesterol metabolism (CYP46A1) in SH-SY5Y cells and synthesis (HMGCR) in U251 cells were altered by inflammation stimulators, including LPS, IL-1β, and TNF-α, through the TLR4/MyD88/NF-κB signaling pathway. The data suggest that chronic neuroinflammation provoked by the administration of LPS into the third ventricle may induce depressive-like symptoms and that the loss of cholesterol might be a biomarker of chronic neuroinflammation. The lack of pathological hallmarks of AD in our model indicates that Gram-negative bacteria infection might not be a single cause of AD.

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

### Abstract

Twins studies indicate that many individual factors are associated with genetic polymorphisms in tobacco use, dependence vulnerability, and the ability to quit smoking. Opioid receptor delta-type 1 (OPRD1) is one of the most important genes in the opioid pathway. Therefore, the current study aimed to investigate the association of variants located in the intron 1 of the OPRD1 gene, including rs2236857, rs2236855, and rs760589, with susceptibility to nicotine dependence among northern Iranians. DNA of 426 individuals, including 224 smokers and 202 healthy people, were extracted with the salting-out standard technique, qualified with Agarose gel, then quantified with Nanodrop, and finally genotyped by Amplification Refractory Mutation System (ARMS) PCR. All statistical analyses were performed by SNPAlyze version 8.1 and SPSS version 20. Results revealed no significant association of all three studied variants with the susceptibility to nicotine dependence in any models of inheritance. However, there were five haplotypes with an overall frequency higher than 0.05; no significant impact of any of them on nicotine dependence was observed. Altogether, rs2236857, rs2236855, and rs760589 were not associated with nicotine dependence among northern Iranians.

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

### Abstract

To study the effect of photobiomodulation (PBM) on axon regeneration and secretion change of dorsal root ganglion (DRG) under oxidative stress after spinal cord injury (SCI), and further explore the effect of changes in DRG secretion caused by PBM on the polarization of macrophages. The PBM-DRG model was constructed to perform PBM on neurons under oxidative stress simulated in vitro. And the irradiation conditions were as follows: wavelength, 810 nm; power density, 2 mW/cm2; irradiation area, 4.5 cm2; and irradiation time, 440 s. Then resulted in an energy of 4 J (2 mW/cm2 × 4.5 cm2 × 440 s). About 100 μM H202 was added to the culture medium to simulate oxidative stress after SCI. An ROS (reactive oxygen species) assay kit was used to measure ROS contend in the DRG. The survival level of the neurons was measured using the CCK-8 method, and the axon regeneration of neurons was observed by using immunofluorescence. The secretion level of CCL2 from DRG was determined by RT-qPCR and ELISA. Further culturing macrophages of DRG-conditioned medium culture, the expression level of iNOS and Arg-1 in macrophages was assessed using Western blot analysis. The expression level of TNF-α and IL-1β was determined by ELISA. After adding the neutralizing antibody of CCL2 to the DRG neuron-conditioned medium following PBM irradiation to culture macrophages to observe the effects on macrophage polarization and secretion. PBM could reduce ROS levels in neurons, increase neuronal survival under oxidative stress, and promote neuronal axon regeneration. In addition, PBM could also promote CCL2 secretion by DRG under oxidative stress. By constructing a DRG supernatant-M1 macrophage adoptive culture model, we found that the supernatant of DRG after PBM intervention could reduce the expression level of iNOS and the secretion of TNF-α and IL-1β in M1 macrophages; at the same time, it could also up-regulate the expression of Arg-1, one of the markers of M2 macrophages. Furthermore, these effects could be prevented by the addition of neutralizing antibodies of CCL2. PBM could promote survival and axonal regeneration of DRG under SCI oxidative stress, increase the secretion level of CCL2 by DRG, and this change can reduce the polarization of macrophages to M1, further indicating that PBM could promote spinal cord injury repair.

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

### Abstract

Behçet syndrome (BS) is a vasculitis characterized by several clinical manifestations including the rare neurological involvement (neuro-BS, NBS). The aim of our pivotal study was to investigate the mutational status of several inflammation-related genes in a cohort of Italian patients with and without the neurological involvement (20 NBS vs 40 no-NBS patients). The preliminary in silico single nucleotide polymorphism (SNP) selection and primer design were performed by NCBI Primer-Blast tool. Genomic DNA was isolated and amplified using PCR. PCR amplicons were sequenced and bioinformatically analysed. Twelve tagSNPs were selected and genotyped: ERAP1 rs30187, rs17482078, and rs27044; IL10 rs1800872 and rs1518111, IL12A rs17810546, IL23R rs17375018, IL23R-IL12RB2 rs924080, STAT4 rs7572482, CCR1 rs7616215, KLRC4 rs2617170, and UBAC2 rs3825427. ERAP1 and IL23R SNPs showed statistically significant higher frequencies in NBS group than no-NBS. ERAP1 rs30187 AA was more common in no-NBS patients (20.0% NBS vs 47.5% no-NBS; p < 0.05), while rs17482078 GA frequency was higher in NBS patients (55.0% NBS vs 22.5% no-NBS; p < 0.05, OR: 4.21). IL23R rs17375018 GG was more frequent in NBS group (65.0% NBS vs 40.0% no-NBS; p < 0.05), according to a previous finding. No other statistically significant differences were found. In conclusion, ERAP1 and IL23R SNPs were found associated with neurological involvement of BS. Additional and larger analyses were required to verify our preliminary findings.

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

### Abstract

Cypermethrin activates microglia, which is found to be decisive in neurodegeneration in the experimental rats. While the involvement of microglial activation in toxicant-induced neurodegeneration is reported, the effect of low concentration of cypermethrin on the expression of inflammatory proteins from the rat primary microglia is not yet properly understood. The study intended to delineate the effect of low concentration of cypermethrin on the expression and release of proteins from the microglia. Rat primary microglial cells were treated with cypermethrin to check the expression of inflammatory proteins. Cypermethrin-treated microglia conditioned media and cells were collected to measure the expression and release of inflammatory proteins. Cypermethrin augmented the protein kinase C-δ (PKC-δ), inducible nitric oxide synthase (iNOS), phosphorylated mitogen-activated protein kinase (MAPK) p38 and p42/44, matrix metalloproteinase (MMP)-3, and MMP-9 levels in the cell lysate and tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in the microglia conditioned media. Pre-treatment with minocycline, a microglial activation inhibitor or rottlerin, a PKC-δ inhibitor, notably reduced the release of TNF-α in the conditioned media and expression of iNOS protein in the microglia. Minocycline reduced the expression of PKC-δ, phosphorylated p38 and p42/44 MAPKs, MMP-3, and MMP-9 proteins in the microglia. While cypermethrin-treated conditioned media induced the toxicity in the rat primary neurons, minocycline or rottlerin reduced the cypermethrin treated microglia conditioned media-induced toxicity. The outcomes of the present study suggest that cypermethrin activates microglia and releases TNF-α and IL-1β as well as up-regulates the expression of PKC-δ, iNOS, phosphorylated p38 and p42/44 MAPKs, MMP-3, and MMP-9 proteins, which could contribute to neurodegeneration.

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

### Abstract

Amyloid-β (Aβ) deposit in the parenchyma is a major characteristic in Alzheimer’s disease (AD), and the impaired glymphatic clearance contributes to the Aβ accumulation. It was reported that L-3-n-butylphthalide (NBP) showed the potential neuroprotective effect in the rodent models of AD. The effects of NBP on the glymphatic system were explored in this study. In the wild-type mice, both CSF tracer influx and perivascular drainage increased after NBP treatment compared with vehicle treatment. Moreover, NBP promoted the perivascular drainage of Aβ via increased cerebral pulsation, which could be inhibited by propranolol. Then, we studied the potential of 3-month NBP treatment on Aβ deposits in 8-month-old APP/PS1 transgenic mice. NBP daily treatments remarkably improved cognitive behavior in Morris water maze. Furthermore, NBP could reduce Aβ deposition and decrease parenchymal Aβ levels. In addition, NBP markedly improved the perivascular AQP4 localization. Our results indicated that NBP could enhance the glymphatic clearance and reduce parenchymal Aβ deposit in the APP/PS1 mice, suggesting that it may have potential in the treatment of AD.

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

### Abstract

Spinal cord injury (SCI) is a devastating traumatic event worldwide. Work from the past decade has highlighted the key involvement of long non-coding RNAs (lncRNAs) in SCI. Nevertheless, the molecular action of lncRNA H19 in SCI is still not fully understood. The levels of H19, microRNA (miR)-325-3p, and neuronal differentiation 4 (NEUROD4) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Flow cytometry was performed to assess cell apoptosis. The levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6 were detected using the enzyme-linked immunosorbent assay (ELISA). Targeted relationships among H19, miR-325-3p, and NEUROD4 were confirmed by dual-luciferase reporter, RNA immunoprecipitation (RIP), or RNA pull-down assays. Our data showed that H19 level was overexpressed in lipopolysaccharide (LPS)-treated BV2 cells. H19 silencing alleviated LPS-evoked cell apoptosis and inflammation. Mechanistically, H19 in BV2 cells directly targeted miR-325-3p, and NEUROD4 was a direct target of miR-325-3p. Moreover, miR-325-3p was a functional target of H19 in regulating cell apoptosis and inflammation induced by LPS. Enforced expression of miR-325-3p relieved LPS-evoked cell apoptosis and inflammation through reducing NEUROD4. Furthermore, H19 in BV2 cells regulated NEUROD4 expression through targeting miR-325-3p. Our results identified that the silencing of H19 attenuated LPS-evoked microglia cell apoptosis and inflammation after SCI at least partially through targeting the miR-325-3p/NEUROD4 axis, highlighting a novel approach for SCI management.

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

### Abstract

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

### Abstract

Glioma is a prevalent primary brain tumor. Temozolomide (TMZ) has been used to treat glioma. However, the resistance of TMZ to glioma poses heavy burden to glioma treatment. In this study, the effects of glioma resistance to TMZ and underlying mechanism were revealed. The expression levels of circ-VPS18, microRNA-370 (miR-370) and runt-related transcription factor 1 (RUNX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of RUNX1, multidrug resistance-associated protein 1 (MRP1), and multi-drug resistance gene-1 (MDR1) was determined by western blot. The functional effects of circ-VPS18 knockdown on TMZ sensitivity and glioma progression were revealed by cell counting kit-8 proliferation (CCK-8), flow cytometry, and transwell assays. The impacts of circ-VPS18 deletion on TMZ sensitivity in vivo were illustrated by in vivo tumor formation assay. The binding relationship between miR-370 and circ-VPS18 or RUNX1 was predicted by starBase v2.0 online database and identified by dual-luciferase reporter assay. Circ-VPS18 expression and the mRNA and protein levels of RUNX1 were dramatically upregulated, and miR-370 expression was significantly downregulated in glioma cells, TMZ-resistant glioma tissues, or tissue compared with control groups. Functionally, circ-VPS18 knockdown improved TMZ sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in U251/TR and LN229/TR cells, which was reversed by miR-370 inhibitor. Additionally, RUNX1 overexpression hindered the effects of miR-370 on TMZ sensitivity and glioma progression. Circ-VPS18 knockdown enhanced TMZ sensitivity in vivo. Mechanistically, circ-VPS18 functioned as a sponge of miR-370 and miR-370 targeted RUNX1. Circ-VPS18 knockdown improved TMZ sensitivity and repressed glioma progression by sponging miR-370 to downregulate RUNX1 expression, which provided a new insight in further studying glioma resistance to TMZ.

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

### Abstract

Alzheimer’s disease (AD) poses a significant threat to human life and health. The intraneuronal accumulation of β-amyloid (Aβ) plaques in the brains of AD patients results in neuronal cell death, which is a key factor that triggers multiple changes in the pathogenesis of AD. The inhibition of Aβ-induced neuronal cell death may potentially help in the intervention and treatment of AD. Our previous study reported that tumor necrosis factor α-induced protein 1 (TNFAIP1) is induced by and promotes Aβ25–35-induced neurotoxicity in mouse neuronal cells, but the roles and regulatory mechanisms of TNFAIP1 are still largely unknown. In this study, our experimental results show that TNFAIP1 and p-TNFAIP1 (phosphorylation of TNFAIP1 at Ser280) are overexpressed in the neurons of the cortex and hippocampus in the brains of APP/PS1 mice, and the transcription factor NF-κB is involved in the Aβ-induced upregulation of TNFAIP1. Moreover, our results suggest that TNFAIP1 contributes to the Aβ-induced reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (∆Ψm), and neuronal cell death in human SH-SY5Y cells. We further revealed that Aβ increases the binding of TNFAIP1 to RhoB, and knockdown of RhoB attenuates the TNFAIP1-induced apoptosis of human SH-SY5Y cells. These data suggest that TNFAIP1 is closely associated with AD pathogenesis, and overexpression of TNFAIP1 in the neurons of the brains of AD patients plays a role in apoptosis, at least in part, via RhoB signaling.

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

### Abstract

Migraine is a prevalent disorder in humans and represents one of the top 10 causes of years lived with disability. Several genetic and environmental factors are involved in the pathobiology of migraine. A number of studies have underscored the role of dysregulated immune reactions. We compared the expression levels IL-2, IL-4, CXCL8, IL-17, IFN-γ, TGF-β and TNF-α cytokines in blood specimens of patients with migraine and those of healthy persons to identify any possible dysregulation in their expression and to propose mechanisms for this disorder. Expression of INF-γ was suggestively higher in migraine cases than in healthy individuals (posterior beta = 0.35, adjusted P value = 0.017). In addition, expression of this cytokine was lower in female subjects than in male subjects (posterior beta = −0.712, adjusted P value = 0.012). Expression of IL-4, TGF-β and TNF-α was also higher in cases compared with controls (posterior beta = 1.34, adjusted P value = 0.04; posterior beta = 0.849, adjusted P value = 0.036; posterior beta = 0.451, adjusted P value = 0.042, respectively). On the other hand, CXCL8 expression was lower in migraine cases than in controls (posterior beta = −0.78, adjusted P value = 0.039). Expression levels of IL-1B, IL-17 and IL-2 were not meaningfully different between cases and controls. The current study highlights the dysregulation of cytokine-coding genes in the blood of patients with migraine.

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

### Abstract

Women with epilepsy are at increased risk of sexual dysfunction. The aim of this cross-sectional study was to investigate the effect of antiepileptic drugs on sexual function and satisfaction in women with epilepsy. In this cross-sectional study, 80 married women with epilepsy who were under treatment with antiepileptic drugs for at least 1 year were evaluated. Sexual function in patients was assessed using the Female Sexual Function Index. The mean age (± standard deviation [SD]) of women was 28.8 (± 5.9) years. The mean (± SD) duration of epilepsy was 8.6 (± 4.1) years. Thirteen women (16.2%) had focal epilepsy and 67 (83.7%) had generalized epilepsy. The mean (± SD) overall sexual performance of patients was 20.5 (± 4.7). Fifteen patients (21.3%) had decreased sexual function and 78.2% had unfavorable sexual performance. Generalized epilepsy, multi-drug regimen, disease duration of more than 10 years, and age > 30 years were associated with sexual dysfunction. Due to the high prevalence of sexual dysfunction in women with epilepsy, special attention should be given to appropriate management of these patients.

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

### Abstract

This study presented two Chinese adult female patients who were diagnosed with adult-onset Krabbe disease (KD) and reviewed this disease in Chinese patients. Two young female adults in their 20s were enrolled in this study. Clinical data, including symptoms, magnetic resonance imaging (MRI) scanning, and laboratory studies were collected. Sequence alignment and structural modeling were carried out to analyze the pathogenesis of the disease. Both patients were adult-onset and both had a mild clinical course, presented with spastic weakness. The MRI study showed demyelination confined to the corticospinal tracts and parieto-occipital white matter. The β-galactocerebrosidase (GALC) activity was obviously decreased in both patients. Gene test of GALC showed that both patients were compound heterozygotes; proband I was a carrier of p.L634S (c.1901 T > C) and p.I250T (c.749 T > C), while proband II was a carrier of p.L634S (c.1901 T > C) and a new variant of c.283_284del. Molecular analysis revealed the variants may influence the function of GALC. We provided two Chinese adult-onset KD, and the clinical and genetic characteristics of proband II was especially rare due to asymmetric symptoms, spinal cord involvement, and the identification of a new point mutation c.283_284del in the GALC gene. Variant c.749 T > C can present mild syndromes except for severe cases. c.283_284del is a new variant that may occur in adult-onset type.

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

### Abstract

Previous studies have shown that lncRNA NEAT1 and miR-29b are closely associated with repair of the injured spinal cord. However, the mechanism by which lncRNA NEAT1 promotes regeneration after spinal cord injury by regulating miR-29b has not been reported. To explore this mechanism, we established a rat model of spinal cord injury (SCI). The experimental rats were randomly assigned to one of six groups: the sham, model, si-NEAT1, miR-29b, si-NEAT1 + negative control and si-NEAT1 + si-miR-29b groups. The hind limb motor function of the rats was evaluated on days 1, 3, 7, 14, and 21 after modelling using the BBB rating scale. Seven days after the operation, attenuation of pathological changes in injured spinal cord tissues was evaluated by HE staining. Anterior horn neurons and cavities in the injured area were counted by Nissl staining. In addition, the TUNEL assay was employed to study neuronal apoptosis in the anterior horn, and the expression of the apoptotic proteins Bcl-2 and Bax was analysed by western blotting. Finally, the protein expression of GFAP, NCAM, GAP43, and SCG10 was measured by immunohistochemistry and western blotting. BBB scores revealed that decreasing the level of NEAT1 improved the hind limb motor function of the rats by increasing miR-29b expression. H&E and Nissl staining showed that silencing NEAT1 attenuated lesions in the spinal cord and decreased the number of cavities in the injured spinal cord by upregulating miR-29b. Immunohistochemistry and western blotting suggested that silencing NEAT1 significantly downregulated GFAP expression and upregulated GAP43, SCG10 and NCAM expression by inducing overexpression of miR-29b. The TUNEL assay and western blotting also showed that silencing NEAT1 attenuated neuronal apoptosis.

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

### Abstract

It has been suggested that dysregulation of hormones is associated with schizophrenia (SCZ). This study aimed to measure the serum levels of progesterone and testosterone in 125 SCZ patients at different stages of treatment and 96 healthy control (HC) subjects. Our results showed that first-episode drug-free SCZ patients had significantly increased testosterone levels when compared with HC subjects, and chronic medication, but not short-term medication, further increased the serum testosterone levels in the patients. Further analysis suggested that the sex of the patients did not affect testosterone levels. In contrast, serum progesterone levels did not show significant differences between first-episode, drug-free SCZ patients and controls, and the antipsychotics increased progesterone levels in the male SCZ patients, but not female patients. Interestingly, our analyses demonstrated that the serum progesterone levels were negatively correlated with PANSS total score and PNASS positive score, suggesting a correlation between blood hormone levels and disease severity in SCZ patients. Taken together, our data showed differential changes in serum testosterone and progesterone levels in SCZ patients with or without antipsychotics, and our results suggest that increased sex hormone levels may be a defensive response to protect the human body under stress.

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

### Abstract

Glioblastoma multiforme (GBM) is one of the most lethal malignancies of the central nervous system characterized by high mortality rate. The complexity of GBM pathogenesis, progression, and prognosis is not fully understood yet. GBM-derived extracellular vesicles (EVs) carry several oncogenic elements that facilitate GBM progression. The purpose of this study was to identify systems level molecular signatures from GBM-derived EVs using integrative analysis of publicly available transcriptomic data generated from plasma and serum samples. The dataset contained 19 samples in total, of which 15 samples were from plasma (11 GBM patients and 4 healthy samples) and 4 samples were from serum (2 GBM and 2 healthy samples). We carried out statistical analysis to identify differentially expressed genes (DEGs), functional enrichment analysis of the DEGs, protein–protein interaction networks, module analysis, transcription factors and target gene regulatory networks analysis, and identification of hub genes. The differential expression of the identified hub genes were validated with the independent TCGA-GBM dataset. We have identified a few crucial genes and pathways associated with GBM prognosis and therapy resistance. The DEGs identified from plasma were associated with inflammatory processes and viral infection. On the other hand, the hub genes identified from the serum samples were significantly associated with protein ubiquitinylation processes and cytokine signaling regulation. The findings indicate that GBM-derived plasma and serum DEGs may be associated with distinct cellular processes and pathways which facilitate GBM progression. The findings will provide better understanding of the molecular mechanisms of GBM pathogenesis and progression. These results can further be utilized for developing and validating minimally invasive diagnostic and therapeutic molecular biomarkers for GBM.

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

### Abstract

Non-nutritive sweeteners (NNSs) are commonly used to prevent weight gain and development of metabolic diseases associated with consumption of high-energy diets. Recent studies have demonstrated that these compounds may have unwanted detrimental effects under specific circumstances in vivo. In particular, an association between NNS consumption and changes in signaling pathways involved in the hunger-satiety system in the brain has been reported. Nonetheless, the extent of alterations in brain signaling pathways associated with consumption of these compounds has not been determined. The objective of this study was to determine the effect of frequent consumption of NNSs on the expression of proteins involved in signaling pathways related to appetite control in the brain in vivo. Eight-week-old BALB/c mice were supplemented with sucrose, sucralose, or steviol glycosides in their daily drinking water for 6 weeks. Subsequently, total brain protein extracts were used to analyze the expression of total and phosphorylated JAK2, STAT5, ERK 1/2, JNK, as well as SHP-2 and POMC, by western blot. Serum concentrations of leptin and α-MSH were quantified by ELISA. Results show that consumption of NNSs promotes significant changes in these signaling pathways, reducing the expression of pSTAT5/STAT5, pERK 1/2, SHP-2, and pJNK/JNK in male mice supplemented with steviol glycosides. Furthermore, consumption of steviol glycosides induced a decrease of α-MSH in male mice. In contrast, steviol glycosides induced overexpression of pSTAT5, pERK, and SHP-2 in females. These data suggest that chronic consumption of NNSs promotes sex-specific changes in signaling pathways related to the central hunger-satiety system in vivo.

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

### Abstract

As an important endogenous growth factor, PDGF-BB can effectively promote neurogenesis, thus is considered as a potential agent for Parkinson’s disease (PD) therapy. However, the protective function of PDGF-BB on neuronal cells, especially the molecular mechanism, remains less clear, which is needed to explore before its clinical practice. In this study, we investigated the function and mechanism of PDGF-BB against 1-methyl-4-phenylpyridinium (MPP+) toxicity in SH-SY5Y cells, a widely used cellular tool for PD-related molecular study. Our results indicated that PDGF-BB exerts a prominent protective effect against neurotoxin MPP+-triggered ROS generation and cellular loss. We further dissected the molecular mechanism involved in this process by using specific pharmacological inhibitors and validated that the distinct signaling pathways PI3K/Akt/GSK-3β and MEK/ERK are involved in the process against MPP+ toxicity upon PDGF-BB treatment. We also detected that activation of upstream PI3K/Akt/GSK-3β and MER/ERK signaling pathways contribute to phosphorylation and nuclear translocation of the downstream effector cyclic response element-binding protein (CREB), a known transcription factor to exhibit neuroprotective and growth-promoting effects. Using genetic approach, we further confirmed that the activation of CREB is involved in PDGF-BB-mediated protection in MPP+-exposed SH-SY5Y cells. Together, these data demonstrated the protective effect of PDGF-BB in MPP+-mediated toxicity in SH-SY5Y cells and verified the involved molecular mechanism in PDGF-BB-mediated neuroprotection.

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

• #### In This Issue [This Week in PNAS]

ENVIRONMENTAL SCIENCES Oceanic islands of the Nusa Tenggara island chain in Indonesia. Pleistocene human colonization and insular faunal extinction Humans have colonized islands since at least the Early Pleistocene Epoch. However, whether early human arrival to previously unoccupied islands contributed to insular faunal extinction during the Quaternary Period remains unclear....

in PNAS on May 18, 2021 03:10 PM.

• #### G2S3: A gene graph-based imputation method for single-cell RNA sequencing data

by Weimiao Wu, Yunqing Liu, Qile Dai, Xiting Yan, Zuoheng Wang

Single-cell RNA sequencing technology provides an opportunity to study gene expression at single-cell resolution. However, prevalent dropout events result in high data sparsity and noise that may obscure downstream analyses in single-cell transcriptomic studies. We propose a new method, G2S3, that imputes dropouts by borrowing information from adjacent genes in a sparse gene graph learned from gene expression profiles across cells. We applied G2S3 and ten existing imputation methods to eight single-cell transcriptomic datasets and compared their performance. Our results demonstrated that G2S3 has superior overall performance in recovering gene expression, identifying cell subtypes, reconstructing cell trajectories, identifying differentially expressed genes, and recovering gene regulatory and correlation relationships. Moreover, G2S3 is computationally efficient for imputation in large-scale single-cell transcriptomic datasets.

in PLoS Computational Biology on May 18, 2021 02:00 PM.

• #### Real-time single-cell characterization of the eukaryotic transcription cycle reveals correlations between RNA initiation, elongation, and cleavage

by Jonathan Liu, Donald Hansen, Elizabeth Eck, Yang Joon Kim, Meghan Turner, Simon Alamos, Hernan Garcia

The eukaryotic transcription cycle consists of three main steps: initiation, elongation, and cleavage of the nascent RNA transcript. Although each of these steps can be regulated as well as coupled with each other, their in vivo dissection has remained challenging because available experimental readouts lack sufficient spatiotemporal resolution to separate the contributions from each of these steps. Here, we describe a novel application of Bayesian inference techniques to simultaneously infer the effective parameters of the transcription cycle in real time and at the single-cell level using a two-color MS2/PP7 reporter gene and the developing fruit fly embryo as a case study. Our method enables detailed investigations into cell-to-cell variability in transcription-cycle parameters as well as single-cell correlations between these parameters. These measurements, combined with theoretical modeling, suggest a substantial variability in the elongation rate of individual RNA polymerase molecules. We further illustrate the power of this technique by uncovering a novel mechanistic connection between RNA polymerase density and nascent RNA cleavage efficiency. Thus, our approach makes it possible to shed light on the regulatory mechanisms in play during each step of the transcription cycle in individual, living cells at high spatiotemporal resolution.

in PLoS Computational Biology on May 18, 2021 02:00 PM.

• #### Robust switches in thalamic network activity require a timescale separation between sodium and T-type calcium channel activations

by Kathleen Jacquerie, Guillaume Drion

Switches in brain states, synaptic plasticity and neuromodulation are fundamental processes in our brain that take place concomitantly across several spatial and timescales. All these processes target neuron intrinsic properties and connectivity to achieve specific physiological goals, raising the question of how they can operate without interfering with each other. Here, we highlight the central importance of a timescale separation in the activation of sodium and T-type calcium channels to sustain robust switches in brain states in thalamic neurons that are compatible with synaptic plasticity and neuromodulation. We quantify the role of this timescale separation by comparing the robustness of rhythms of six published conductance-based models at the cellular, circuit and network levels. We show that robust rhythm generation requires a T-type calcium channel activation whose kinetics are situated between sodium channel activation and T-type calcium channel inactivation in all models despite their quantitative differences.

in PLoS Computational Biology on May 18, 2021 02:00 PM.

• #### scHiCTools: A computational toolbox for analyzing single-cell Hi-C data

by Xinjun Li, Fan Feng, Hongxi Pu, Wai Yan Leung, Jie Liu

Single-cell Hi-C (scHi-C) sequencing technologies allow us to investigate three-dimensional chromatin organization at the single-cell level. However, we still need computational tools to deal with the sparsity of the contact maps from single cells and embed single cells in a lower-dimensional Euclidean space. This embedding helps us understand relationships between the cells in different dimensions, such as cell-cycle dynamics and cell differentiation. We present an open-source computational toolbox, scHiCTools, for analyzing single-cell Hi-C data comprehensively and efficiently. The toolbox provides two methods for screening single cells, three common methods for smoothing scHi-C data, three efficient methods for calculating the pairwise similarity of cells, three methods for embedding single cells, three methods for clustering cells, and a build-in function to visualize the cells embedding in a two-dimensional or three-dimensional plot. scHiCTools, written in Python3, is compatible with different platforms, including Linux, macOS, and Windows.

in PLoS Computational Biology on May 18, 2021 02:00 PM.

• #### Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure

by Saskia Haupt, Alexander Zeilmann, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

in PLoS Computational Biology on May 18, 2021 02:00 PM.

• #### Correction: Time of day is associated with paradoxical reductions in global signal fluctuation and functional connectivity

by Csaba Orban, Ru Kong, Jingwei Li, Michael W. L. Chee, B. T. Thomas Yeo

in PLoS Biology on May 18, 2021 02:00 PM.

• #### Integrated transcriptomics and epigenomics reveal chamber-specific and species-specific characteristics of human and mouse hearts

by Junpeng Gao, Yuxuan Zheng, Lin Li, Minjie Lu, Xiangjian Chen, Yu Wang, Yanna Li, Xiaomeng Liu, Yun Gao, Yunuo Mao, Peng Zhao, Jinan Zhang, Fuchou Tang, Lei Song, Lu Wen, Jizheng Wang

DNA methylation, chromatin accessibility, and gene expression represent different levels information in biological process, but a comprehensive multiomics analysis of the mammalian heart is lacking. Here, we applied nucleosome occupancy and methylome sequencing, which detected DNA methylation and chromatin accessibility simultaneously, as well as RNA-seq, for multiomics analysis of the 4 chambers of adult and fetal human hearts, and adult mouse hearts. Our results showed conserved region-specific patterns in the mammalian heart at transcriptome and DNA methylation level. Adult and fetal human hearts showed distinct features in DNA methylome, chromatin accessibility, and transcriptome. Novel long noncoding RNAs were identified in the human heart, and the gene expression profiles of major cardiovascular diseases associated genes were displayed. Furthermore, cross-species comparisons revealed human-specific and mouse-specific differentially expressed genes between the atria and ventricles. We also reported the relationship among multiomics and found there was a bell-shaped relationship between gene-body methylation and expression in the human heart. In general, our study provided comprehensive spatiotemporal and evolutionary insights into the regulation of gene expression in the heart.

in PLoS Biology on May 18, 2021 02:00 PM.

• #### Streaming cascade-based speech translation leveraged by a direct segmentation model

Publication date: Available online 17 May 2021

Source: Neural Networks

Author(s): Javier Iranzo-Sánchez, Javier Jorge, Pau Baquero-Arnal, Joan Albert Silvestre-Cerdà, Adrià Giménez, Jorge Civera, Albert Sanchis, Alfons Juan

in Neural Networks on May 18, 2021 01:00 PM.

• #### Geometrically regulating evolutionary dynamics in biofilms

Author(s): Youness Azimzade and Abbas Ali Saberi

The theoretical understanding of evolutionary dynamics in spatially structured populations often relies on nonspatial models. Biofilms are among such populations where a more accurate understanding is of theoretical interest and can reveal new solutions to existing challenges. Here, we studied how t...

[Phys. Rev. E 103, L050401] Published Tue May 18, 2021

in Physical Review E: Biological physics on May 18, 2021 10:00 AM.

• #### Exploring dissipative sources of non-Markovian biochemical reaction systems

Author(s): Xiyan Yang, Yiren Chen, Tianshou Zhou, and Jiajun Zhang

Many biological processes including important intracellular processes are governed by biochemical reaction networks. Usually, these reaction systems operate far from thermodynamic equilibrium, implying free-energy dissipation. On the other hand, single reaction events happen often in a memory manner...

[Phys. Rev. E 103, 052411] Published Tue May 18, 2021

in Physical Review E: Biological physics on May 18, 2021 10:00 AM.

• #### Universal Regular Conditional Distributions via Probability Measure-Valued Deep Neural Models. (arXiv:2105.07743v1 [cs.LG])

This paper introduces a general framework for explicitly constructing universal deep neural models with inputs from a complete, separable, and locally-compact metric space $\mathcal{X}$ and outputs in the Wasserstein-1 $\mathcal{P}_1(\mathcal{Y})$ space over a complete and separable metric space $\mathcal{Y}$. We find that any model built using the proposed framework is dense in the space $C(\mathcal{X},\mathcal{P}_1(\mathcal{Y}))$ of continuous functions from $\mathcal{X}$ to $\mathcal{P}_1(\mathcal{Y})$ in the corresponding uniform convergence on compacts topology, quantitatively. We identify two methods in which the curse of dimensionality can be broken. The first approach constructs subsets of $C(\mathcal{X},\mathcal{P}_1(\mathcal{Y}))$ consisting of functions that can be efficiently approximated. In the second approach, given any fixed $f \in C(\mathcal{X},\mathcal{P}_1(\mathcal{Y}))$, we build non-trivial subsets of $\mathcal{X}$ on which $f$ can be efficiently approximated. The results are applied to three open problems lying at the interface of applied probability and computational learning theory. We find that the proposed models can approximate any regular conditional distribution of a $\mathcal{Y}$-valued random element $Y$ depending on an $\mathcal{X}$-valued random element $X$, with arbitrarily high probability. The proposed models are also shown to be capable of generically expressing the aleatoric uncertainty present in most randomized machine learning models. The proposed framework is used to derive an affirmative answer to the open conjecture of Bishop (1994); namely: mixture density networks are generic regular conditional distributions. Numerical experiments are performed in the contexts of extreme learning machines, randomized DNNs, and heteroscedastic regression.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 18, 2021 01:30 AM.

• #### Chimeras unfolded. (arXiv:2105.07541v1 [nlin.CD])

The instability of mixing in the Kuramoto model of coupled phase oscillators is the key to understanding a range of spatiotemporal patterns, which feature prominently in collective dynamics of systems ranging from neuronal networks, to coupled lasers, to power grids. In this paper, we describe a codimension-2 bifurcation of mixing whose unfolding, in addition to the classical scenario of the onset of synchronization, also explains the formation of clusters and chimeras. We use a combination of linear stability analysis and Penrose diagrams to identify and analyze a variety of spatiotemporal patterns including stationary and traveling coherent clusters and twisted states, as well as their combinations with regions of incoherent behavior called chimera states. The linear stability analysis is used to estimate of the velocity distribution within these structures. Penrose diagrams, on the other hand, predict accurately the basins of their existence. Furthermore, we show that network topology can endow chimera states with nontrivial spatial organization. In particular, we present twisted chimera states, whose coherent regions are organized as stationary or traveling twisted states. The analytical results are illustrated with numerical bifurcation diagrams computed for the Kuramoto model with uni-, bi-, and tri-modal frequency distributions and all-to-all and nonlocal nearest-neighbor connectivity.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### Bayesian reconstruction of memories stored in neural networks from their connectivity. (arXiv:2105.07416v1 [q-bio.NC])

The advent of comprehensive synaptic wiring diagrams of large neural circuits has created the field of connectomics and given rise to a number of open research questions. One such question is whether it is possible to reconstruct the information stored in a recurrent network of neurons, given its synaptic connectivity matrix. Here, we address this question by determining when solving such an inference problem is theoretically possible in specific attractor network models and by providing a practical algorithm to do so. The algorithm builds on ideas from statistical physics to perform approximate Bayesian inference and is amenable to exact analysis. We study its performance on three different models and explore the limitations of reconstructing stored patterns from synaptic connectivity.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### Towards a Predictive Processing Implementation of the Common Model of Cognition. (arXiv:2105.07308v1 [cs.AI])

In this article, we present a cognitive architecture that is built from powerful yet simple neural models. Specifically, we describe an implementation of the common model of cognition grounded in neural generative coding and holographic associative memory. The proposed system creates the groundwork for developing agents that learn continually from diverse tasks as well as model human performance at larger scales than what is possible with existant cognitive architectures.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### A brain basis of dynamical intelligence for AI and computational neuroscience. (arXiv:2105.07284v1 [q-bio.NC])

The deep neural nets of modern artificial intelligence (AI) have not achieved defining features of biological intelligence, including abstraction, causal learning, and energy-efficiency. While scaling to larger models has delivered performance improvements for current applications, more brain-like capacities may demand new theories, models, and methods for designing artificial learning systems. Here, we argue that this opportunity to reassess insights from the brain should stimulate cooperation between AI research and theory-driven computational neuroscience (CN). To motivate a brain basis of neural computation, we present a dynamical view of intelligence from which we elaborate concepts of sparsity in network structure, temporal dynamics, and interactive learning. In particular, we suggest that temporal dynamics, as expressed through neural synchrony, nested oscillations, and flexible sequences, provide a rich computational layer for reading and updating hierarchical models distributed in long-term memory networks. Moreover, embracing agent-centered paradigms in AI and CN will accelerate our understanding of the complex dynamics and behaviors that build useful world models. A convergence of AI/CN theories and objectives will reveal dynamical principles of intelligence for brains and engineered learning systems. This article was inspired by our symposium on dynamical neuroscience and machine learning at the 6th Annual US/NIH BRAIN Initiative Investigators Meeting.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### FOGA: Flag Optimization with Genetic Algorithm. (arXiv:2105.07202v1 [cs.NE])

Recently, program autotuning has become very popular especially in embedded systems, when we have limited resources such as computing power and memory where these systems run generally time-critical applications. Compiler optimization space gradually expands with the renewed compiler options and inclusion of new architectures. These advancements bring autotuning even more important position. In this paper, we introduced Flag Optimization with Genetic Algorithm (FOGA) as an autotuning solution for GCC flag optimization. FOGA has two main advantages over the other autotuning approaches: the first one is the hyperparameter tuning of the genetic algorithm (GA), the second one is the maximum iteration parameter to stop when no further improvement occurs. We demonstrated remarkable speedup in the execution time of C++ source codes with the help of optimization flags provided by FOGA when compared to the state of the art framework OpenTuner.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 18, 2021 01:30 AM.

• #### Joint estimation of multiple Granger causal networks: Inference of group-level brain connectivity. (arXiv:2105.07196v1 [cs.LG])

This paper considers joint learning of multiple sparse Granger graphical models to discover underlying common and differential Granger causality (GC) structures across multiple time series. This can be applied to drawing group-level brain connectivity inferences from a homogeneous group of subjects or discovering network differences among groups of signals collected under heterogeneous conditions. By recognizing that the GC of a single multivariate time series can be characterized by common zeros of vector autoregressive (VAR) lag coefficients, a group sparse prior is included in joint regularized least-squares estimations of multiple VAR models. Group-norm regularizations based on group- and fused-lasso penalties encourage a decomposition of multiple networks into a common GC structure, with other remaining parts defined in individual-specific networks. Prior information about sparseness and sparsity patterns of desired GC networks are incorporated as relative weights, while a non-convex group norm in the penalty is proposed to enhance the accuracy of network estimation in low-sample settings. Extensive numerical results on simulations illustrated our method's improvements over existing sparse estimation approaches on GC network sparsity recovery. Our methods were also applied to available resting-state fMRI time series from the ADHD-200 data sets to learn the differences of causality mechanisms, called effective brain connectivity, between adolescents with ADHD and typically developing children. Our analysis revealed that parts of the causality differences between the two groups often resided in the orbitofrontal region and areas associated with the limbic system, which agreed with clinical findings and data-driven results in previous studies.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### NeuroGen: activation optimized image synthesis for discovery neuroscience. (arXiv:2105.07140v1 [q-bio.NC])

Functional MRI (fMRI) is a powerful technique that has allowed us to characterize visual cortex responses to stimuli, yet such experiments are by nature constructed based on a priori hypotheses, limited to the set of images presented to the individual while they are in the scanner, are subject to noise in the observed brain responses, and may vary widely across individuals. In this work, we propose a novel computational strategy, which we call NeuroGen, to overcome these limitations and develop a powerful tool for human vision neuroscience discovery. NeuroGen combines an fMRI-trained neural encoding model of human vision with a deep generative network to synthesize images predicted to achieve a target pattern of macro-scale brain activation. We demonstrate that the reduction of noise that the encoding model provides, coupled with the generative network's ability to produce images of high fidelity, results in a robust discovery architecture for visual neuroscience. By using only a small number of synthetic images created by NeuroGen, we demonstrate that we can detect and amplify differences in regional and individual human brain response patterns to visual stimuli. We then verify that these discoveries are reflected in the several thousand observed image responses measured with fMRI. We further demonstrate that NeuroGen can create synthetic images predicted to achieve regional response patterns not achievable by the best-matching natural images. The NeuroGen framework extends the utility of brain encoding models and opens up a new avenue for exploring, and possibly precisely controlling, the human visual system.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### Edges in Brain Networks: Contributions to Models of Structure and Function. (arXiv:2105.07069v1 [q-bio.NC])

Network models describe the brain as sets of nodes and edges that represent its distributed organization. So far, most discoveries in network neuroscience have prioritized insights that highlight distinct groupings and specialized functional contributions of network nodes. Importantly, these functional contributions are determined and expressed by the web of their interrelationships, formed by network edges. Here, we underscore the important contributions made by brain network edges for understanding distributed brain organization. Different types of edges represent different types of relationships, including connectivity and similarity among nodes. Adopting a specific definition of edges can fundamentally alter how we analyze and interpret a brain network. Furthermore, edges can associate into collectives and higher-order arrangements, describe time series, and form edge communities that provide insights into brain network topology complementary to the traditional node-centric perspective. Focusing on the edges, and the higher-order or dynamic information they can provide, discloses previously underappreciated aspects of structural and functional network organization.

in arXiv: Quantitative Biology: Neurons and Cognition on May 18, 2021 01:30 AM.

• #### Author Correction: Investigation of the fine structure of antihydrogen

Nature, Published online: 18 May 2021; doi:10.1038/s41586-021-03367-9

Author Correction: Investigation of the fine structure of antihydrogen

in Nature on May 18, 2021 12:00 AM.

• #### Global effects of land-use intensity on local pollinator biodiversity

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23228-3

Anthropogenic losses of animal pollinators threaten ecosystem functioning. Here the authors report a global analysis showing geographically varied yet widespread declines of pollinator diversity and abundance with land use intensification, particularly in tropical biomes.

in Nature Communications on May 18, 2021 12:00 AM.

• #### Biomimetic high performance artificial muscle built on sacrificial coordination network and mechanical training process

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23204-x

Artificial muscles have a wide range of applications yet truly mimetic designs remain a challenge. Here, the authors use dynamic sacrificial bonds which are rearranged via a mechanical training process to optimise the characteristics of self-strengthening, strain-adaptive stiffening and actuation.

in Nature Communications on May 18, 2021 12:00 AM.

• #### Superconductor-insulator transition in space charge doped one unit cell Bi2.1Sr1.9CaCu2O8+x

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23183-z

Previous work on critical scaling at the superconductor-to-insulator transition has shown variations across different materials. Here, the authors use a space charge doping technique to tune the transition in a single layer cuprate sample and present evidence of the universal scaling behaviour.

in Nature Communications on May 18, 2021 12:00 AM.

• #### Spectral bias and task-model alignment explain generalization in kernel regression and infinitely wide neural networks

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23103-1

Canatar et al. propose a predictive theory of generalization in kernel regression applicable to real data. This theory explains various generalization phenomena observed in wide neural networks, which admit a kernel limit and generalize well despite being overparameterized.

in Nature Communications on May 18, 2021 12:00 AM.

• #### A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23084-1

Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.

in Nature Communications on May 18, 2021 12:00 AM.

• #### Low coordination number copper catalysts for electrochemical CO2 methanation in a membrane electrode assembly

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23065-4

Electrochemical conversion of carbon dioxide to methane can store intermittent renewable electricity in a staple of global energy. Here, the authors develop a moderator strategy to maintain the catalyst in a low coordination state, thereby enabling stable and selective electrochemical methanation.

in Nature Communications on May 18, 2021 12:00 AM.

• #### A well-timed shift from local to global agreements accelerates climate change mitigation

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23056-5

Do we mitigate climate change in a Kyoto style global agreement or via multiple agreements among smaller groups of states? Here the authors show that the best strategy may begin with regional legally binding, aggressive agreements and, as these become common, renew pursuit of a global legally-binding treaty.

in Nature Communications on May 18, 2021 12:00 AM.

• #### The effect of generic market entry on antibiotic prescriptions in the United States

Nature Communications, Published online: 18 May 2021; doi:10.1038/s41467-021-23049-4

Generics contribute to increased availability of antibiotics, benefiting healthcare systems but potentially leading to increased consumption with implications for antibiotic stewardship and resistance. Here, the authors found no consistent changes in prescribing patterns of the 13 antibiotics that entered the US market as generics from 2000–2012.

in Nature Communications on May 18, 2021 12:00 AM.

• #### Why the China Mars rover’s landing site has geologists excited

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01340-0

Scientists flag ancient mud volcanoes, impact craters, subsurface ice and sand dunes as potential stopping-off points on Zhurong’s dream itinerary.

in Nature on May 18, 2021 12:00 AM.

• #### Contrails: tweaking flight altitude could be a climate win

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01339-7

Contrails: tweaking flight altitude could be a climate win

in Nature on May 18, 2021 12:00 AM.

• #### UNESCO embraces open science to shape society’s future

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01338-8

UNESCO embraces open science to shape society’s future

in Nature on May 18, 2021 12:00 AM.

• #### University of Cape Town’s battle to tackle a racist legacy

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01321-3

Six years after a statue of Cecil Rhodes was toppled, students and staff at the South African university are still working to improve equity and representation.

in Nature on May 18, 2021 12:00 AM.

• #### How COVID is changing the study of human behaviour

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01317-z

The pandemic is teaching us key lessons about crisis, communication and misinformation, and is spurring changes in the way scientists study public-health questions.

in Nature on May 18, 2021 12:00 AM.

• #### Universal health care must be a priority — even amid COVID

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01313-3

A focus on specific diseases has derailed efforts to achieve health care for all before. The world must not repeat that mistake with COVID-19.

in Nature on May 18, 2021 12:00 AM.

• #### Virus variants: GISAID policies incentivize surveillance in global south

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01310-6

Virus variants: GISAID policies incentivize surveillance in global south

in Nature on May 18, 2021 12:00 AM.

• #### Statistics: unify ecosystems valuation

Nature, Published online: 18 May 2021; doi:10.1038/d41586-021-01309-z

Statistics: unify ecosystems valuation

in Nature on May 18, 2021 12:00 AM.

• #### Journal of Computational Neuroscience

in Journal of Computational Neuroscience on May 18, 2021 12:00 AM.

• #### Cortical propagating waves: amplifying and suppressive?

in Journal of Computational Neuroscience on May 18, 2021 12:00 AM.

### Abstract

A woman, age 44, with a positive anti-YO paraneoplastic cerebellar syndrome and normal imaging developed an ocular motor disorder including periodic alternating nystagmus (PAN), gaze-evoked nystagmus (GEN) and rebound nystagmus (RN). During fixation there was typical PAN but changes in gaze position evoked complex, time-varying oscillations of GEN and RN. To unravel the pathophysiology of this unusual pattern of nystagmus, we developed a mathematical model of normal function of the circuits mediating the vestibular-ocular reflex and gaze-holding including their adaptive mechanisms. Simulations showed that all the findings of our patient could be explained by two, small, isolated changes in cerebellar circuits: reducing the time constant of the gaze-holding integrator, producing GEN and RN, and increasing the gain of the vestibular velocity-storage positive feedback loop, producing PAN. We conclude that the gaze- and time-varying pattern of nystagmus in our patient can be accounted for by superposition of one model that produces typical PAN and another model that produces typical GEN and RN, without requiring a new oscillator in the gaze-holding system or a more complex, nonlinear interaction between the two models. This analysis suggest a strategy for uncovering gaze-evoked and rebound nystagmus in the setting of a time-varying nystagmus such as PAN. Our results are also consistent with current ideas of compartmentalization of cerebellar functions for the control of the vestibular velocity-storage mechanism (nodulus and ventral uvula) and for holding horizontal gaze steady (the flocculus and tonsil).

in Journal of Computational Neuroscience on May 18, 2021 12:00 AM.

### Abstract

It has previously been shown that the encoding of time-dependent signals by feedforward networks (FFNs) of processing units exhibits suprathreshold stochastic resonance (SSR), which is an optimal signal transmission for a finite level of independent, individual stochasticity in the single units. In this study, a recurrent spiking network is simulated to demonstrate that SSR can be also caused by network noise in place of intrinsic noise. The level of autonomously generated fluctuations in the network can be controlled by the strength of synapses, and hence the coding fraction (our measure of information transmission) exhibits a maximum as a function of the synaptic coupling strength. The presence of a coding peak at an optimal coupling strength is robust over a wide range of individual, network, and signal parameters, although the optimal strength and peak magnitude depend on the parameter being varied. We also perform control experiments with an FFN illustrating that the optimized coding fraction is due to the change in noise level and not from other effects entailed when changing the coupling strength. These results also indicate that the non-white (temporally correlated) network noise in general provides an extra boost to encoding performance compared to the FFN driven by intrinsic white noise fluctuations.

in Journal of Computational Neuroscience on May 18, 2021 12:00 AM.

• #### Decoding Spatial Memory Retrieval in Cubical Space Using fMRI Signals

The way spatial memory retrieval is represented in the brain remains unclear to date. Previous studies have displayed a hippocampus-centered navigation network using functional magnetic resonance imaging (fMRI) analysis. There have been some studies on the representation of navigation behavior by signal distribution patterns, but only in the hippocampus and adjacent structures. In this study, we aimed to determine (1) the brain regions that represent information in both intensity and distribution patterns during spatial memory retrieval and (2) whether the patterns of neural responses represent spatial memory retrieval behavior performance. Both univariate analysis [general linear model (GLM)] and multivariate pattern analysis (MVPA) were employed to reveal the spatial distributions of brain responses elicited by spatial memory retrieval. Correlation analyses were performed to detect the correspondences between brain responses and behavior performance. We found that spatial memory retrieval occurred in widespread brain regions, including the bilateral hippocampi, bilateral superior frontal gyrus, bilateral superior parietal lobules, bilateral occipital lobes, and cerebellum. The amplitude of activation in the left hippocampus showed a significant negative correlation (r = −0.46, p = 0.039) with the number of task completions. Additionally, within-subject classification accuracies based on the blood oxygenation level-dependent (BOLD) signal patterns of the right middle temporal gyrus (rMTG) rostral areas in the Brainnetome Atlas showed a significant positive correlation (r = 0.78, p < 0.0001) with retrieval accuracy. In summary, our findings have implications for understanding the separation between navigational and non-navigational states and emphasizing the utility of MVPA in the whole brain.

in Frontiers in Neural Circuits on May 18, 2021 12:00 AM.

• #### Upregulation of lncRNA147410.3 in the Brain of Mice With Chronic Toxoplasma Infection Promoted Microglia Apoptosis by Regulating Hoxb3

Toxoplasma gondii is neurotropic and affects the function of nerve cells, while the mechanism is unclear. LncRNAs are abundantly enriched in the brain and participated in the delicate regulation of the central nervous system (CNS) development. However, whether these lncRNAs are involved in the regulation of microglia activation during the process of T. gondii infection is largely unknown. In this study, the upregulation of a novel lncRNA147410.3 (ENSMUST00000147410.3) was identified as a key factor to influence this process. The target gene of lncRNA147410.3 was predicted and identified as Hoxb3. The localization of lncRNA147410.3 in the brain and cells was proved in the nucleus of neuroglia through FISH assay. Furthermore, the function of lncRNA147410.3 on neuronal cell was confirmed that lncRNA147410.3 could affect proliferation, differentiation, and apoptosis of mouse microglia by positively regulating Hoxb3. Thus, our study explored the modulatory action of lncRNA147410.3 in T. gondii infected mouse brain, providing a scientific basis for using lncRNA147410.3 as a therapeutic target to treat neurological disorder induced by T. gondii.

in Frontiers in Cellular Neuroscience on May 18, 2021 12:00 AM.

• #### Avoiding culture shock with the SARS-CoV-2 spike protein

When culturing SARS-CoV-2 in the laboratory it is vital to avoid deletions in the gene for the spike protein that could affect the interpretation of experiments.

in eLife on May 18, 2021 12:00 AM.

• #### PHAROH lncRNA regulates Myc translation in hepatocellular carcinoma via sequestering TIAR

Hepatocellular carcinoma, the most common type of liver malignancy, is one of the most lethal forms of cancer. We identified a long non-coding RNA, Gm19705, that is over-expressed in hepatocellular carcinoma and mouse embryonic stem cells. We named this RNA Pluripotency and Hepatocyte Associated RNA Overexpressed in HCC, or PHAROH. Depletion of PHAROH impacts cell proliferation and migration, which can be rescued by ectopic expression of PHAROH. RNA-seq analysis of PHAROH knockouts revealed that a large number of genes with decreased expression contain a Myc motif in their promoter. MYC is decreased at the protein level, but not the mRNA level. RNA-antisense pulldown identified nucleolysin TIAR, a translational repressor, to bind to a 71-nt hairpin within PHAROH, sequestration of which increases MYC translation. In summary, our data suggest that PHAROH regulates MYC translation by sequestering TIAR and as such represents a potentially exciting diagnostic or therapeutic target in hepatocellular carcinoma.

in eLife on May 18, 2021 12:00 AM.

• #### The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry

Background: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis.

in eLife on May 18, 2021 12:00 AM.

• #### Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

in eLife on May 18, 2021 12:00 AM.

• #### Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics

Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS CoV-2 spread is largely unknown.

in eLife on May 18, 2021 12:00 AM.

• #### Random sub-diffusion and capture of genes by the nuclear pore reduces dynamics and coordinates interchromosomal movement

Hundreds of genes interact with the yeast nuclear pore complex (NPC), localizing at the nuclear periphery and clustering with co-regulated genes. Dynamic tracking of peripheral genes shows that they cycle on and off the NPC and that interaction with the NPC slows their sub-diffusive movement. Furthermore, NPC-dependent inter-chromosomal clustering leads to coordinated movement of pairs of loci separated by hundreds of nanometers. We developed Fractional Brownian Motion simulations for chromosomal loci in the nucleoplasm and interacting with NPCs. These simulations predict the rate and nature of random sub-diffusion during repositioning from nucleoplasm to periphery and match measurements from two different experimental models, arguing that recruitment to the nuclear periphery is due to random sub-diffusion and transient capture by NPCs. Finally, the simulations do not lead to inter-chromosomal clustering or coordinated movement, suggesting that interaction with the NPC is necessary, but not sufficient, to cause clustering.

in eLife on May 18, 2021 12:00 AM.

• #### R7 photoreceptor axon targeting depends on the relative levels of lost and found expression in R7 and its synaptic partners

As neural circuits form, growing processes select the correct synaptic partners through interactions between cell surface proteins. The presence of such proteins on two neuronal processes may lead to either adhesion or repulsion; however, the consequences of mismatched expression have rarely been explored. Here we show that the Drosophila CUB-LDL protein Lost and found (Loaf) is required in the UV-sensitive R7 photoreceptor for normal axon targeting only when Loaf is also present in its synaptic partners. Although targeting occurs normally in loaf mutant animals, removing loaf from photoreceptors or expressing it in their postsynaptic neurons Tm5a/b or Dm9 in a loaf mutant causes mistargeting of R7 axons. Loaf localizes primarily to intracellular vesicles including endosomes. We propose that Loaf regulates the trafficking or function of one or more cell surface proteins, and an excess of these proteins on the synaptic partners of R7 prevents the formation of stable connections.

in eLife on May 18, 2021 12:00 AM.

• #### Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell type-dependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.

in eLife on May 18, 2021 12:00 AM.

• #### Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception

Hedgehog (Hh) signaling patterns embryonic tissues and contributes to homeostasis in adults. In Drosophila, Hh transport and signaling are thought to occur along a specialized class of actin-rich filopodia, termed cytonemes. Here, we report that Interference hedgehog (Ihog) not only forms a Hh receptor complex with Patched to mediate intracellular signaling, but Ihog also engages in trans-homophilic binding leading to cytoneme stabilization in a manner independent of its role as the Hh receptor. Both functions of Ihog (trans-homophilic binding for cytoneme stabilization and Hh binding for ligand sensing) involve a heparin-binding site on the first fibronectin repeat of the extracellular domain. Thus, the Ihog-Ihog interaction and the Hh-Ihog interaction cannot occur simultaneously for a single Ihog molecule. By combining experimental data and mathematical modeling, we determined that Hh-Ihog heterophilic interaction dominates and Hh can disrupt and displace Ihog molecules involved in trans-homophilic binding. Consequently, we proposed that the weaker Ihog-Ihog trans interaction promotes and stabilizes direct membrane contacts along cytonemes and that, as the cytoneme encounters secreted Hh ligands, the ligands trigger release of Ihog from trans Ihog-Ihog complex enabling transport or internalization of the Hh ligand-Ihog-Patched -receptor complex. Thus, the seemingly incompatible functions of Ihog in homophilic adhesion and ligand binding cooperate to assist Hh transport and reception along the cytonemes.

in eLife on May 18, 2021 12:00 AM.

• #### Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection

Bacterial pathogens that infect phagocytic cells must deploy mechanisms that sense and neutralize host microbicidal effectors. For Mycobacterium tuberculosis, the causative agent of tuberculosis, these mechanisms allow the bacterium to rapidly adapt from aerosol transmission to initial growth in the lung alveolar macrophage. Here, we identify a branched signaling circuit in M. tuberculosis that controls growth in the lung through integrated direct sensing of copper ions and nitric oxide by coupled activity of the Rip1 intramembrane protease and the PdtaS/R two-component system. This circuit uses a two-signal mechanism to inactivate the PdtaS/PdtaR two-component system, which constitutively represses virulence gene expression. Cu and NO inhibit the PdtaS sensor kinase through a dicysteine motif in the N-terminal GAF domain. The NO arm of the pathway is further controlled by sequestration of the PdtaR RNA binding response regulator by an NO-induced small RNA, controlled by the Rip1 intramembrane protease. This coupled Rip1/PdtaS/PdtaR circuit controls NO resistance and acute lung infection in mice by relieving PdtaS/R-mediated repression of isonitrile chalkophore biosynthesis. These studies identify an integrated mechanism by which M. tuberculosis senses and resists macrophage chemical effectors to achieve pathogenesis

in eLife on May 18, 2021 12:00 AM.

• #### Polymerization of misfolded Z alpha-1antitrypin protein lowers CX3CR1 expression in human PBMCs

The CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host`s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human PBMCs. This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.

in eLife on May 18, 2021 12:00 AM.

• #### Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics and treatment regimens

The success of antimicrobial treatment is threatened by the evolution of drug resistance. Population genetic models are an important tool in mitigating that threat. However, most such models consider resistance emergence via a single mutational step. Here, we assembled experimental evidence that drug resistance evolution follows two patterns: i) a single mutation, which provides a large resistance benefit, or ii) multiple mutations, each conferring a small benefit, which combine to yield high-level resistance. Using stochastic modeling we then investigated the consequences of these two patterns for treatment failure and population diversity under various treatments. We find that resistance evolution is substantially limited if more than two mutations are required and that the extent of this limitation depends on the combination of drug type and pharmacokinetic profile. Further, if multiple mutations are necessary, adaptive treatment, which only suppresses the bacterial population, delays treatment failure due to resistance for a longer time than aggressive treatment, which aims at eradication.

in eLife on May 18, 2021 12:00 AM.

• #### Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. Using mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

in eLife on May 18, 2021 12:00 AM.

• #### PIE-1 SUMOylation promotes germline fates and piRNA-dependent silencing in C. elegans

Germlines shape and balance heredity, integrating and regulating information from both parental and foreign sources. Insights into how germlines handle information have come from the study of factors that specify or maintain the germline fate. In early Caenorhabditis elegans embryos, the CCCH zinc finger protein PIE-1 localizes to the germline where it prevents somatic differentiation programs. Here, we show that PIE-1 also functions in the meiotic ovary where it becomes SUMOylated and engages the small ubiquitin-like modifier (SUMO)-conjugating machinery. Using whole-SUMO-proteome mass spectrometry, we identify HDAC SUMOylation as a target of PIE-1. Our analyses of genetic interactions between pie-1 and SUMO pathway mutants suggest that PIE-1 engages the SUMO machinery both to preserve the germline fate in the embryo and to promote Argonaute-mediated surveillance in the adult germline.

in eLife on May 18, 2021 12:00 AM.

• #### HDAC1 SUMOylation promotes Argonaute-directed transcriptional silencing in C. elegans

Eukaryotic cells use guided search to coordinately control dispersed genetic elements. Argonaute proteins and their small RNA cofactors engage nascent RNAs and chromatin-associated proteins to direct transcriptional silencing. The small ubiquitin-like modifier (SUMO) has been shown to promote the formation and maintenance of silent chromatin (called heterochromatin) in yeast, plants, and animals. Here, we show that Argonaute-directed transcriptional silencing in Caenorhabditis elegans requires SUMOylation of the type 1 histone deacetylase HDA-1. Our findings suggest how SUMOylation promotes the association of HDAC1 with chromatin remodeling factors and with a nuclear Argonaute to initiate de novo heterochromatin silencing.

in eLife on May 18, 2021 12:00 AM.

• #### Integrated transcriptomic and neuroimaging brain model decodes biological mechanisms in aging and Alzheimer’s disease

Both healthy aging and Alzheimer’s disease (AD) are characterized by concurrent alterations in several biological factors. However, generative brain models of aging and AD are limited in incorporating the measures of these biological factors at different spatial resolutions. Here, we propose a personalized bottom-up spatiotemporal brain model that accounts for the direct interplay between hundreds of RNA transcripts and multiple macroscopic neuroimaging modalities (PET, MRI). In normal elderly and AD participants, the model identifies top genes modulating tau and amyloid-β burdens, vascular flow, glucose metabolism, functional activity, and atrophy to drive cognitive decline. The results also revealed that AD and healthy aging share specific biological mechanisms, even though AD is a separate entity with considerably more altered pathways. Overall, this personalized model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying effective genetic targets for extending healthy aging and treating AD progression.

in eLife on May 18, 2021 12:00 AM.

• #### ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß2-arrestin dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß2-arrestin deficient mice and instead find no connection between ß2-arrestin and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.

in eLife on May 18, 2021 12:00 AM.

• #### Live-imaging of endothelial Erk activity reveals dynamic and sequential signalling events during regenerative angiogenesis

The formation of new blood vessel networks occurs via angiogenesis during development, tissue repair and disease. Angiogenesis is regulated by intracellular endothelial signalling pathways, induced downstream of Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). A major challenge in understanding angiogenesis is interpreting how signalling events occur dynamically within endothelial cell populations during sprouting, proliferation and migration. Erk is a central downstream effector of Vegf-signalling and reports the signalling that drives angiogenesis. We generated a vascular Erk biosensor transgenic line in zebrafish using a kinase translocation reporter that allows live-imaging of Erk-signalling dynamics. We demonstrate the utility of this line to live-image Erk activity during physiologically relevant angiogenic events. Further, we reveal dynamic and sequential endothelial cell Erk-signalling events following blood vessel wounding. Initial signalling is dependent upon Ca2+ in the earliest responding endothelial cells, but is independent of Vegfr-signalling and local inflammation. The sustained regenerative response however, involves a Vegfr-dependent mechanism that initiates concomitant with the wound inflammatory response. This work reveals a highly dynamic sequence of signalling events in regenerative angiogenesis and validates a new resource for the study of vascular Erk-signalling in real-time.

in eLife on May 18, 2021 12:00 AM.

• #### HSPCs display within-family homogeneity in differentiation and proliferation despite population heterogeneity

High-throughput single cell methods have uncovered substantial heterogeneity in the pool of hematopoietic stem and progenitor cells (HSPCs), but how much instruction is inherited by offspring from their heterogeneous ancestors remains unanswered. Using a method that enables simultaneous determination of common ancestor, division number, and differentiation status of a large collection of single cells, our data revealed that murine cells that derived from a common ancestor had significant similarities in their division progression and differentiation outcomes. Although each family diversifies, the overall collection of cell types observed is composed of homogeneous families. Heterogeneity between families could be explained, in part, by differences in ancestral expression of cell-surface markers. Our analyses demonstrate that fate decision by cells are largely inherited from ancestor cells, indicating the importance of common ancestor effects. These results may have ramifications for bone marrow transplantation and leukemia, where substantial heterogeneity in HSPC behavior is observed.

in eLife on May 18, 2021 12:00 AM.

• #### The severity of microstrokes depends on local vascular topology and baseline perfusion

Cortical microinfarcts are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of blood flow disturbance has not yet been identified. We employed blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single capillary occlusions. Our simulations reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in perfusion are observed in capillaries with two in- and two outflows. This specific topological configuration only occurs with a frequency of 8%. The majority of capillaries has one in- and one outflow and is likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes bear potential to induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally.

in eLife on May 18, 2021 12:00 AM.

• #### Novel cell types and developmental lineages revealed by single-cell RNA-seq analysis of the mouse crista ampullaris

This study provides transcriptomic characterization of the cells of the crista ampullaris, sensory structures at the base of the semicircular canals that are critical for vestibular function. We performed single cell RNA-seq on ampullae microdissected from E16, E18, P3 and P7 mice. Cluster analysis identified the hair cells, support cells and glia of the crista as well as dark cells and other nonsensory epithelial cells of the ampulla, mesenchymal cells, vascular cells, macrophages and melanocytes. Cluster-specific expression of genes predicted their spatially restricted domains of gene expression in the crista and ampulla. Analysis of cellular proportions across developmental time showed dynamics in cellular composition. The new cell types revealed by single cell RNA-seq could be important for understanding crista function and the markers identified in this study will enable the examination of their dynamics during development and disease.

in eLife on May 18, 2021 12:00 AM.

• #### The organizational principles of de-differentiated topographic maps in somatosensory cortex

Topographic maps are a fundamental feature of cortex architecture in the mammalian brain. One common theory is that the de-differentiation of topographic maps links to impairments in everyday behavior due to less precise functional map readouts. Here, we tested this theory by characterizing de-differentiated topographic maps in primary somatosensory cortex (SI) of younger and older adults by means of ultra-high resolution functional magnetic resonance imaging together with perceptual finger individuation and hand motor performance. Older adults' SI maps showed similar amplitude and size to younger adults' maps, but presented with less representational similarity between distant fingers. Larger population receptive field sizes in older adults' maps did not correlate with behavior, whereas reduced cortical distances between D2 and D3 related to worse finger individuation but better motor performance. Our data uncover the drawbacks of a simple de-differentiation model of topographic map function, and motivate the introduction of feature-based models of cortical reorganization.

in eLife on May 18, 2021 12:00 AM.

• #### Astrocyte Ca2+ Signaling is Facilitated in an Scn1a+/- Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A, which encodes a subunit of the voltage-gated sodium channel, Nav1.1, in neurons. The roles played by astrocytes, the most abundant glial cell type in the brain, have been investigated in the pathogenesis of epilepsy; however, the specific involvement of astrocytes in DS has not been clarified. In this study, we evaluated Ca2+ signaling in astrocytes using genetically modified mice that have a loss-of-function mutation in Scn1a. We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/- astrocytes. In addition, ATP-induced transient Ca2+ influx and the slope of Ca2+ spiking were also increased in Scn1a+/- astrocytes. These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Subcellular localization of PKA catalytic subunits provides a basis for their distinct functions in the retina

PKA signaling is essential for numerous processes but the subcellular localization of specific PKA isoforms has yet to be explored comprehensively in tissues. Expression of the C{beta} protein, in particular, has not been mapped previously at the tissue level. In this study we used retina as a window into PKA signaling in the brain and characterized localization of PKA C, C{beta}, RII, and RII{beta} subunits. Each subunit presented a distinct localization pattern. C and C{beta} were localized in all tissue layers, while RII and RII{beta} were enriched in the photoreceptor cells in contrast to the cell body and retinal portion of retinal ganglion cells. Only C was observed in photoreceptor outer segments and the cilia transition zone, while C{beta} was localized primarily to mitochondria and was especially prominent in the ellipsoid of the cone cells. In contrast to C, C{beta} also never colocalized with RII or RII{beta}. Using BaseScope technology to track expression of the C{beta} isoforms we find that C{beta}4 and C{beta}4ab are prominently expressed and, therefore, likely code for mitochondrial-C{beta} proteins. Our data indicates that PKA subunits are functionally nonredundant in the retina and suggesting that C{beta} might be important for mitochondrial-associated neurodegenerative diseases previously linked to PKA dysfunction.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### The mirror neuron system compensates for amygdala dysfunction-associated social deficits in individuals with higher autistic traits

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher as opposed to lower autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed reduced left amygdala responses to imitation and enhanced responses in the left superior temporal sulcus (STS) of the MNS to observation, imagination and imitation. Additionally, functional connectivity between the left amygdala and the left STS as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The amygdala-MNS connectivity significantly moderated autistic group differences on recognition memory for fearful faces and real-life social network indices, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased cortical MNS activity and amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Mobile Footprinting: Linking Individual Distinctiveness in Mobility Patterns to Mood, Sleep, and Brain Functional Connectivity

Mapping individual differences in behavior is fundamental to personalized neuroscience. Here, we establish that statistical patterns of smartphone-based mobility features represent unique footprints that allow individual identification. Critically, mobility footprints exhibit varying levels of person-specific distinctiveness and are associated with individual differences in affective instability, circadian irregularity, and brain functional connectivity. Together, this work suggests that real-world mobility patterns may provide an individual-specific signature linking brain, behavior, and mood.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Basal Ganglia Responses to Electrical Stimulation of the Posterior Hypothalamic Nucleus

Electrical or chemical stimulation of the posterior hypothalamic nucleus (PH) elicits highly adaptive locomotion, demonstrating both evidence of flexibility and variety in exhibited motor behaviours. However, the neural substrates of PH stimulation elicited behavioural changes are poorly understood. The basal ganglia are postulated to be critically involved in the process of action selection in conjunction with thalamo-cortical systems. The present study examines changes in basal ganglia activities in response to the high-frequency stimulation of the PH. Under urethane anaesthesia, ensemble and single-unit recordings were obtained from the striatum (STR), globus pallidus externa (GPe), entopeduncular nucleus (EP), subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Upon PH stimulation, increases in firing rates were observed in the STR, GPe, and STN, a decrease was observed in the SNr and no changes were seen in the EP. The increase in spike rate in the STR and GPe was dependent on the stimulation intensity but not duration. Despite the differences in the direction of firing changes during PH stimulation, all examined areas including those not part of the basal ganglia demonstrated an elevated spiking rate upon stimulus train termination. Taking into account the known anatomical connections between the PH and the basal ganglia, it is hypothesized responses seen during PH stimulus trains are mediated through thalamic and cortical relays whereas the overall post-stimulus excitatory response is related to the impact of the PH on brainstem arousal systems.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Δ133p53α Protects Human Astrocytes from Amyloid-Beta Induced Senescence and Neurotoxicity

Cellular senescence is an important contributor to aging and age-related diseases such as Alzheimer's disease (AD). Senescent cells are characterized by a durable cell proliferation arrest and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP), which participates in the progression of neurodegenerative disorders. Clearance of senescent glial cells in an AD mouse model prevented cognitive decline suggesting pharmacological agents targeting cellular senescence might provide novel therapeutic approaches for AD. {Delta}133p53, a natural protein isoform of p53, was previously shown to be a negative regulator of cellular senescence in primary human astrocytes, with clinical implications from its diminished expression in brain tissues from AD patients. Here we show that treatment of proliferating human astrocytes with amyloid-beta oligomers (A{beta}), an endogenous pathogenic agent of AD, results in reduced expression of {Delta}133p53, as well as induces the cells to become senescent and express proinflammatory SASP cytokines such as IL-6, IL-1{beta} and TNF. Our data suggest that A{beta}-induced astrocyte cellular senescence is associated with accelerated DNA damage, and upregulation of full-length p53 and its senescence-inducing target gene p21WAF1. We also show that exogenously enhanced expression of {Delta}133p53 rescues human astrocytes from A{beta}-induced cellular senescence and SASP through both protection from DNA damage and dominant-negative inhibition of full-length p53, leading to inhibition of A{beta}-induced, astrocyte-mediated neurotoxicity. The results presented here demonstrate that {Delta}133p53 manipulation could modulate cellular senescence in the context of AD, possibly opening new therapeutic avenues.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Spatiotemporal context modulates encoding and retrieval of overlapping events

Overlap between events can lead to interference due to a tradeoff between encoding the present event and retrieving the past event. Temporal context information -- 'when' something occurred, a defining feature of episodic memory -- can cue retrieval of a past event. However, the influence of temporal overlap, or proximity in time, on the mechanisms of interference are unclear. Here, by identifying brain states using scalp electroencephalography (EEG) from male and female human subjects, we show the extent to which temporal overlap promotes interference and induces retrieval. In this experiment, subjects were explicitly directed to either encode the present event or retrieve a past, overlapping event while perceptual input was held constant. We find that the degree of temporal overlap between events leads to selective interference. Specifically, greater temporal overlap between two events leads to impaired memory for the past event selectively when the top-down goal is to encode the present event. Using pattern classification analyses to measure neural evidence for a retrieval state, we find that greater temporal overlap leads to automatic retrieval of a past event, independent of top-down goals. Critically, the retrieval evidence we observe likely reflects a general retrieval mode, rather than retrieval success or effort. Collectively, our findings provide insight into the role of temporal overlap on interference and memory formation.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Attentional modulation of intrinsic timescales in visual cortex and spatial networks

Neural activity fluctuates endogenously on timescales varying across the neocortex. The variation in these intrinsic timescales relates to the functional specialization of cortical areas and their involvement in the temporal integration of information. Yet, it is unknown whether the timescales can adjust rapidly and selectively to the demands of a cognitive task. We measured intrinsic timescales of local spiking activity within columns of area V4 while monkeys performed spatial attention tasks. The ongoing spiking activity unfolded across at least two distinct timescales---fast and slow---and the slow timescale increased when monkeys attended to the receptive fields location. A recurrent network model shows that multiple timescales in local dynamics arise from spatial connectivity mimicking vertical and horizontal interactions in visual cortex and that slow timescales increase with the efficacy of recurrent interactions. Our results reveal that targeted neural populations integrate information over variable timescales following the demands of a cognitive task and propose an underlying network mechanism.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Cortical network structure mediates response to stimulation: an optogenetic study in non-human primates

Brain stimulation interventions are used for the treatment of neurological disorders such as Parkinson's and depression. Despite some success, the effects of stimulation are poorly understood, as evidenced by unknown mechanisms governing therapeutic outcomes, widespread side-effects, and inconsistent results in clinical translation. This incomplete understanding may originate from incomplete treatment of the effects of stimulation, as most studies limit their scale and subject of analysis to local effects of various stimulation protocols. Indeed, in a recent paper we demonstrated that neural stimulation impacts the brain at the network scale; here, we leverage advances in neural interfaces and interpretable machine learning to reveal that the cortical network is the primary controlling factor of the response to stimulation. Using optogenetic stimulation and micro-electrocorticography (ECoG) recording in two awake rhesus macaques, we induce and record widespread functional connectivity changes over large-scale sensorimotor cortical networks. We then use a novel nonparametric modeling framework to predict these changes from the stimulation protocol and from characteristics of the underlying cortical network. We observe that the stimulation protocol only explains a small portion of the network response to stimulation while the network structure characteristics explain much more of the response, implicating the underlying network as the primary mediator of the response to stimulation. We extract the relationships linking the stimulation and network characteristics to the functional connectivity changes and observe that the mappings diverge over frequency bands and successive stimulations. Finally, we uncover shared processes governing real-time and longer-term effects of stimulation, demonstrating that all neural stimulation interventions must consider both timescales for their effects to be fully understood. The insights and developments generated in this work represent a paradigm shift for the field of neural stimulation.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Rat sensitivity to multipoint statistics is predicted by efficient coding of natural scenes

Efficient processing of sensory data requires adapting the neuronal encoding strategy to the statistics of natural stimuli. Humans, for instance, are most sensitive to multipoint correlations that vary the most across natural images. Here we show that rats possess the same sensitivity ranking to multipoint statistics as humans, thus extending a classic demonstration of efficient coding to a species where neuronal and developmental processes can be interrogated and causally manipulated.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Synaptic Plasticity in the Agranular Insular Cortex Predicts Escalated Ethanol Consumption

The Agranular Insular Cortex (AIC) is implicated in alcohol use disorder and pharmacologically relevant concentrations of acute ethanol inhibit N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic synaptic transmission and plasticity onto layer 2/3 AIC pyramidal neurons. However, it is not known whether the actions of ethanol on glutamatergic synapses are means by which chronic ethanol alters mechanisms of learning and memory in AIC as alcohol drinking transitions from controlled to problematic. We utilized the chronic intermittent ethanol (CIE) vapor model of ethanol exposure in adult male mice, alone or in combination with voluntary ethanol consumption, to determine whether glutamatergic synapses on layer 2/3 AIC pyramidal neurons are differentially regulated by different durations and intensities of chronic ethanol exposure. We observed evidence of both ethanol- and age-related metaplasticity of AIC layer 2/3 glutamatergic synapses, as only young adult, ethanol-naive mice exhibited NMDAR-dependent long term depression ex vivo. Our findings also indicated that voluntary ethanol consumption alone can elicit glutamatergic plasticity in vivo. We found that the ratio of NMDAR- to AMPAR-mediated postsynaptic currents was reduced not only in CIE-treated, but also in air-treated, chronically drinking mice relative to ethanol-naive controls. Furthermore, lower NMDA/AMPA ratios were predictive of greater escalation of ethanol consumption. These findings suggest that even moderate exposure to ethanol may elicit plasticity in the agranular insular cortex that contributes to the progression toward uncontrolled drinking.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Deconstructing the Cortical Sources of Frequency Following Responses to Speech: A Cross-species Approach

Time-varying pitch is a vital cue in the processing of speech signals. Neural processing of time-varying pitch cues in speech has been extensively assayed using scalp-recorded frequency-following responses (FFRs), which are thought to reflect integrated phase-locked activity from neural ensembles exclusively along the subcortical auditory pathway. Emerging evidence however suggests that the auditory cortex contributes to the FFRs as well. However, the response properties and the relative cortical contribution to the scalp-recorded FFR are only beginning to be explored. Here we used direct intracortical recordings from human subjects and animal models (macaque, guinea pig) to deconstruct the cortical sources of FFRs and leveraged representational similarity analysis as a translational bridge to characterize similarities between the human and animal models. We found robust FFRs in the auditory cortex that emerged from the thalamorecepient layers of the auditory cortex and contributed to the scalp-recorded FFRs via volume conduction.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Cortical Oscillatory Dysrhythmias in Visual Snow Syndrome: A MEG Study

Visual Snow (VS) refers to the persistent visual experience of static in the whole visual field of both eyes. It is often reported by patients with migraine and co-occurs with conditions like tinnitus and tremor. The underlying pathophysiology of the condition is poorly understood. Previously we hypothesised, that VSS may be characterised by disruptions to rhythmical activity within the visual system. To test this, data from 18 patients diagnosed with visual snow syndrome (VSS), and 16 matched controls, were acquired using Magnetoencephalography (MEG). Participants were presented with visual grating stimuli, known to elicit decreases in alpha-band (8-13Hz) power and increases in gamma-band power (40-70Hz). Data were mapped to source-space using a beamformer. Across both groups, decreased alpha power and increased gamma power localised to early visual cortex. Data from primary visual cortex (V1) were compared between groups. No differences were found in either alpha or gamma peak frequency or the magnitude of alpha power, p>.05. However, compared with controls, our VSS cohort displayed significantly increased V1 gamma power, p=.035. This new electromagnetic finding concurs with previous fMRI and PET findings suggesting that in VSS, the visual cortex is hyper-excitable. The coupling of alpha-phase to gamma amplitude (i.e., phase-amplitude coupling, PAC) within V1 was also quantified. Compared with controls, the VSS group had significantly reduced alpha-gamma PAC, p<.05, indicating a potential excitation-inhibition imbalance in VSS, as well as a potential disruption to top-down 'noise-cancellation' mechanisms. Overall, these results suggest that rhythmical brain activity in primary visual cortex is both hyperexcitable and disorganised in VSS, consistent with visual snow being a condition of thalamocortical dysrhythmia.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Fiberoptic Probe For Hemodynamic Spectroscopy in Freely Moving Mice Shows Cerebrovascular Dysregulation In Alzheimers and Glioma Models

Significance: Cerebral vascular reactivity is critical parameters of brain homeostasis in health and disease, but the investigational value of brain oxymetry is diminished by anesthesia and mechanical fixation of the mouse scull. Aim: We needed to reduce the physical restrictivity of hemodynamic spectroscopy to enable cancer and Alzheimers disease (AD) studies in freely-moving mice. Approach: We combined spectroscopy, spectral analysis software and a magnetic, implantable device to measure vascular reactivity in unanesthetized, freely-moving mice. We measured cerebral blood volume fraction (CBVF) and oxygen saturation (SO2). Results: CBVF and SO2 demonstrated delayed cerebrovascular recovery from hypoxia in an orthotopic xenograft glioma model and we found increased CBVF during hypercapnia in a mouse model of AD compared to wild-type littermates. Conclusions: Our optomechanical approach to reproducibly getting light into and out of the brain enabled us to successfully measure CBVF and SO2 during hypercapnia in unanesthetized freely-moving mice. We present hardware and software enabling oximetric analysis of metabolic activity, which provides a safe and reliable method for rapid assessment of vascular reactivity in murine disease models as well as CBVF and SO2.

in bioRxiv: Neuroscience on May 18, 2021 12:00 AM.

• #### Profile of Scott Edwards [Profiles]

Looking through Scott Edwards’ curriculum vitae is like wandering the halls of the natural history collections he curates: an invitation to dive deeply into one area combined with permission to think broadly and zip enthusiastically from one exhibit to another. Zoologist and curator of ornithology of Harvard’s Museum of Comparative...

in PNAS on May 17, 2021 07:49 PM.

• #### Thermal resistance effect on anomalous diffusion of molecules under confinement [Chemistry]

Diffusion is generally faster at higher temperatures. Here, a counterintuitive behavior is observed in that the movement of long-chain molecules slows as the temperature increases under confinement. This report confirms that this anomalous diffusion is caused by the “thermal resistance effect,” in which the diffusion resistance of linear-chain molecules is...

in PNAS on May 17, 2021 07:49 PM.

• #### Encapsulation of ribozymes inside model protocells leads to faster evolutionary adaptation [Biophysics and Computational Biology]

Functional biomolecules, such as RNA, encapsulated inside a protocellular membrane are believed to have comprised a very early, critical stage in the evolution of life, since membrane vesicles allow selective permeability and create a unit of selection enabling cooperative phenotypes. The biophysical environment inside a protocell would differ fundamentally from...

in PNAS on May 17, 2021 07:49 PM.

• #### Moving beyond the constraints of chemistry via crystal structure discovery with isotropic multiwell pair potentials [Applied Physical Sciences]

The rigid constraints of chemistry—dictated by quantum mechanics and the discrete nature of the atom—limit the set of observable atomic crystal structures. What structures are possible in the absence of these constraints? Here, we systematically crystallize one-component systems of particles interacting with isotropic multiwell pair potentials. We investigate two tunable...

in PNAS on May 17, 2021 07:49 PM.

• #### Circulating immunity protects the female reproductive tract from Chlamydia infection [Immunology and Inflammation]

Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4...

in PNAS on May 17, 2021 07:10 PM.

• #### Roles of KLF4 and AMPK in the inhibition of glycolysis by pulsatile shear stress in endothelial cells [Physiology]

Vascular endothelial cells (ECs) sense and respond to hemodynamic forces such as pulsatile shear stress (PS) and oscillatory shear stress (OS). Among the metabolic pathways, glycolysis is differentially regulated by atheroprone OS and atheroprotective PS. Studying the molecular mechanisms by which PS suppresses glycolytic flux at the epigenetic, transcriptomic, and...

in PNAS on May 17, 2021 07:10 PM.

• #### The unintended consequences of US immigration enforcement policies [Social Sciences]

US immigration enforcement policy seeks to change the behaviors and views of not only individuals in the United States but also those of prospective migrants outside the United States. Yet we still know relatively little about the behavioral and attitudinal effects of US enforcement policy on the population abroad. This...

in PNAS on May 17, 2021 07:10 PM.

• #### Trapping a cross-linked lysine-tryptophan radical in the catalytic cycle of the radical SAM enzyme SuiB [Biochemistry]

The radical S-adenosylmethionine (rSAM) enzyme SuiB catalyzes the formation of an unusual carbon–carbon bond between the sidechains of lysine (Lys) and tryptophan (Trp) in the biosynthesis of a ribosomal peptide natural product. Prior work on SuiB has suggested that the Lys–Trp cross-link is formed via radical electrophilic aromatic substitution (rEAS),...

in PNAS on May 17, 2021 07:10 PM.

• #### Short-lived intermediate in N2O generation by P450 NO reductase captured by time-resolved IR spectroscopy and XFEL crystallography [Chemistry]

Nitric oxide (NO) reductase from the fungus Fusarium oxysporum is a P450-type enzyme (P450nor) that catalyzes the reduction of NO to nitrous oxide (N2O) in the global nitrogen cycle. In this enzymatic reaction, the heme-bound NO is activated by the direct hydride transfer from NADH to generate a short-lived intermediate...

in PNAS on May 17, 2021 07:10 PM.

• #### HIV envelope tail truncation confers resistance to SERINC5 restriction [Microbiology]

SERINC5 is a potent lentiviral restriction factor that gets incorporated into nascent virions and inhibits viral fusion and infectivity. The envelope glycoprotein (Env) is a key determinant for SERINC restriction, but many aspects of this relationship remain incompletely understood, and the mechanism of SERINC5 restriction remains unresolved. Here, we have...

in PNAS on May 17, 2021 07:10 PM.

• #### Terahertz detection based on nonlinear Hall effect without magnetic field [Applied Physical Sciences]

We propose a method for broadband long-wavelength photodetection using the nonlinear Hall effect in noncentrosymmetric quantum materials. The inherently quadratic relation between transverse current and input voltage at zero magnetic field is used to rectify the incident terahertz or infrared electric field into a direct current, without invoking any diode....

in PNAS on May 17, 2021 07:10 PM.

• #### Permafrost carbon feedbacks threaten global climate goals [Sustainability Science]

Rapid Arctic warming has intensified northern wildfires and is thawing carbon-rich permafrost. Carbon emissions from permafrost thaw and Arctic wildfires, which are not fully accounted for in global emissions budgets, will greatly reduce the amount of greenhouse gases that humans can emit to remain below 1.5 °C or 2 °C....

in PNAS on May 17, 2021 07:10 PM.

L-type voltage-gated CaV1.2 channels crucially regulate cardiac muscle contraction. Activation of β-adrenergic receptors (β-AR) augments contraction via protein kinase A (PKA)–induced increase of calcium influx through CaV1.2 channels. To date, the full β-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a CaV1.2 inhibitory protein, as essential...

in PNAS on May 17, 2021 07:10 PM.

• #### Plant species richness at archaeological sites suggests ecological legacy of Indigenous subsistence on the Colorado Plateau [Anthropology]

Humans have both intentional and unintentional impacts on their environment, yet identifying the enduring ecological legacies of past small-scale societies remains difficult, and as such, evidence is sparse. The present study found evidence of an ecological legacy that persists today within an semiarid ecosystem of western North America. Specifically, the...

in PNAS on May 17, 2021 07:10 PM.

• #### Gut microbiome contributions to altered metabolism in a pig model of undernutrition [Microbiology]

The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, we developed a feature-selection algorithm to identify representative characteristics distinguishing DR fecal microbiomes from...

in PNAS on May 17, 2021 07:10 PM.

• #### Critical slowing down suggests that the western Greenland Ice Sheet is close to a tipping point [Earth, Atmospheric, and Planetary Sciences]

The Greenland Ice Sheet (GrIS) is a potentially unstable component of the Earth system and may exhibit a critical transition under ongoing global warming. Mass reductions of the GrIS have substantial impacts on global sea level and the speed of the Atlantic Meridional Overturning Circulation, due to the additional freshwater...

in PNAS on May 17, 2021 07:10 PM.

• #### Background-free dual-mode optical and 13C magnetic resonance imaging in diamond particles [Chemistry]

Multimodal imaging—the ability to acquire images of an object through more than one imaging mode simultaneously—has opened additional perspectives in areas ranging from astronomy to medicine. In this paper, we report progress toward combining optical and magnetic resonance (MR) imaging in such a “dual” imaging mode. They are attractive in...

in PNAS on May 17, 2021 07:10 PM.

• #### Microchemomechanical devices using DNA hybridization [Applied Physical Sciences]

The programmability of DNA oligonucleotides has led to sophisticated DNA nanotechnology and considerable research on DNA nanomachines powered by DNA hybridization. Here, we investigate an extension of this technology to the micrometer-colloidal scale, in which observations and measurements can be made in real time/space using optical microscopy and holographic optical...

in PNAS on May 17, 2021 07:10 PM.

• #### Global abundance estimates for 9,700 bird species [Ecology]

Quantifying the abundance of species is essential to ecology, evolution, and conservation. The distribution of species abundances is fundamental to numerous longstanding questions in ecology, yet the empirical pattern at the global scale remains unresolved, with a few species’ abundance well known but most poorly characterized. In large part because...

in PNAS on May 17, 2021 07:10 PM.

• #### Genomic basis of parallel adaptation varies with divergence in Arabidopsis and its relatives [Evolution]

Parallel adaptation provides valuable insight into the predictability of evolutionary change through replicated natural experiments. A steadily increasing number of studies have demonstrated genomic parallelism, yet the magnitude of this parallelism varies depending on whether populations, species, or genera are compared. This led us to hypothesize that the magnitude of...

in PNAS on May 17, 2021 07:10 PM.

• #### A synthetic C4 shuttle via the {beta}-hydroxyaspartate cycle in C3 plants [Plant Biology]

Plants depend on the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) for CO2 fixation. However, especially in C3 plants, photosynthetic yield is reduced by formation of 2-phosphoglycolate, a toxic oxygenation product of Rubisco, which needs to be recycled in a high-flux–demanding metabolic process called photorespiration. Canonical photorespiration dissipates energy and causes carbon and...

in PNAS on May 17, 2021 07:10 PM.

• #### On the evolution of chaperones and cochaperones and the expansion of proteomes across the Tree of Life [Biophysics and Computational Biology]

Across the Tree of Life (ToL), the complexity of proteomes varies widely. Our systematic analysis depicts that from the simplest archaea to mammals, the total number of proteins per proteome expanded ∼200-fold. Individual proteins also became larger, and multidomain proteins expanded ∼50-fold. Apart from duplication and divergence of existing proteins,...

in PNAS on May 17, 2021 07:10 PM.

• #### Short hydrogen bonds enhance nonaromatic protein-related fluorescence [Biophysics and Computational Biology]

Fluorescence in biological systems is usually associated with the presence of aromatic groups. Here, by employing a combined experimental and computational approach, we show that specific hydrogen bond networks can significantly affect fluorescence. In particular, we reveal that the single amino acid L-glutamine, by undergoing a chemical transformation leading to...

in PNAS on May 17, 2021 07:10 PM.

• #### An additive algorithm for origami design [Applied Physical Sciences]

Inspired by the allure of additive fabrication, we pose the problem of origami design from a different perspective: How can we grow a folded surface in three dimensions from a seed so that it is guaranteed to be isometric to the plane? We solve this problem in two steps: by...

in PNAS on May 17, 2021 07:10 PM.

• #### Coastal eutrophication drives acidification, oxygen loss, and ecosystem change in a major oceanic upwelling system [Environmental Sciences]

Global change is leading to warming, acidification, and oxygen loss in the ocean. In the Southern California Bight, an eastern boundary upwelling system, these stressors are exacerbated by the localized discharge of anthropogenically enhanced nutrients from a coastal population of 23 million people. Here, we use simulations with a high-resolution,...

in PNAS on May 17, 2021 07:10 PM.

• #### Oligomodal metamaterials with multifunctional mechanics [Applied Physical Sciences]

Mechanical metamaterials are artificial composites that exhibit a wide range of advanced functionalities such as negative Poisson’s ratio, shape shifting, topological protection, multistability, extreme strength-to-density ratio, and enhanced energy dissipation. In particular, flexible metamaterials often harness zero-energy deformation modes. To date, such flexible metamaterials have a single property, for example,...

in PNAS on May 17, 2021 07:10 PM.

• #### The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody [Biochemistry]

The goal of cancer-drug delivery is to achieve high levels of therapeutics within tumors with minimal systemic exposure that could cause toxicity. Producing biologics directly in situ where they diffuse and act locally is an attractive alternative to direct administration of recombinant therapeutics, as secretion by the tumor itself provides...

in PNAS on May 17, 2021 07:10 PM.

• #### Odor-driven face-like categorization in the human infant brain [Psychological and Cognitive Sciences]

Understanding how the young infant brain starts to categorize the flurry of ambiguous sensory inputs coming in from its complex environment is of primary scientific interest. Here, we test the hypothesis that senses other than vision play a key role in initiating complex visual categorizations in 20 4-mo-old infants exposed...

in PNAS on May 17, 2021 07:10 PM.

• #### G-quadruplex structural variations in human genome associated with single-nucleotide variations and their impact on gene activity [Biochemistry]

G-quadruplexes (G4s) formed by guanine-rich nucleic acids play a role in essential biological processes such as transcription and replication. Besides the >1.5 million putative G-4–forming sequences (PQSs), the human genome features >640 million single-nucleotide variations (SNVs), the most common type of genetic variation among people or populations. An SNV may...

in PNAS on May 17, 2021 07:10 PM.

• #### MiMeNet: Exploring microbiome-metabolome relationships using neural networks

by Derek Reiman, Brian T. Layden, Yang Dai

The advance in microbiome and metabolome studies has generated rich omics data revealing the involvement of the microbial community in host disease pathogenesis through interactions with their host at a metabolic level. However, the computational tools to uncover these relationships are just emerging. Here, we present MiMeNet, a neural network framework for modeling microbe-metabolite relationships. Using ten iterations of 10-fold cross-validation on three paired microbiome-metabolome datasets, we show that MiMeNet more accurately predicts metabolite abundances (mean Spearman correlation coefficients increase from 0.108 to 0.309, 0.276 to 0.457, and -0.272 to 0.264) and identifies more well-predicted metabolites (increase in the number of well-predicted metabolites from 198 to 366, 104 to 143, and 4 to 29) compared to state-of-art linear models for individual metabolite predictions. Additionally, we demonstrate that MiMeNet can group microbes and metabolites with similar interaction patterns and functions to illuminate the underlying structure of the microbe-metabolite interaction network, which could potentially shed light on uncharacterized metabolites through “Guilt by Association”. Our results demonstrated that MiMeNet is a powerful tool to provide insights into the causes of metabolic dysregulation in disease, facilitating future hypothesis generation at the interface of the microbiome and metabolomics.

in PLoS Computational Biology on May 17, 2021 02:00 PM.

• #### Cortical propagation tracks functional recovery after stroke

by Gloria Cecchini, Alessandro Scaglione, Anna Letizia Allegra Mascaro, Curzio Checcucci, Emilia Conti, Ihusan Adam, Duccio Fanelli, Roberto Livi, Francesco Saverio Pavone, Thomas Kreuz

Stroke is a debilitating condition affecting millions of people worldwide. The development of improved rehabilitation therapies rests on finding biomarkers suitable for tracking functional damage and recovery. To achieve this goal, we perform a spatiotemporal analysis of cortical activity obtained by wide-field calcium images in mice before and after stroke. We compare spontaneous recovery with three different post-stroke rehabilitation paradigms, motor training alone, pharmacological contralesional inactivation and both combined. We identify three novel indicators that are able to track how movement-evoked global activation patterns are impaired by stroke and evolve during rehabilitation: the duration, the smoothness, and the angle of individual propagation events. Results show that, compared to pre-stroke conditions, propagation of cortical activity in the subacute phase right after stroke is slowed down and more irregular. When comparing rehabilitation paradigms, we find that mice treated with both motor training and pharmacological intervention, the only group associated with generalized recovery, manifest new propagation patterns, that are even faster and smoother than before the stroke. In conclusion, our new spatiotemporal propagation indicators could represent promising biomarkers that are able to uncover neural correlates not only of motor deficits caused by stroke but also of functional recovery during rehabilitation. In turn, these insights could pave the way towards more targeted post-stroke therapies.

in PLoS Computational Biology on May 17, 2021 02:00 PM.

• #### Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

by Kenzo Ivanovitch, Pablo Soro-Barrio, Probir Chakravarty, Rebecca A. Jones, Donald M. Bell, S. Neda Mousavy Gharavy, Despina Stamataki, Julien Delile, James C. Smith, James Briscoe

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

in PLoS Biology on May 17, 2021 02:00 PM.

• #### A brian-inspired computational model for spatio-temporal information processing

Publication date: Available online 16 May 2021

Source: Neural Networks

Author(s): Xiaohan Lin, Xiaolong Zou, Zilong Ji, Tiejun Huang, Si Wu, Yuanyuan Mi

in Neural Networks on May 17, 2021 01:00 PM.

• #### Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2

Objective The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2‐abs) in patients with autoimmune encephalitis, and describe the clinical‐immunological features and antibody effects. Methods Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell‐based assay (CBA) with GluK2‐expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2‐ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2‐expressing HEK293 cells. Results Patients’ antibodies precipitated GluK2. GluK2 antibody‐specificity was confirmed by CBA, immunoprecipitation, GluK2‐immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno‐absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non‐kainate receptors (alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors [AMPAR] and N‐methyl‐D‐aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2‐abs among patients with anti‐AMPAR (5/71) or anti‐NMDAR encephalitis (1/73). GluK2‐abs internalized GluK2 in HEK293 cells and neurons; these antibody‐effects were reversible in neurons. A significant reduction of GluK2‐mediated currents was observed in cells treated with patients’ GluK2 serum following the time frame of antibody‐mediated GluK2 internalization. Interpretation GluK2‐abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021

in Annals of Neurology on May 17, 2021 11:41 AM.

• #### Effectiveness of glass beads for plating cell cultures

Author(s): Alidivinas Prusokas, Michelle Hawkins, Conrad A. Nieduszynski, and Renata Retkute

Cell plating, the spreading out of a liquid suspension of cells on a surface followed by colony growth, is a common laboratory procedure in microbiology. Despite this, the exact impact of its parameters on colony growth has not been extensively studied. A common protocol involves the shaking of glas...

[Phys. Rev. E 103, 052410] Published Mon May 17, 2021

in Physical Review E: Biological physics on May 17, 2021 10:00 AM.

• #### Dynamics of genetic code evolution: The emergence of universality

Author(s): John-Antonio Argyriadis, Yang-Hui He, Vishnu Jejjala, and Djordje Minic

We study the dynamics of genetic code evolution. The model of Vetsigian et al. [Proc. Natl. Acad. Sci. USA 103, 10696 (2006)] and Vetsigian [Collective evolution of biological and physical systems, Ph.D. thesis, 2005] uses the mechanism of horizontal gene transfer to demonstrate convergence of the g...

[Phys. Rev. E 103, 052409] Published Mon May 17, 2021

in Physical Review E: Biological physics on May 17, 2021 10:00 AM.

• #### Adaptive ensemble perception tracking

Publication date: Available online 15 May 2021

Source: Neural Networks

Author(s): Zikun Zhou, Nana Fan, Kai Yang, Hongpeng Wang, Zhenyu He

in Neural Networks on May 17, 2021 07:00 AM.

• #### Multiple clustering for identifying subject clusters and brain sub-networks using functional connectivity matrices without vectorization

Publication date: Available online 15 May 2021

Source: Neural Networks

Author(s): Tomoki Tokuda, Okito Yamashita, Junichiro Yoshimoto

in Neural Networks on May 17, 2021 07:00 AM.

• #### Robust Optimization and Validation of Echo State Networks for learning chaotic dynamics

Publication date: Available online 14 May 2021

Source: Neural Networks

Author(s): Alberto Racca, Luca Magri

in Neural Networks on May 17, 2021 07:00 AM.

• #### Learning to recognize while learning to speak: Self-supervision and developing a speaking motor

Publication date: Available online 14 May 2021

Source: Neural Networks

Author(s): Xiang Wu, Juyang Weng

in Neural Networks on May 17, 2021 07:00 AM.

• #### Probabilistic robustness estimates for feed-forward neural networks

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Nicolas Couellan

in Neural Networks on May 17, 2021 07:00 AM.

• #### Applying stem cells and CRISPR engineering to uncover the etiology of schizophrenia

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Peter James Michael Deans, Kristen J. Brennand

in Current Opinion in Neurobiology on May 17, 2021 07:00 AM.

• #### Issue Information

Annals of Neurology, Volume 89, Issue 6, Page i-viii, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Annals of Neurology: Volume 89, Number 6, June 2021

A laser speckle contrast image showing blood flow in the face of a migraineur who had received an infusion of pramlinitide, an agonist for amylin receptors. Amylin is a peptide in the same family as CGRP, with which it shares agonist activity at the AMY1 receptor. Amylin can also provoke migraine‐like attacks, suggesting that an dual amylin‐CGRP antagonist may be effective for migraine. See Ghanizada et al. (pp. 1157–1171) in this issue.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Alpha‐Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure

Objective To explore the role of alpha‐synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). Methods Well‐characterized patients with PAF (n = 32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. Results Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non‐converters. ASyn‐PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. Interpretation αSyn‐PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α‐synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212–1220

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Neuromyelitis Optica Spectrum Disorder: Therapeutic Innovations and Complex Decision‐Making

Annals of Neurology, Volume 89, Issue 6, Page 1084-1087, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### To Reduce the Risk of Dementia, Focus on the Patient

Annals of Neurology, Volume 89, Issue 6, Page 1080-1083, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Gut Microbiome in Progressive Multiple Sclerosis

Objective This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease. Methods We sequenced the microbiota from healthy controls and relapsing–remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS‐derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE). Results Microbiota β‐diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease‐modifying therapies. Disease status had the greatest effect on the microbiome β‐diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL‐17–producing γδ T cells. Interpretation Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195–1211

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Superficial Siderosis: A Clinical Review

Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low‐grade bleeding into the subarachnoid space. The confluent and marginal subpial hemosiderin is best appreciated on iron‐sensitive magnetic resonance imaging sequences. With widespread use of magnetic resonance imaging, the disorder is increasingly being recognized, including in asymptomatic individuals. Gait ataxia, often with hearing impairment is a common clinical presentation. A clinical history of subarachnoid hemorrhage is generally not present. A macrovascular pathology is generally not causative. The most common etiology is dural disease, often dural tears. Prior or less commonly ongoing symptoms of craniospinal hypovolemia may be present. Common etiologies for dural tears include disc disease and trauma, including surgical trauma. Patients with dural tears due to herniated and calcified discs often have a ventral intraspinal fluid collection due to cerebrospinal fluid leak. A precise identification of the dural tear relies on multimodality imaging. It has been speculated that chronic bleeding from fragile blood vessels around the dural tear may be the likely underlying mechanism. Surgical correction of the bleeding source is a logical therapeutic strategy. Clinical outcomes are variable, although neuroimaging evidence of successful dural tear repair is noted. The currently available data regarding use of deferiprone in patients with superficial siderosis is insufficient to recommend its routine use in patients. ANN NEUROL 2021;89:1068–1079

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### A Recurrent EIF2AK2 Missense Variant Causes Autosomal‐Dominant Isolated Dystonia

Annals of Neurology, Volume 89, Issue 6, Page 1257-1258, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Detection of Brain Somatic Mutations in Cerebrospinal Fluid from Refractory Epilepsy Patients

Brain mosaic mutations are a major cause of refractory focal epilepsies with cortical malformations such as focal cortical dysplasia, hemimegalencephaly, malformation of cortical development with oligodendroglial hyperplasia in epilepsy, and ganglioglioma. Here, we collected cerebrospinal fluid (CSF) during epilepsy surgery to search for somatic variants in cell‐free DNA (cfDNA) using targeted droplet digital polymerase chain reaction. In 3 of 12 epileptic patients with known somatic mutations previously identified in brain tissue, we here provide evidence that brain mosaicism can be detected in the CSF‐derived cfDNA. These findings suggest future opportunities for detecting the mutant allele driving epilepsy in CSF. ANN NEUROL 2021;89:1248–1252

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Unravelling the Neural Basis of Spatial Delusions After Stroke

Objective Knowing explicitly where we are is an interpretation of our spatial representations. Reduplicative paramnesia is a disrupting syndrome in which patients present a firm belief of spatial mislocation. Here, we studied the largest sample of patients with delusional misidentifications of space (ie, reduplicative paramnesia) after stroke to shed light on their neurobiology. Methods In a prospective, cumulative, case‐control study, we screened 400 patients with acute right‐hemispheric stroke. We included 64 cases and 233 controls. First, lesions were delimited and normalized. Then, we computed structural and functional disconnection maps using methods of lesion‐track and network‐mapping. The maps were compared, controlling for confounders. Second, we built a multivariate logistic model, including clinical, behavioral, and neuroimaging data. Finally, we performed a nested cross‐validation of the model with a support‐vector machine analysis. Results The most frequent misidentification subtype was confabulatory mislocation (56%), followed by place reduplication (19%), and chimeric assimilation (13%). Our results indicate that structural disconnection is the strongest predictor of the syndrome and included 2 distinct streams, connecting right fronto‐thalamic and right occipitotemporal structures. In the multivariate model, the independent predictors of reduplicative paramnesia were the structural disconnection map, lesion sparing of right dorsal fronto‐parietal regions, age, and anosognosia. Good discrimination accuracy was demonstrated (area under the curve = 0.80 [0.75–0.85]). Interpretation Our results localize the anatomic circuits that may have a role in the abnormal spatial‐emotional binding and in the defective updating of spatial representations underlying reduplicative paramnesia. This novel data may contribute to better understand the pathophysiology of delusional syndromes after stroke. ANN NEUROL 2021;89:1181–1194

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Approaches to Understanding COVID‐19 and its Neurological Associations

There is an accumulating volume of research into neurological manifestations of coronavirus disease 2019 (COVID‐19). However, inconsistent study designs, inadequate controls, poorly validated tests, and differing settings, interventions, and cultural norms weaken study quality and comparability, hence the understanding of the spectrum, burden, and pathophysiology of these complications. Therefore, a global COVID‐19 Neuro Research Coalition, together with the World Health Organization, has reviewed reports of COVID‐19 neurological complications and harmonized clinical measures for future research. This will facilitate well‐designed studies using precise, consistent case definitions of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and neurological complications, with standardized forms for pooled data analyses that nonspecialists can use, including those in low‐income settings. ANN NEUROL 2021;89:1059–1067

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Characterization of the Insular Role in Cardiac Function through Intracranial Electrical Stimulation of the Human Insula

Objective The link between brain function and cardiovascular dynamics is an important issue yet to be elucidated completely. The insula is a neocortical brain area that is thought to have a cardiac chronotropic regulatory function, but its role in cardiac contractility is unknown. We aimed to analyze the variability in heart rate and cardiac contractility after functional activation of different insular regions through direct electrical stimulation (E‐stim) in humans. Methods This was an observational, prospective study, including patients admitted for stereo‐electroencephalographic recording because of refractory epilepsy, in whom the insular cortex was implanted. Patients with anatomical or electrophysiological insular abnormalities and those in whom E‐stim produced subjective symptoms were excluded. Variations in heart rate (HR), stroke volume (SV), and cardiac output (CO) were analyzed during insular E‐stim and compared with control E‐stim of non‐eloquent brain regions and sham stimulations. Results Ten patients were included, 5 implanted in the right insula (52 E‐stim) and 5 in the left (37 E‐stim). Demographic and clinical characteristics of both groups were similar. E‐stim of both right and left insulas induced a significant decrease of the CO and HR, and an increase of the SV. E‐stim of control electrodes and sham stimulations were not associated with variations in cardiac function. Blood pressure and respiratory rate remained unaltered. Interpretation Our results suggest a direct chronotropic and inotropic cardiac depressor function of the right and left insulas. The evidence of an insular direct cardiac regulatory function might open a path in the prevention or treatment of heart failure, arrhythmias, and sudden unexpected death in epilepsy. ANN NEUROL 2021;89:1172–1180

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Amylin Analog Pramlintide Induces Migraine‐like Attacks in Patients

Objective Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene‐related peptide (CGRP). Methods Thirty‐six migraine without aura patients were enrolled in a randomized, double‐blind, 2‐way, crossover, positive‐controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted. Results Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine‐like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide‐induced migraine‐like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide‐provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice. Interpretation Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157–1171

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### NIA‐AA Alzheimer's Disease Framework: Clinical Characterization of Stages

Background To operationalize the National Institute on Aging – Alzheimer's Association (NIA‐AA) Research Framework for Alzheimer's Disease 6‐stage continuum of clinical progression for persons with abnormal amyloid. Methods The Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross‐sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months. Results Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44–59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short‐term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1). Interpretation The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145–1156

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

Objective Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female‐specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. Methods Prolactin, CGRP, and receptor antagonists CGRP8‐37 or Δ1‐9‐G129R‐hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back‐labeled trigeminal ganglia (TG) neurons was used to assess PRL‐induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. Results We found that dural PRL produced sustained and long‐lasting migraine‐like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little‐to‐no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8‐37 decreases migraine‐like responses to dural PRL. Reciprocally, Δ1‐9‐G129R‐hPRL attenuates dural CGRP‐induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine‐like responses to dural CGRP. Interpretation This CGRP‐PRL interaction in the meninges is a mechanism by which these peptides could produce female‐selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129–1144

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Staufen1 in Human Neurodegeneration

Objective Mutations in the ATXN2 gene (CAG expansions ≥32 repeats) can be a rare cause of Parkinson's disease and amyotrophic lateral sclerosis (ALS). We recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS‐TDP‐43 fibroblasts, and provided a link between SG formation and autophagy. We aimed to test if STAU1 overabundance has a role in the pathogenesis of other neurodegenerative diseases. Methods With multiple neurodegenerative patient‐derived cell models, animal models, and human postmortem ALS tissue, we evaluate STAU1 function using biochemical and immunohistological analyses. Results We demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP‐43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations. Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post‐transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs. Targeting STAU1 by RNAi normalized mTOR, suggesting a potential role for therapy in diseases associated with STAU1 overabundance. Interpretation STAU1 overabundance in neurodegeneration is a common phenomenon associated with hyperactive mTOR. Targeting STAU1 with ASOs or miRNA viral vectors may represent a novel, efficacious therapy for neurodegenerative diseases characterized by overabundant STAU1. ANN NEUROL 2021;89:1114–1128

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### How Can an Na+ Channel Inhibitor Ameliorate Seizures in Lennox–Gastaut Syndrome?

Objective Lennox–Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASDs) according to simplistic categorical grouping. Methods The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors was quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors. Results With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed with hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWDs) on electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD‐associated seizures in pentylenetetrazol or AY‐9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures, including LGS. Interpretation Na+ channel inhibitors shall have sufficiently fast binding to exert an action during the short bursts and then suppress SWDs, in which cases rufinamide is superior. For the epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASDs according to in‐depth molecular pharmacology and the attributes of ictal discharges is advisable. ANN NEUROL 2021;89:1099–1113

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Frailty and Risk of Dementia in Mild Cognitive Impairment Subtypes

Risk factors for developing dementia from mild cognitive impairment (MCI) probably differ between MCI subtypes. We investigated how frailty relates to dementia risk in amnestic MCI (a‐MCI; n = 2,799) and non‐amnestic MCI (na‐MCI; n = 629) in the National Alzheimer's Coordinating Center database. Although higher frailty increased dementia risk for people with either a‐MCI or na‐MCI, the larger risk was in na‐MCI (interaction hazard ratio = 1.35 [95% confidence interval = 1.15–1.59], p < 0.001). Even after the onset of clinically significant cognitive impairment, poor general health, quantified by a high degree of frailty, is a significant risk for dementia. ANN NEUROL 2021;89:1221–1225

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty‐four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240–1247

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Multiple Sclerosis Is Rare in Epstein–Barr Virus–Seronegative Children with Central Nervous System Inflammatory Demyelination

Although Epstein–Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV‐seronegative. When re‐evaluating 25 EBV‐seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti–myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV‐seronegative but only 9 of 164 (5.5%, p < 0.001) EBV‐seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV‐seronegative/MOG antibody–negative patients. In children with an MS‐like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG‐antibody disease. ANN NEUROL 2021;89:1234–1239

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Pembrolizumab‐Induced Migrating Cortico‐Subcortical Brain Lesions

Annals of Neurology, Volume 89, Issue 6, Page 1255-1256, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Long‐Term Safety and Efficacy of Eculizumab in Aquaporin‐4 IgG‐Positive NMOSD

Objective During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy. Methods Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. Results Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. Interpretation This analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Prediction Model of Amyotrophic Lateral Sclerosis by Deep Learning with Patient Induced Pluripotent Stem Cells

In amyotrophic lateral sclerosis (ALS), early diagnosis is essential for both current and potential treatments. To find a supportive approach for the diagnosis, we constructed an artificial intelligence‐based prediction model of ALS using induced pluripotent stem cells (iPSCs). Images of spinal motor neurons derived from healthy control subject and ALS patient iPSCs were analyzed by a convolutional neural network, and the algorithm achieved an area under the curve of 0.97 for classifying healthy control and ALS. This prediction model by deep learning algorithm with iPSC technology could support the diagnosis and may provide proactive treatment of ALS through future prospective research. ANN NEUROL 2021;89:1226–1233

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### To Zoom or Not to Zoom: The Should I Travel Index Revisited during the Coronavirus Disease Pandemic

Annals of Neurology, Volume 89, Issue 6, Page 1057-1058, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Cocaine and Levamisole Cerebral Toxicity

Annals of Neurology, Volume 89, Issue 6, Page 1253-1254, June 2021.

in Annals of Neurology on May 17, 2021 06:00 AM.

• #### Efficient Spiking Neural Networks with Radix Encoding. (arXiv:2105.06943v1 [cs.NE])

Spiking neural networks (SNNs) have advantages in latency and energy efficiency over traditional artificial neural networks (ANNs) due to its event-driven computation mechanism and replacement of energy-consuming weight multiplications with additions. However, in order to reach accuracy of its ANN counterpart, it usually requires long spike trains to ensure the accuracy. Traditionally, a spike train needs around one thousand time steps to approach similar accuracy as its ANN counterpart. This offsets the computation efficiency brought by SNNs because longer spike trains mean a larger number of operations and longer latency. In this paper, we propose a radix encoded SNN with ultra-short spike trains. In the new model, the spike train takes less than ten time steps. Experiments show that our method demonstrates 25X speedup and 1.1% increment on accuracy, compared with the state-of-the-art work on VGG-16 network architecture and CIFAR-10 dataset.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### Multi-Objective Optimisation of Cortical Spiking Neural Networks With Genetic Algorithms. (arXiv:2105.06824v1 [cs.NE])

Spiking neural networks (SNNs) communicate through the all-or-none spiking activity of neurons. However, fitting the large number of SNN model parameters to observed neural activity patterns, for example, in biological experiments, remains a challenge. Previous work using genetic algorithm (GA) optimisation on a specific efficient SNN model, using the Izhikevich neuronal model, was limited to a single parameter and objective. This work applied a version of GA, called non-dominated sorting GA (NSGA-III), to demonstrate the feasibility of performing multi-objective optimisation on the same SNN, focusing on searching network connectivity parameters to achieve target firing rates of excitatory and inhibitory neuronal types, including across different network connectivity sparsity. We showed that NSGA-III could readily optimise for various firing rates. Notably, when the excitatory neural firing rates were higher than or equal to that of inhibitory neurons, the errors were small. Moreover, when connectivity sparsity was considered as a parameter to be optimised, the optimal solutions required sparse network connectivity. We also found that for excitatory neural firing rates lower than that of inhibitory neurons, the errors were generally larger. Overall, we have successfully demonstrated the feasibility of implementing multi-objective GA optimisation on network parameters of recurrent and sparse SNN.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### Quantifying the Impact of Boundary Constraint Handling Methods on Differential Evolution. (arXiv:2105.06757v1 [cs.NE])

Constraint handling is one of the most influential aspects of applying metaheuristics to real-world applications, which can hamper the search progress if treated improperly. In this work, we focus on a particular case - the box constraints, for which many boundary constraint handling methods (BCHMs) have been proposed. We call for the necessity of studying the impact of BCHMs on metaheuristics' performance and behavior, which receives seemingly little attention in the field. We target quantifying such impacts through systematic benchmarking by investigating 28 major variants of Differential Evolution (DE) taken from the modular DE framework (by combining different mutation and crossover operators) and $13$ commonly applied BCHMs, resulting in $28 \times 13 = 364$ algorithm instances after pairing DE variants with BCHMs. After executing the algorithm instances on the well-known BBOB/COCO problem set, we analyze the best-reached objective function value (performance-wise) and the percentage of repaired solutions (behavioral) using statistical ranking methods for each combination of mutation, crossover, and BBOB function group. Our results clearly show that the choice of BCHMs substantially affects the empirical performance as well as the number of generated infeasible solutions, which allows us to provide general guidelines for selecting an appropriate BCHM for a given scenario.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### Verification of Size Invariance in DNN Activations using Concept Embeddings. (arXiv:2105.06727v1 [cs.CV])

The benefits of deep neural networks (DNNs) have become of interest for safety critical applications like medical ones or automated driving. Here, however, quantitative insights into the DNN inner representations are mandatory. One approach to this is concept analysis, which aims to establish a mapping between the internal representation of a DNN and intuitive semantic concepts. Such can be sub-objects like human body parts that are valuable for validation of pedestrian detection. To our knowledge, concept analysis has not yet been applied to large object detectors, specifically not for sub-parts. Therefore, this work first suggests a substantially improved version of the Net2Vec approach (arXiv:1801.03454) for post-hoc segmentation of sub-objects. Its practical applicability is then demonstrated on a new concept dataset by two exemplary assessments of three standard networks, including the larger Mask R-CNN model (arXiv:1703.06870): (1) the consistency of body part similarity, and (2) the invariance of internal representations of body parts with respect to the size in pixels of the depicted person. The findings show that the representation of body parts is mostly size invariant, which may suggest an early intelligent fusion of information in different size categories.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### SpikeMS: Deep Spiking Neural Network for Motion Segmentation. (arXiv:2105.06562v1 [cs.CV])

Spiking Neural Networks (SNN) are the so-called third generation of neural networks which attempt to more closely match the functioning of the biological brain. They inherently encode temporal data, allowing for training with less energy usage and can be extremely energy efficient when coded on neuromorphic hardware. In addition, they are well suited for tasks involving event-based sensors, which match the event-based nature of the SNN. However, SNNs have not been as effectively applied to real-world, large-scale tasks as standard Artificial Neural Networks (ANNs) due to the algorithmic and training complexity. To exacerbate the situation further, the input representation is unconventional and requires careful analysis and deep understanding. In this paper, we propose \textit{SpikeMS}, the first deep encoder-decoder SNN architecture for the real-world large-scale problem of motion segmentation using the event-based DVS camera as input. To accomplish this, we introduce a novel spatio-temporal loss formulation that includes both spike counts and classification labels in conjunction with the use of new techniques for SNN backpropagation. In addition, we show that \textit{SpikeMS} is capable of \textit{incremental predictions}, or predictions from smaller amounts of test data than it is trained on. This is invaluable for providing outputs even with partial input data for low-latency applications and those requiring fast predictions. We evaluated \textit{SpikeMS} on challenging synthetic and real-world sequences from EV-IMO, EED and MOD datasets and achieving results on a par with a comparable ANN method, but using potentially 50 times less power.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### Distilling Optimal Neural Networks: Rapid Search in Diverse Spaces. (arXiv:2012.08859v2 [cs.LG] UPDATED)

Today, state-of-the-art Neural Architecture Search (NAS) methods cannot scale to many hardware platforms or scenarios at a low training costs and/or can only handle non-diverse, heavily constrained architectural search-spaces. To solve these issues, we present DONNA (Distilling Optimal Neural Network Architectures), a novel pipeline for rapid and diverse NAS, that scales to many user scenarios. In DONNA, a search consists of three phases. First, an accuracy predictor is built using blockwise knowledge distillation. This predictor enables searching across diverse networks with varying macro-architectural parameters such as layer types and attention mechanisms as well as across micro-architectural parameters such as block repeats and expansion rates. Second, a rapid evolutionary search phase finds a set of Pareto-optimal architectures for any scenario using the accuracy predictor and on-device measurements. Third, optimal models are quickly finetuned to training-from-scratch accuracy. With this approach, DONNA is up to 100x faster than MNasNet in finding state-of-the-art architectures on-device. Classifying ImageNet, DONNA architectures are 20% faster than EfficientNet-B0 and MobileNetV2 on a Nvidia V100 GPU and 10% faster with 0.5% higher accuracy than MobileNetV2-1.4x on a Samsung S20 smartphone. In addition to NAS, DONNA is used for search-space extension and exploration, as well as hardware-aware model compression.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 17, 2021 01:30 AM.

• #### Publisher Correction: Closing the gate to distractors during decision-making

Nature Neuroscience, Published online: 17 May 2021; doi:10.1038/s41593-021-00870-0

Publisher Correction: Closing the gate to distractors during decision-making

in Nature Neuroscience on May 17, 2021 12:00 AM.

• #### Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting

Nature Neuroscience, Published online: 17 May 2021; doi:10.1038/s41593-021-00854-0

Biglari et al. reveal subgroups of arcuate nucleus hypothalamic neurons that exhibit distinct molecular signatures and feeding-regulatory functions, thus uncovering new regulatory principles in body weight control.

in Nature Neuroscience on May 17, 2021 12:00 AM.

• #### Diversity in immunogenomics: the value and the challenge

Nature Methods, Published online: 17 May 2021; doi:10.1038/s41592-021-01169-5

Immunogenomics studies have been largely limited to individuals of European ancestry, restricting the ability to identify variation in human adaptive immune responses across populations. Inclusion of a greater diversity of individuals in immunogenomics studies will substantially enhance our understanding of human immunology.

in Nature Methods on May 17, 2021 12:00 AM.

• #### PYMEVisualize: an open-source tool for exploring 3D super-resolution data

Nature Methods, Published online: 17 May 2021; doi:10.1038/s41592-021-01165-9

PYMEVisualize: an open-source tool for exploring 3D super-resolution data

in Nature Methods on May 17, 2021 12:00 AM.

• #### Ultrahigh-energy photons up to 1.4 petaelectronvolts from 12 γ-ray Galactic sources

Nature, Published online: 17 May 2021; doi:10.1038/s41586-021-03498-z

Observations of γ-rays with energies up to 1.4 PeV find that 12 sources in the Galaxy are PeVatrons, one of which is the Crab Nebula.

in Nature on May 17, 2021 12:00 AM.

• #### Author Correction: Generalized superradiance for producing broadband coherent radiation with transversely modulated arbitrarily diluted bunches

Nature Physics, Published online: 17 May 2021; doi:10.1038/s41567-021-01257-5

in Nature Physics on May 17, 2021 12:00 AM.

• #### Free electron to electride transition in dense liquid potassium

Nature Physics, Published online: 17 May 2021; doi:10.1038/s41567-021-01244-w

Alkali metals at high pressures have a liquid–liquid transition that is difficult to study in detail. Numerical calculations now suggest that the higher-pressure state is an electride liquid, in which electrons behave like localized anions.

in Nature Physics on May 17, 2021 12:00 AM.

• #### Generation and measurement of intense few-femtosecond superradiant extreme-ultraviolet free-electron laser pulses

Nature Photonics, Published online: 17 May 2021; doi:10.1038/s41566-021-00815-w

By amplifying a soliton in a multistage cascade, few-femtosecond extreme-ultraviolet free-electron laser pulses are achieved.

in Nature Photomics on May 17, 2021 12:00 AM.

• #### Community composition of microbial microcosms follows simple assembly rules at evolutionary timescales

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23247-0

Evolution affects microbial community composition, but it is still unknown how commonly compositions change, and how predictable such changes are. Using experimental evolution, Meroz et al. show that compositional changes typically occur within ~400 generations, and are predictable by a bottom-up approach.

in Nature Communications on May 17, 2021 12:00 AM.

• #### Polymer-free corticosteroid dimer implants for controlled and sustained drug delivery

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23232-7

Polymer-based systems are often considered a necessity for controlled drug delivery, but have well-known limitations. Here, the authors report on drug delivery implants formed solely from corticosteroid dimers, which demonstrate controlled release and overcome many of the challenges of polymer-based systems.

in Nature Communications on May 17, 2021 12:00 AM.

• #### A universal strategy towards high–energy aqueous multivalent–ion batteries

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23209-6

Rechargeable multivalent-ion batteries are promising candidates for future energy storage technologies. Here, the authors develop various aqueous multivalent-ion cells using concentrated aqueous gel electrolytes, sulfur-containing anodes, and high-voltage metal oxide cathodes.

in Nature Communications on May 17, 2021 12:00 AM.

• #### Genetic fate-mapping reveals surface accumulation but not deep organ invasion of pleural and peritoneal cavity macrophages following injury

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23197-7

Body cavity macrophages reside on the serous surfaces of organs and believed to participate in organ repair following injury. Here the authors show with a fate-mapping reporter system that these cells, although accumulate at the surfaces of injured liver or lung, don’t penetrate deeply into the tissue.

in Nature Communications on May 17, 2021 12:00 AM.

• #### Author Correction: Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23193-x

Author Correction: Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination

in Nature Communications on May 17, 2021 12:00 AM.

• #### Electrochemical ammonia synthesis via nitrate reduction on Fe single atom catalyst

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23115-x

Developing green and delocalized routes for ammonia synthesis is highly important but still very challenging. Here the authors report an efficient ammonia synthesis process via nitrate reduction to ammonia on Fe single atom catalyst.

in Nature Communications on May 17, 2021 12:00 AM.

• #### A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at pathogenwatch

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23091-2

Whole genome sequencing data are increasingly becoming routinely available but generating actionable insights is challenging. Here, the authors describe Pathogenwatch, a web tool for genomic surveillance of S. Typhi, and demonstrate its use for antimicrobial resistance assignment and strain risk assessment.

in Nature Communications on May 17, 2021 12:00 AM.

• #### Early turbulence and pulsatile flows enhance diodicity of Tesla’s macrofluidic valve

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-23009-y

Nguyen et al. take a fresh look at Tesla’s concept of an asymmetric fluidic conduit. They show that for alternating flow at high frequencies the device can almost be operated as a diode, enabled by a transition to turbulent-like flow at rather low Reynolds numbers.

in Nature Communications on May 17, 2021 12:00 AM.

• #### On-demand synthesis of phosphoramidites

Nature Communications, Published online: 17 May 2021; doi:10.1038/s41467-021-22945-z

The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers.

in Nature Communications on May 17, 2021 12:00 AM.

• #### Daily briefing: Why it took so long to grapple with airborne COVID-19

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01342-y

The struggle to overturn outdated guidance about airborne coronavirus, an ‘extinction event’ in our gut bacteria and a T-cell test for SARS-CoV-2.

in Nature on May 17, 2021 12:00 AM.

• #### First nuclear detonation created ‘impossible’ quasicrystals

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01332-0

Their structures were once controversial. Now researchers have discovered quasicrystals in the aftermath of a 1945 bomb test.

in Nature on May 17, 2021 12:00 AM.

• #### Settling in: the first four years of a lab leader

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01330-2

Beth Penrose describes her experiences starting a lab, recruiting staff and creating a research philosophy.

in Nature on May 17, 2021 12:00 AM.

• #### COVID vaccines can block variant hitting Asia, lab study finds

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01329-9

Assays using live SARS-CoV-2 offer hope that the vaccines made by Pfizer and Moderna will protect against a viral strain first seen in India.

in Nature on May 17, 2021 12:00 AM.

• #### Designing nano-sized chemotherapy

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01322-2

Nanoparticles carrying chemotherapeutic drugs could help people with cancer escape some of the drugs’ side effects, hopes Silvia Giordani.

in Nature on May 17, 2021 12:00 AM.

• #### The singing neutrino Nobel laureate who nearly bombed Nevada

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01318-y

From desert to gold mine — Frederick Reines was a larger-than-life physicist who did larger-than-life experiments.

in Nature on May 17, 2021 12:00 AM.

• #### How new principal investigators tackled a tumultuous year

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01311-5

Starting a research group as the COVID-19 pandemic took hold across the world presented extra challenges.

in Nature on May 17, 2021 12:00 AM.

• #### Ancient human faeces reveal gut microbes of the past

Nature, Published online: 17 May 2021; doi:10.1038/d41586-021-01266-7

Appreciation is growing of how our gut microbes shape health and disease. Now, a study of ancient human faeces sheds light on how microbial populations in the gut have changed during the past 2,000 years.

in Nature on May 17, 2021 12:00 AM.

• #### Journal of Neurology

in Journal of Neurology on May 17, 2021 12:00 AM.

### Abstract

Fish escape from approaching threats via a stereotyped escape behavior. This behavior, and the underlying neural circuit organized around the Mauthner cell command neurons, have both been extensively investigated experimentally, mainly in two laboratory model organisms, the goldfish and the zebrafish. However, fish biodiversity is enormous, a number of variants of the basal escape behavior exist. In marine gobies (a family of small benthic fishes) which share burrows with alpheid shrimp, the escape behavior has likely been partially modified into a tactile communication system which allow the fish to communicate the approach of a predatory fish to the shrimp. In this communication system, the goby responds to intermediate-strength threats with a brief tail-flick which the shrimp senses with its antennae.

We investigated the shrimp goby escape and communication system with computational models. We asked how the circuitry of the basal escape behavior could be modified to produce behavior akin to the shrimp-goby communication system. In a simple model, we found that mutual inhibitions between Mauthner cells can be tuned to produce an oscillatory response to intermediate strength inputs, albeit only in a narrow parameter range.

Using a more detailed model, we found that two modifications of the fish locomotor system transform it into a model reproducing the shrimp goby behavior. These modifications are: 1. modifying the central pattern generator which drives swimming such that it is quiescent when receiving no inputs; 2. introducing a direct sensory input to this central pattern generator, bypassing the Mauthner cells.

in Journal of Computational Neuroscience on May 17, 2021 12:00 AM.

### Abstract

The worldwide treatment gap for migraine before COVID-19 inevitably widens as attention focuses on an international emergency. Migraine hits people particularly in their early and middle years, potentially reduces quality of life and productivity, and remains a common emergency presentation. This article examines the impact of COVID-19 on migraine, and changing aspects of migraine care during and after the pandemic. Many risk factors for severe COVID-19—older age, male gender, cardiac and respiratory diseases, diabetes, obesity, and immunosuppression—are less frequent in migraineurs. Telemedicine is effective for migraine follow-up, and needs ongoing evaluation. Most migraine treatments can start or continue in acute COVID-19, with care to avoid drug interactions. Close contact procedures (botulinum toxin, acupuncture and steroid injections) are avoided in lockdown or in the vulnerable. Secondary effects of COVID-19, including long COVID and its economic impact, are probably equal or greater in people with migraine. Migraine and other long-term conditions need adequate resourcing to prevent personal, social and economic suffering. Treating migraine, a sequel of COVID, potentially reduces the impact of long COVID.

in Journal of Neurology on May 17, 2021 12:00 AM.

• #### Cannabinoid Signaling in Auditory Function and Development

Plants of the genus Cannabis have been used by humans for millennia for a variety of purposes. Perhaps most notable is the use of certain Cannabis strains for their psychoactive effects. More recently, several biologically active molecules within the plants of these Cannabis strains, called phytocannabinoids or simply cannabinoids, have been identified. Furthermore, within human cells, endogenous cannabinoids, or endocannabinoids, as well as the receptors and secondary messengers that give rise to their neuromodulatory effects, have also been characterized. This endocannabinoid system (ECS) is composed of two primary ligands—anandamide and 2-arachidonyl glycerol; two primary receptors—cannabinoid receptors 1 and 2; and several enzymes involved in biosynthesis and degradation of endocannabinoid ligands including diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL). Here we briefly summarize cannabinoid signaling and review what has been discerned to date with regard to cannabinoid signaling in the auditory system and its roles in normal physiological function as well as pathological conditions. While much has been uncovered regarding cannabinoid signaling in the central nervous system, less attention has been paid to the auditory system specifically. Still, evidence is emerging to suggest that cannabinoid signaling is critical for the development, maturation, function, and survival of cochlear hair cells (HCs) and spiral ganglion neurons (SGNs). Furthermore, cannabinoid signaling can have profound effects on synaptic connectivity in CNS structures related to auditory processing. While clinical cases demonstrate that endogenous and exogenous cannabinoids impact auditory function, this review highlights several areas, such as SGN development, where more research is warranted.

in Frontiers in Molecular Neuroscience on May 17, 2021 12:00 AM.

• #### Transcriptome Analysis Reveals the Role of Cellular Calcium Disorder in Varicella Zoster Virus-Induced Post-Herpetic Neuralgia

As a typical neuropathic pain, post-herpetic neuralgia (PHN) is a common complication of herpes zoster (HZ), which seriously affects the normal life and work of patients. The unclear pathogenesis and lack of effective drugs make the clinical efficacy of PHN unsatisfactory. Here, we obtained the transcriptome profile of neuroblastoma cells (SH-SY5Y) and DRG in rats infected with varicella zoster virus (VZV) by transcriptome sequencing (RNA-Seq) combined with publicly available gene array data sets. Next, the data processing of the transcriptome map was analyzed using bioinformatics methods, including the screening of differentially expressed genes (DEGs), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, real-time fluorescent quantitative PCR (qRT-PCR) was used to detect the expression of calcium-related genes, and calcium fluorescent probes and calcium colorimetry were used to evaluate the distribution and content of calcium ions in cells after VZV infection. Transcriptome data analysis (GO and KEGG enrichment analysis) showed that calcium disorder played an important role in SH-SY5Y cells infected by VZV and dorsal root ganglion (DRG) of the PHN rat model. The results of qRT-PCR showed that the expression levels of calcium-related genes BHLHA15, CACNA1F, CACNG1, CHRNA9, and STC2 were significantly upregulated, while the expression levels of CHRNA10, HRC, and TNNT3 were significantly downregulated in SH-SY5Y cells infected with VZV. Our calcium fluorescent probe and calcium colorimetric test results showed that VZV could change the distribution of calcium ions in infected cells and significantly increase the intracellular calcium content. In conclusion, our results revealed that the persistence of calcium disorder caused by VZV in nerve cells might be a crucial cause of herpetic neuralgia, and a potential target for clinical diagnosis and treatment of PHN.

in Frontiers in Molecular Neuroscience on May 17, 2021 12:00 AM.

• #### Single-Nucleus Chromatin Accessibility Landscape Reveals Diversity in Regulatory Regions Across Distinct Adult Rat Cortex

Rats have been widely used as an experimental organism in psychological, pharmacological, and behavioral studies by modeling human diseases such as neurological disorders. It is critical to identify and characterize cell fate determinants and their regulatory mechanisms in single-cell resolutions across rat brain regions. Here, we applied droplet-based single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) to systematically profile the single-cell chromatin accessibility across four dissected brain areas in adult Sprague–Dawley (SD) rats with a total of 59,023 single nuclei and identified 16 distinct cell types. Interestingly, we found that different cortex regions exhibit diversity in both cellular compositions and gene regulatory regions. Several cell-type-specific transcription factors (TFs), including SPI1, KLF4, KLF6, and NEUROD2, have been shown to play important roles during the pathogenesis of various neurological diseases, such as Alzheimer’s disease (AD), astrocytic gliomas, autism spectrum disorder (ASD), and intellectual disabilities. Therefore, our single-nucleus atlas of rat cortex could serve as an invaluable resource for dissecting the regulatory mechanisms underlying diverse cortex cell fates and further revealing the regulatory networks of neuropathogenesis.

in Frontiers in Molecular Neuroscience on May 17, 2021 12:00 AM.

• #### Photoacoustic Mouse Brain Imaging Using an Optical Fabry-Pérot Interferometric Ultrasound Sensor

Photoacoustic (PA, or optoacoustic, OA) mesoscopy is a powerful tool for mouse cerebral imaging, which offers high resolution three-dimensional (3D) images with optical absorption contrast inside the optically turbid brain. The image quality of a PA mesoscope relies on the ultrasonic transducer which detects the PA signals. An all-optical ultrasound sensor based on a Fabry-Pérot (FP) polymer cavity has the following advantages: broadband frequency response, wide angular coverage and small footprint. Here, we present 3D PA mesoscope for mouse brain imaging using such an optical sensor. A heating laser was used to stabilize the sensor’s cavity length during the imaging process. To acquire data for a 3D angiogram of the mouse brain, the sensor was mounted on a translation stage and raster scanned. 3D images of the mouse brain vasculature were reconstructed which showed cerebrovascular structure up to a depth of 8 mm with high quality. Imaging segmentation and dual wavelength imaging were performed to demonstrate the potential of the system in preclinical brain research.

in Frontiers in Neuroscience: Brain Imaging Methods on May 17, 2021 12:00 AM.

• #### The Distribution of Skull Score and Skull Density Ratio in Tremor Patients for MR-Guided Focused Ultrasound Thalamotomy

Objective

Magnetic resonance-guided focused ultrasound (MRgFUS) is a minimum-invasive surgical approach to non-incisionally cause the thermos-coagulation inside the human brain. The skull score (SS) has already been approved as one of the most dominant factors related to a successful MRgFUS treatment. In this study, we first reveal the SS distribution of the tremor patients, and correlate the SS with the image feature from customized skull density ratio (cSDR). This correlation might give a direction to future clinical studies for improving the SS.

Methods

Two hundred and forty-six patients received a computed tomography (CT) scan of the brain, and a bone-enhanced filter was applied and reconstructed to a high spatial resolution CT images. The SS of all patients would be estimated by the MRgFUS system after importing the reconstructed CT images into the MRgFUS system. The histogram and the cumulative distribution of the SS from all the patients were calculated to show the percentage of the patients whose SS lower than 0.3 and 0.4. The same CT images of all patients were utilized to calculated the cSDR by first segmented the trabecular bone and the cortical bone from the CT images and divided the average trabecular bone intensity (aTBI) by the average cortical bone intensity (aCBI). The Pearson’s correlations between the SS and the cSDR, aTBI, and the aCBI were calculated, respectively.

Results

There were 19.19 and 50% of the patient who had the SS lower than the empirical threshold 0.3 and 0.4, respectively. The Pearson’s correlation between the SS and the cSDR, aCBI, and the aTBI were R = 0.8145, 0.5723, and 0.8842.

Conclusion

Half of the patients were eligible for the MRgFUS thalamotomy based on the SS, and nearly 20% of patients were empirically difficult to achieve a therapeutic temperature during MRgFUS. The SS and our cSDR are highly correlated, and the SS had a higher correlation with aTBI than with aCBI. This is the first report to explicitly reveal the SS population and indicate a potential way to increase the chance to achieve a therapeutic temperature for those who originally have low SS.

in Frontiers in Neuroscience: Brain Imaging Methods on May 17, 2021 12:00 AM.

• #### A Probabilistic Atlas of the Pineal Gland in the Standard Space

Pineal gland (PG) is a structure located in the midline of the brain, and is considered as a main part of the epithalamus. There are numerous reports on the facilitatory role of this area for brain function; hormone secretion and its role in sleep cycle are the major reports. However, reports are rarely available on the direct role of this structure in brain cognition and in information processing. A suggestion for the limited number of such studies is the lack of a standard atlas for the PG; none of the available MRI templates and atlases has provided parcellations for this structure. In this study, we used the three-dimensional (3D) T1-weighted MRI data of 152 healthy young volunteers, and provided a probabilistic map of the PG in the standard Montreal Neurologic Institute (MNI) space. The methods included collecting the data using a 64-channel head coil on a 3-Tesla Prisma MRI Scanner, manual delineation of the PG by two experts, and robust template and atlas construction algorithms. This atlas is freely accessible, and we hope importing this atlas in the well-known neuroimaging software packages would help to identify other probable roles of the PG in brain function. It could also be used to study pineal cysts, for volumetric analyses, and to test any associations between the cognitive abilities of the human and the structure of the PG.

in Frontiers in Neuroinformatics on May 17, 2021 12:00 AM.

• #### Idiosyncratic Characteristics of Postural Sway in Normal and Perturbed Standing

Objective

Are people with a characteristically large physiological sway rendered particularly unstable when standing on a moving surface? Is postural sway in standing individuals idiosyncratic? In this study, we examine postural sway in individuals standing normally, and when subtle continuous sinusoidal disturbances are applied to their support platform. We calculate consistency between conditions to verify if sway can be considered characteristic of each individual. We also correlate two different aspects of participants’ responses to disturbance; their sway velocity and their regulation of body orientation.

Methods

Nineteen healthy adults (age 29.2 ± 3.2 years) stood freely on footplates coaxially aligned with their ankles and attached to a motorized platform. They had their eyes closed, and hips and knees locked with a light wooden board attached to their body. Participants either stood quietly on a fixed platform or on a slowly tilting platform (0.1 Hz sinusoid; 0.2 and 0.4 deg). Postural sway size was separated into two entities: (1) the spontaneous sway velocity component (natural random relatively rapid postural adjustments, RMS body angular velocity) and (2) the evoked tilt gain component (much slower 0.1 Hz synchronous tilt induced by the movement of the platform, measured as peak-to-peak (p-p) gain, ratio of body angle to applied footplate rotation).

Results

There was no correlation between the velocity of an individual’s sway and their evoked tilt gain (r = 0.34, p = 0.15 and r = 0.30, p = 0.22). However, when considered separately, each of the two measurements showed fair to good absolute agreement within conditions. Spontaneous sway velocity consistently increased as participants were subjected to increasing disturbance. Participants who swayed more (or less) did so across all conditions [ICC(3,k) = 0.95]. Evoked tilt gain also showed consistency between conditions [ICC(3,k) = 0.79], but decreased from least to most disturbed conditions.

Conclusion

The two measurements remain consistent between conditions. Consistency between conditions of two very distinct unrelated measurements reflects the idiosyncratic nature of postural sway. However, sway velocity and tilt gain are not related, which supports the idea that the short-term regulation of stability and the longer-term regulation of orientation are controlled by different processes.

in Frontiers in Human Neuroscience on May 17, 2021 12:00 AM.

• #### The Role of the Dorsolateral Prefrontal Cortex for Speech and Language Processing

This review article summarizes various functions of the dorsolateral prefrontal cortex (DLPFC) that are related to language processing. To this end, its connectivity with the left-dominant perisylvian language network was considered, as well as its interaction with other functional networks that, directly or indirectly, contribute to language processing. Language-related functions of the DLPFC comprise various aspects of pragmatic processing such as discourse management, integration of prosody, interpretation of nonliteral meanings, inference making, ambiguity resolution, and error repair. Neurophysiologically, the DLPFC seems to be a key region for implementing functional connectivity between the language network and other functional networks, including cortico-cortical as well as subcortical circuits. Considering clinical aspects, damage to the DLPFC causes psychiatric communication deficits rather than typical aphasic language syndromes. Although the number of well-controlled studies on DLPFC language functions is still limited, the DLPFC might be an important target region for the treatment of pragmatic language disorders.

in Frontiers in Human Neuroscience on May 17, 2021 12:00 AM.

• #### Indirect Vibration of the Upper Limbs Alters Transmission Along Spinal but Not Corticospinal Pathways

The use of upper limb vibration (ULV) during exercise and rehabilitation continues to gain popularity as a modality to improve function and performance. Currently, a lack of knowledge of the pathways being altered during ULV limits its effective implementation. Therefore, the aim of this study was to investigate whether indirect ULV modulates transmission along spinal and corticospinal pathways that control the human forearm. All measures were assessed under CONTROL (no vibration) and ULV (30 Hz; 0.4 mm displacement) conditions while participants maintained a small contraction of the right flexor carpi radialis (FCR) muscle. To assess spinal pathways, Hoffmann reflexes (H-reflexes) elicited by stimulation of the median nerve were recorded from FCR with motor response (M-wave) amplitudes matched between conditions. An H-reflex conditioning paradigm was also used to assess changes in presynaptic inhibition by stimulating the superficial radial (SR) nerve (5 pulses at 300Hz) 37 ms prior to median nerve stimulation. Cutaneous reflexes in FCR elicited by stimulation of the SR nerve at the wrist were also recorded. To assess corticospinal pathways, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation of the contralateral motor cortex were recorded from the right FCR and biceps brachii (BB). ULV significantly reduced H-reflex amplitude by 15.7% for both conditioned and unconditioned reflexes (24.0 ± 15.7 vs. 18.4 ± 11.2% Mmax; p < 0.05). Middle latency cutaneous reflexes were also significantly reduced by 20.0% from CONTROL (−1.50 ± 2.1% Mmax) to ULV (−1.73 ± 2.2% Mmax; p < 0.05). There was no significant effect of ULV on MEP amplitude (p > 0.05). Therefore, ULV inhibits cutaneous and H-reflex transmission without influencing corticospinal excitability of the forearm flexors suggesting increased presynaptic inhibition of afferent transmission as a likely mechanism. A general increase in inhibition of spinal pathways with ULV may have important implications for improving rehabilitation for individuals with spasticity (SCI, stroke, MS, etc.).

in Frontiers in Human Neuroscience on May 17, 2021 12:00 AM.

• #### Layer-Skipping Connections Improve the Effectiveness of Equilibrium Propagation on Layered Networks

Equilibrium propagation is a learning framework that marks a step forward in the search for a biologically-plausible implementation of deep learning, and could be implemented efficiently in neuromorphic hardware. Previous applications of this framework to layered networks encountered a vanishing gradient problem that has not yet been solved in a simple, biologically-plausible way. In this paper, we demonstrate that the vanishing gradient problem can be mitigated by replacing some of a layered network's connections with random layer-skipping connections in a manner inspired by small-world networks. This approach would be convenient to implement in neuromorphic hardware, and is biologically-plausible.

in Frontiers in Computational Neuroscience on May 17, 2021 12:00 AM.

• #### Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson’s Disease

Dopamine is an important chemical messenger in the brain, which modulates movement, reward, motivation, and memory. Different populations of neurons can produce and release dopamine in the brain and regulate different behaviors. Here we focus our discussion on a small but distinct group of dopamine-producing neurons, which display the most profound loss in the ventral substantia nigra pas compacta of patients with Parkinson’s disease. This group of dopaminergic neurons can be readily identified by a selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and accounts for 70% of total nigrostriatal dopaminergic neurons in both human and mouse brains. Recently, we presented the first whole-brain circuit map of these ALDH1A1-positive dopaminergic neurons and reveal an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. In this review, we first summarize previous findings of ALDH1A1-positive nigrostriatal dopaminergic neurons and their connectivity and functionality, and then provide perspectives on how the activity of ALDH1A1-positive nigrostriatal dopaminergic neurons is regulated through integrating diverse presynaptic inputs and its implications for potential Parkinson’s disease treatment.

in Frontiers in Neural Circuits on May 17, 2021 12:00 AM.

• #### Editorial: Stem Cells and Aging

in Frontiers in Ageing Neuroscience on May 17, 2021 12:00 AM.

• #### Circulating Neurofilament Light Predicts Cognitive Decline in Patients With Post-stroke Subjective Cognitive Impairment

Background

Subjective cognitive impairment (SCI) is common after acute ischemic stroke and adversely affects the quality of life. SCI is associated with an increased risk of developing mild cognitive impairment and dementia. Identifying biomarkers which could predict long-term cognitive outcomes of post-stroke SCI is of importance for early intervention. This study aims to investigate the association between circulating neurofilament light (NfL) and long-term cognitive function in patients with post-stroke SCI.

Methods

This longitudinal study recruited 304 patients with post-stroke SCI, and serum NfL levels were determined at baseline. These patients were followed up for 12 months for the observation of cognitive change. Cognitive performances were assessed by a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) scale.

Results

The patients were divided into a progression group (as determined by decreased TICS-40 scores) and a stable group (as determined by increased or unchanged TICS-40 scores). The progression group had significantly higher serum NfL levels than the stable group at baseline. Serum NfL levels were predictive for longitudinal cognitive decline during follow-up.

Conclusion

These findings imply that circulating NfL could predict the long-term cognitive change of patients with post-stroke SCI.

in Frontiers in Ageing Neuroscience on May 17, 2021 12:00 AM.

• #### Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy

in Frontiers in Ageing Neuroscience on May 17, 2021 12:00 AM.

• #### Danger zone

What level of Ras genes activity leads to the development of cancer?

in eLife on May 17, 2021 12:00 AM.

• #### Signaling levels mold the RAS mutation tropism of urethane

RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a ‘tropism’ towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine Kras gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12 Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.

in eLife on May 17, 2021 12:00 AM.

• #### The crystal structure of bromide-bound GtACR1 reveals a pre-activated state in the transmembrane anion tunnel

The crystal structure of the light-gated anion channel GtACR1 reported in our previous Research Article (Li et al., 2019) revealed a continuous tunnel traversing the protein from extracellular to intracellular pores. We proposed the tunnel as the conductance channel closed by three constrictions: C1 in the extracellular half, mid-membrane C2 containing the photoactive site, and C3 on the cytoplasmic side. Reported here, the crystal structure of bromide-bound GtACR1 reveals structural changes that relax the C1 and C3 constrictions, including a novel salt-bridge switch mechanism involving C1 and the photoactive site. These findings indicate that substrate binding induces a transition from an inactivated state to a pre-activated state in the dark that facilitates channel opening by reducing free energy in the tunnel constrictions. The results provide direct evidence that the tunnel is the closed form of the channel of GtACR1 and shed light on the light-gated channel activation mechanism.

in eLife on May 17, 2021 12:00 AM.

• #### Clustered functional domains for curves and corners in cortical area V4

The ventral visual pathway is crucially involved in integrating low-level visual features into complex representations for objects and scenes. At an intermediate stage of the ventral visual pathway, V4 plays a crucial role in supporting this transformation. Many V4 neurons are selective for shape segments like curves and corners, however it remains unclear whether these neurons are organized into clustered functional domains, a structural motif common across other visual cortices. Using two-photon calcium imaging in awake macaques, we confirmed and localized cortical domains selective for curves or corners in V4. Single-cell resolution imaging confirmed that curve or corner selective neurons were spatially clustered into such domains. When tested with hexagonal-segment stimuli, we find that stimulus smoothness is the cardinal difference between curve and corner selectivity in V4. Combining cortical population responses with single neuron analysis, our results reveal that curves and corners are encoded by neurons clustered into functional domains in V4. This functionally-specific population architecture bridges the gap between the early and late cortices of the ventral pathway and may serve to facilitate complex object recognition.

in eLife on May 17, 2021 12:00 AM.

• #### Causal relationship of CA3 back-projection to the dentate gyrus and its role in CA1 fast ripple generation

Pathophysiological evidence from temporal lobe epilepsy models highlights the hippocampus as the most affected structure due to its high degree of neuroplasticity and control of the dynamics of limbic structur...

in BMC Neuroscience on May 17, 2021 12:00 AM.

• #### Inhibitory control training reveals a common neurofunctional basis for generic executive functions and language switching in bilinguals

The neural networks underpinning language control and domain-general executive functions overlap in bilinguals, but existing evidence is mainly correlative. Here, we present the first neurofunctional evidence ...

in BMC Neuroscience on May 17, 2021 12:00 AM.

• #### Nicotinic acetylcholine receptor partial antagonist polyamides from tunicates and their predatory sea slugs

In our efforts to discover new drugs to treat pain, we identified molleamines A-E (1-5) as major neuroactive components of the sea slug, Pleurobranchus forskalii and their prey, Didemnum molle tunicates. The chemical structures of molleamines were elucidated by spectroscopy and confirmed by the total synthesis of molleamines A (1) and C (3). Synthetic 3 completely blocked acetylcholine-induced calcium flux in peptidergic nociceptors (PNs) in the somatosensory nervous system. Compound 3 affected neither the 7 nAChR nor the muscarinic acetylcholine receptors in calcium flux assays. In addition to nociceptors, 3 partially blocked the acetylcholine-induced calcium flux in the sympathetic nervous system, including neurons from the superior cervical ganglion. Electrophysiology revealed a block of 3{beta}4 (mouse) and 6/3{beta}4 (rat) nicotinic acetylcholine receptors (nAChRs), with IC50 values of 1.4 and 3.1 M, respectively. Molleamine C (3) is a partial antagonist, reaching a maximum block of 76-82% of the acetylcholine signal and showing no partial agonist response. Molleamine C (3) may thus provide a lead compound for the development of neuroactive compounds with unique biological properties.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Transcriptome analysis provides genome annotation and expression profiles in the central nervous system of Lymnaea stagnalis at different ages

Molecular studies of the freshwater snail Lymnaea stagnalis, a unique model organism for neurobiology research, has been severely hindered by the lack of sufficient genomic information. As part of our ongoing effort studying L. stagnalis neuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young, adult, and old L. stagnalis central nervous system (CNS). RNA sequencing using Illumina NovaSeq 6000 platform produced 56-69 millions of 150 bp paired-end reads, and 74% of these reads were mapped to the draft genome of L. stagnalis. We provide gene annotations for 32,288 coding sequences with a minimum of 100 codons, contributing to the largest number of annotated genes for the L. stagnalis genome to date. Lastly, transcriptomic analyses reveal age-specific differentially expressed genes and enriched pathways in young, adult, and old CNS. These datasets represent the largest and most updated L. stagnalis CNS transcriptomes.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### In mice and humans, the brain's blood vessels mature postnatally to acquire barrier and contractile properties

The brain dense vascular network is essential for distributing oxygen and nutrients to neural cells. The network develops during embryogenesis and leads to the formation of the endothelial blood-brain barrier (BBB). This barrier is surrounded by mural cells (pericytes and vascular smooth muscle cells (VSMCs)) and fibroblasts. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (ECs), VSMCs and fibroblasts follow specific molecular maturation programs over this time period. In particular, ECs acquire P-glycoprotein (P-gP)-mediated efflux capacities. The arterial VSMC network expands, acquires contractile proteins (such as smooth muscle actin (SMA) and myosin heavy chain 11 (Myh11)) and becomes contractile. We also analyzed samples of human brain cortex from the early prenatal stage through to adulthood: the expression of endothelial P-gP increased at birth and Myh11 in VSMCs acts as a developmental switch (as in the mouse) at birth and up to the age of 2 of 5 years. Thus, in both mice and humans, the early postnatal phase is a critical period during which the essential properties of cerebral blood vessels (i.e. the endothelial efflux of xenobiotics and other molecules, and the VSMC contractility required for vessel tone and brain perfusion) are acquired and mature.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Synaptic targets of functionally specialized R7 and R8 photoreceptors in the central eye and dorsal rim area of Drosophila

Color and polarization provide complementary information about the world and are detected by specialized photoreceptors. However, the downstream neural circuits that process these distinct modalities are incompletely understood in any animal. We have systematically reconstructed, using light and electron microscopy, the synaptic targets of the photoreceptors specialized to detect color and polarized light in Drosophila. We identified known and novel downstream targets that are selective for different wavelengths as well as for polarized light and followed their projections to other areas in the optic lobes and the central brain. Strikingly, photoreceptors in the polarization-sensitive dorsal rim area target fewer cell types, that lack strong connections to the lobula, a neuropil with a proposed role in color processing. Our reconstruction identifies shared wiring and modality-specific specializations for color and polarization vision, and provides a comprehensive view of the first steps of the pathways processing color and polarized light inputs.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Alcohol Use Disrupts Age-Appropriate Cortical Thinning in Adolescence: A Data Driven Approach

Objective: Cortical thickness changes dramatically during development and is influenced by adolescent drinking. However, previous findings have been inconsistent and limited by region-of-interest approaches that are underpowered because they do not conform to the underlying heterogeneity from the effects of alcohol. Methods: Adolescents (n=657; 12-22 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) who endorsed little to no alcohol use at baseline were assessed with structural MRI and followed longitudinally at four yearly intervals. Seven unique spatially covarying patterns of cortical thickness were obtained from the baseline scans by applying a novel data-driven method called non-negative matrix factorization (NMF). The cortical thickness maps of all participants' longitudinal scans were projected onto vertex-level cortical patterns to obtain participant-specific coefficients for each pattern. Linear mixed-effects models were fit to each pattern to investigate longitudinal effects of alcohol consumption on cortical thickness. Results: In most NMF-derived cortical thickness patterns, the longitudinal rate of decline in no/low drinkers was similar for all age cohorts, among moderate drinkers the decline was faster in the younger cohort and slower in the older cohort, among heavy drinkers the decline was fastest in the younger cohort and slowest in the older cohort (FDR corrected p-values < 0.01). Conclusions: The NMF method can delineate spatially coordinated patterns of cortical thickness at the vertex level that are unconstrained by anatomical features. Age-appropriate cortical thinning is more rapid in younger adolescent drinkers and slower in older adolescent drinkers.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Gymnasts' ability for general motor imagery evaluated by bioelectric sensorimotor rhythms

Introduction: Previous psychological studies using questionnaires have consistently reported that athletes have superior motor imagery ability, both for sports-specific movements and general movements. However, regarding general motor imagery, no physiological studies have demonstrated differences in neural activity between athletes and non-athletes. Gymnasts may be a suitable population for investigating this issue because they are likely to have particularly superior motor imagery ability due to their frequent usage of motor imagery as part of daily practice. Purpose: The purpose of the present study was to examine differences in bioelectric sensorimotor rhythms during kinesthetic motor imagery of general movements between gymnasts and non-gymnasts. Methods: Healthy young participants (16 gymnasts and 16 non-gymnasts) performed repeated motor execution and motor imagery of general movements (wrist dorsiflexion and shoulder abduction of the dominant hand). Scalp electroencephalogram (EEG) was recorded over the contralateral sensorimotor cortex. During motor execution and motor imagery, sensorimotor EEG power is known to decrease in the - (8-15 Hz) and {beta}-bands (16-35 Hz), referred to as event-related desynchronization (ERD). We calculated the maximal peak of ERD both in the - (ERDmax) and {beta}-bands ({beta}ERDmax) as a measure of changes in corticospinal excitability. Results: ERD magnitude during motor imagery was significantly greater in gymnasts, who subjectively evaluated their motor imagery as being more vivid. In particular, ERDmax was greater in gymnasts compared with non-gymnasts for both motor imagery tasks, whereas {beta}ERDmax was greater in gymnasts only for shoulder abduction imagery. Conclusion: We observed gymnasts' signature of flexibly modulating sensorimotor rhythm with no movement, which may be the basis of their superior general motor imagery ability.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Unsupervised learning for robust working memory

Working memory is a core component of critical cognitive functions such as planning and decision-making. Persistent activity that lasts long after the stimulus offset has been considered a neural substrate for working memory. Attractor dynamics based on network interactions can successfully reproduce such persistent activity. However, it suffers from a fine-tuning of network connectivity, in particular, to form continuous attractors suggested for working memory encoding analog signals. Here, we investigate whether a specific form of synaptic plasticity rules can mitigate such tuning problems in two representative working memory models, namely, rate-coded and location-coded persistent activity. We consider two prominent types of plasticity rules, differential plasticity targeting the slip of instant neural activity and homeostatic plasticity regularizing the long-term average of activity, both of which have been proposed to fine-tune the weights in an unsupervised manner. Consistent with the findings of previous works, differential plasticity alone was enough to recover a graded-level persistent activity with less sensitivity to learning parameters. However, for the maintenance of spatially structured persistent activity, differential plasticity could recover persistent activity, but its pattern can be irregular for different stimulus locations. On the other hand, homeostatic plasticity shows a robust recovery of smooth spatial patterns under particular types of synaptic perturbations, such as perturbations in incoming synapses onto the entire or local populations, while it was not effective against perturbations in outgoing synapses from local populations. Instead, combining it with differential plasticity recovers location-coded persistent activity for a broader range of perturbations, suggesting compensation between two plasticity rules.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC); this rare type of leukodystrophy is characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes (PvAPs, which along with blood vessels form the gliovascular unit (GVU)). We analyzed the GVU in the Mlc1 knock-out mouse model of MLC. The absence of MLC1 led to an accumulation of fluid in the brain but did not modify the endothelial organization or the integrity of the blood-brain barrier. From P10 onward, the postnatal acquisition of vascular smooth muscle cell contractility was altered, resulting in a marked reduction in arterial perfusion and neurovascular coupling. These anomalies were correlated with alterations in astrocyte morphology, astrocyte polarity and the structural organization of the PvAP's perivascular coverage, and poor intraparenchymal circulation of the cerebrospinal fluid (CSF). Hence, MLC1 is required for the postnatal development and organization of PvAPs and controls vessel contractility and intraparenchymal interstitial fluid clearance. Our data suggest that (i) MLC is a developmental disorder of the GVU, and (ii) PvAP and VSMC maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### LACTATE IS A MAJOR ENERGY SUBSTRATE FOR CORTICAL NEURONS AND ENHANCES THEIR FIRING ACTIVITY

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with Kir6.2 and SUR1 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Probabilistically Weighted Multilayer Networks disclose the link between default mode network instability and psychosis-like experiences in healthy adults

The brain is a complex, multilayer system in which the functional interactions among its subunits vary over time. The trajectories of this dynamic variation contribute to inter-individual behavioral differences and psychopathologic phenotypes. Despite many methodological advancements, the study of dynamic brain networks still relies on biased assumptions in the temporal domain. The current paper has two goals. First, we present a novel method to study multilayer networks by modelling intra-nodal connections in a probabilistic and biologically driven way. We introduce a temporal resolution of the multilayer network based on signal similarity within time series. This new method is tested on synthetic networks by varying the number of modules and the sources of noise in the simulation. Secondly, we implement these probabilistically weighted (PW) multilayer networks to study the association between network dynamics and subclinical, psychosis-relevant personality traits in healthy adults. We show that the PW method for multilayer networks outperform the standard procedure in modular detection and is less affected by increasing noise levels. Additionally, the PW method highlighted associations between the temporal instability of default mode network connections and psychosis-like experiences in healthy adults. PW multilayer networks allow an unbiased study of dynamic brain functioning and its behavioral correlates.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Compensatory changes in contralesional node strength, brain wide modularity and cross-modular functional interactions in a rat model of traumatic brain injury

Penetrating cortical impact injuries alter neuronal communication beyond the injury epicenter, across regions involved in affective, sensorimotor, and cognitive processing. Understanding how traumatic brain injury (TBI) reorganizes local and brain wide nodal functional interactions may provide valuable quantitative parameters for monitoring pathological progression and functional recovery. To this end, we investigated spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal obtained at 11.1 Tesla in rats sustaining controlled cortical impact (CCI) and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12,879 pairwise correlations between fMRI signals from 162 regions. Our data indicate that on days 2 and 30 post-CCI there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic, and basal forebrain areas. Rats imaged on day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality, and participation coefficient track early and late TBI effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to CCI may be unfavorable to brain wide communication in the early post-injury period.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Schema representations in distinct brain networks support narrative memory during encoding and retrieval

Schematic prior knowledge can scaffold the construction of event memories during perception and also provide structured cues to guide memory search during retrieval. We measured the activation of story-specific and schematic representations using fMRI while participants were presented with 16 stories and then recalled each of the narratives, and related these activations to memory for specific story details. We predicted that schema representations in mPFC would be correlated with successful recall of story details. In keeping with this prediction, an anterior mPFC region showed a significant correlation between activation of schema representations at encoding and subsequent behavioral recall performance; however, this mPFC region was not implicated in schema representation during retrieval. More generally, our analyses revealed largely distinct brain networks at encoding and retrieval in which schema activation was related to successful recall. These results provide new insight into when and where event knowledge can support narrative memory.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Human fetal neural stem cell-derived astrocytes maintain glutamate transport after hypoxic injury in vitro

Astrocytes are the most abundant glial cells that play many critical roles in the central nervous system physiology including the uptake of excess glutamate from the synapse by Excitatory Amino Acid Transporters (EAATs). Among the EAATs, EAAT2 are predominantly functional, astrocyte-specific glutamate transporters in the forebrain. Hypoxic brain injury is a pathological phenomenon seen in various clinical conditions including stroke and neonatal hypoxic ischemic encephalopathy. Glutamate excitotoxicity is an important cause of neuronal cell death in disorders involving hypoxic brain injury. As findings from rodent models cannot always be reliably extrapolated to humans, we aimed to develop a homogenous population of primary human astrocytes to study the effect of hypoxic injury on astrocyte function, especially glutamate uptake. We successfully isolated, established and characterized cultures of human fetal neural stem cells (FNSCs) from aborted fetal brains. FNSCs were differentiated into astrocytes, and characterized by increased expression of the astrocyte marker, glial fibrillary acidic protein (GFAP), and a concomitant decrease in neural stem cell marker, Nestin. Differentiated astrocytes were exposed to various oxygen concentrations mimicking normoxia (20% and 6%), moderate and severe hypoxia (2% and 0.2% respectively). Interestingly, no change was observed in the expression of glutamate transporter, EAAT2 and glutamate uptake by astrocytes, even after exposure to hypoxia. Our novel model of human FNSC derived astrocytes exposed to hypoxic injury, establishes that astrocytes are able to maintain glutamate uptake even after exposure to severe hypoxia for 48 hours, and thus provides evidence for the neuroprotective role of astrocytes in hypoxic injury.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer's disease

In neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of alpha-tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL+/- mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimer's disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Abeta1-42 and that TTL, by promoting microtubule entry into spines, prevents Abeta1-42-induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### A Meta-Analysis of fMRI Studies of Semantic Cognition in Children

Our capacity to derive meaning from things that we see and words that we hear is unparalleled in other animal species and current AI systems. Despite a wealth of functional magnetic resonance imaging (fMRI) studies on where different semantic features are processed in the adult brain, the development of these systems in children is poorly understood. Here we conducted an extensive database search and identified 50 fMRI experiments investigating semantic world knowledge, semantic relatedness judgments, and the differentiation of visual semantic object categories in children (total N = 1,018, mean age = 10.1 years, range 4-15 years). Synthesizing the results of these experiments, we found consistent activation in the bilateral inferior frontal gyri (IFG), fusiform gyri (FG), and supplementary motor areas (SMA), as well as in the left middle and superior temporal gyri (MTG/STG). Within this system, we found little evidence for age-related changes across childhood and high overlap with the adult semantic system. In sum, the identification of these cortical areas provides the starting point for further research on the mechanisms by which the developing brain learns to make sense of its environment.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Slow Cortical Waves via Cyclicity

Fine-grained information about dynamic structure of cortical networks is crucial in unpacking brain function. Here,we introduced a novel analytical method to characterize the dynamic interaction between distant brain regions,based on cyclicity analysis, and applied it to data from the Human Connectome Project. Resting-state fMRI time series are aperiodic and, hence, lack a base frequency. Cyclicity analysis, which is time-reparametrization invariant, is effective in recovering dynamic temporal ordering of such time series along a circular trajectory without assuming any time scale. Our analysis detected the propagation of slow cortical waves across thebrain with consistent shifts in lead-lag relationships between specific brain regions. We also observed short bursts of strong temporal ordering that dominated overall lead-lag relationships between pairs of regions in the brain, which were modulated by tasks. Our results suggest the possible role played by slow waves of ordered information between brain regions that underlie emergent cognitive function.

in bioRxiv: Neuroscience on May 17, 2021 12:00 AM.

• #### Characterization of extracranial giant cell arteritis with intracranial involvement and its rapidly progressive subtype

in Annals of Neurology on May 16, 2021 12:38 PM.

• #### Biological Cybernetics

in Biological Cybernetics on May 16, 2021 12:00 AM.

• #### Experimental Brain Research

in Experimental Brain Research on May 16, 2021 12:00 AM.

### Abstract

Detection of looming obstacles is a vital task for both natural and artificial systems. Locusts possess a visual nervous system with an extensively studied obstacle detection pathway, culminating in the lobula giant movement detector (LGMD) neuron. While numerous models of this system exist, none to date have incorporated recent data on the anatomy and function of feedforward and global inhibitory systems in the input network of the LGMD. Moreover, the possibility that global and lateral inhibition shape the feedforward inhibitory signals to the LGMD has not been investigated. To address these points, a novel model of feedforward inhibitory neurons in the locust optic lobe was developed based on the recent literature. This model also incorporated global and lateral inhibition into the afferent network of these neurons, based on their observed behaviour in existing data and the posited role of these mechanisms in the inputs to the LGMD. Tests with the model showed that it accurately replicates the behaviour of feedforward inhibitory neurons in locusts; the model accurately coded for stimulus angular size in an overall linear fashion, with decreasing response saturation and increasing linearity as stimulus size increased or approach velocity decreased. The model also exhibited only phasic responses to the appearance of a grating, along with sustained movement by it at constant speed. By observing the effects of altering inhibition schemes on these responses, it was determined that global inhibition serves primarily to normalize growing excitation as collision approaches, and keeps coding for subtense angle linear. Lateral inhibition was determined to suppress tonic responses to wide-field stimuli translating at constant speed. Based on these features being shared with characterizations of the LGMD input network, it was hypothesized that the feedforward inhibitory neurons and the LGMD share the same excitatory afferents; this necessitates further investigation.

in Biological Cybernetics on May 16, 2021 12:00 AM.

• #### Locomotor action sequences impact the scale of representation in hippocampus and posterior parietal cortex

Abstract The hippocampus and posterior parietal cortex are implicated in both episodic memory and encoding of position in an environment. In the present study, we examine the impact of locomotor behaviors associated with movement in both the horizontal and vertical dimensions on population activity patterns in these two brain structures. We utilized a five‐looped, squared spiral track containing stair segments, ramp segments, and flat segments. In addition to encoding locations along the full route, posterior parietal cortex population activity demonstrates strong pattern recurrence for similar action types at different locations in the environment. Additionally, posterior parietal and hippocampal neurons exhibit parallel modulation in the scale of representation that follows behavioral dynamics required for track traversal. These findings build on prior work examining spatial mapping in the vertical dimension and provide a better understanding of how a series of actions and visited locations can be coordinated in the generation of episodic memory.

in Hippocampus on May 15, 2021 09:10 AM.

• #### Effects of subclinical depression on prefrontal–striatal model-based and model-free learning

by Suyeon Heo, Yoondo Sung, Sang Wan Lee

Depression is characterized by deficits in the reinforcement learning (RL) process. Although many computational and neural studies have extended our knowledge of the impact of depression on RL, most focus on habitual control (model-free RL), yielding a relatively poor understanding of goal-directed control (model-based RL) and arbitration control to find a balance between the two. We investigated the effects of subclinical depression on model-based and model-free learning in the prefrontal–striatal circuitry. First, we found that subclinical depression is associated with the attenuated state and reward prediction error representation in the insula and caudate. Critically, we found that it accompanies the disrupted arbitration control between model-based and model-free learning in the predominantly inferior lateral prefrontal cortex and frontopolar cortex. We also found that depression undermines the ability to exploit viable options, called exploitation sensitivity. These findings characterize how subclinical depression influences different levels of the decision-making hierarchy, advancing previous conflicting views that depression simply influences either habitual or goal-directed control. Our study creates possibilities for various clinical applications, such as early diagnosis and behavioral therapy design.

in PLoS Computational Biology on May 14, 2021 02:00 PM.

• #### What we can and what we cannot see with extracellular multielectrodes

by Chaitanya Chintaluri, Marta Bejtka, Władysław Średniawa, Michał Czerwiński, Jakub M. Dzik, Joanna Jędrzejewska-Szmek, Kacper Kondrakiewicz, Ewa Kublik, Daniel K. Wójcik

Extracellular recording is an accessible technique used in animals and humans to study the brain physiology and pathology. As the number of recording channels and their density grows it is natural to ask how much improvement the additional channels bring in and how we can optimally use the new capabilities for monitoring the brain. Here we show that for any given distribution of electrodes we can establish exactly what information about current sources in the brain can be recovered and what information is strictly unobservable. We demonstrate this in the general setting of previously proposed kernel Current Source Density method and illustrate it with simplified examples as well as using evoked potentials from the barrel cortex obtained with a Neuropixels probe and with compatible model data. We show that with conceptual separation of the estimation space from experimental setup one can recover sources not accessible to standard methods.

in PLoS Computational Biology on May 14, 2021 02:00 PM.

• #### Classification of visuomotor tasks based on electroencephalographic data depends on age-related differences in brain activity patterns

Publication date: Available online 13 May 2021

Source: Neural Networks

Author(s): C. Goelz, K. Mora, J. Rudisch, R. Gaidai, E. Reuter, B. Godde, C. Reinsberger, C. Voelcker-Rehage, S. Vieluf

in Neural Networks on May 14, 2021 01:00 PM.

• #### Anti-transfer learning for task invariance in convolutional neural networks for speech processing

Publication date: Available online 14 May 2021

Source: Neural Networks

Author(s): Eric Guizzo, Tillman Weyde, Giacomo Tarroni

in Neural Networks on May 14, 2021 01:00 PM.

• #### Specific neuronal subpopulations in the rat basolateral amygdala express high levels of nonphosphorylated neurofilaments

Dual‐labeling immunohistochemistry and retrograde tracing were used to characterize neurons in the basolateral amygdala that express SMI‐32+ nonphosphorylated neurofilaments (NNFs). Most of the neurons with strong somatic and dendritic expression of NNFs were parvalbumin+ (PV+) interneurons, as well as nonpyramidal neurons (NPNs) that project to the mediodorsal thalamic nucleus. The graphical abstract shows six SMI‐32+ neurons (diffuse brown staining); five are also stained for PV (blue particulate staining) and one is PV‐negative (arrow). Studies in the cortex suggest that the SMI‐32+ neurons identified in this study may be especially vulnerable to degeneration in Alzheimer's disease. Abstract Cortical pyramidal neurons (PNs) containing nonphosphorylated neurofilaments (NNFs) localized with the SMI‐32 monoclonal antibody have been shown to be especially vulnerable to degeneration in Alzheimer's disease (AD). The present investigation is the first to study the expression of SMI‐32+ NNFs in neurons of the basolateral nuclear complex of the amygdala (BNC), which contains cortex‐like PNs and nonpyramidal neurons (NPNs). We observed that PNs in the rat basolateral nucleus (BL), but not in the lateral (LAT) or basomedial (BM) nuclei, have significant levels of SMI‐32‐ir in their somata with antibody diluents that did not contain Triton X‐100, but staining in these cells was greatly attenuated when the antibody diluent contained 0.3% Triton. Using Triton‐containing diluents, we found that all SMI‐32+ neurons in all three of the BNC nuclei were NPNs. Using a dual‐labeling immunoperoxidase technique, we demonstrated that most of these SMI‐32+ NPNs were parvalbumin‐positive (PV+) or somatostatin‐positive NPNs but not vasoactive intestinal peptide‐positive or neuropeptide Y‐positive NPNs. Using a technique that combines retrograde tracing with SMI‐32 immunohistochemistry using intermediate levels of Triton in the diluent, we found that all BNC neurons projecting to the mediodorsal thalamic nucleus (MD) were large NPNs, and most were SMI‐32+. In contrast, BNC neurons projecting to the ventral striatum or cerebral cortex were PNs that expressed low levels of SMI‐32 immunoreactivity (SMI‐32‐ir) in the BL, and no SMI‐32‐ir in the LAT or BM. These data suggest that the main neuronal subpopulations in the BNC that degenerate in AD may be PV+ and MD‐projecting NPNs.

in Journal of Comparative Neurology on May 14, 2021 12:08 PM.

• #### SCAU: Modeling spectral causality for multivariate time series with applications to electroencephalograms. (arXiv:2105.06418v1 [stat.ME])

Electroencephalograms (EEG) are noninvasive measurement signals of electrical neuronal activity in the brain. One of the current major statistical challenges is formally measuring functional dependency between those complex signals. This paper, proposes the spectral causality model (SCAU), a robust linear model, under a causality paradigm, to reflect inter- and intra-frequency modulation effects that cannot be identifiable using other methods. SCAU inference is conducted with three main steps: (a) signal decomposition into frequency bins, (b) intermediate spectral band mapping, and (c) dependency modeling through frequency-specific autoregressive models (VAR). We apply SCAU to study complex dependencies during visual and lexical fluency tasks (word generation and visual fixation) in 26 participants' EEGs. We compared the connectivity networks estimated using SCAU with respect to a VAR model. SCAU networks show a clear contrast for both stimuli while the magnitude links also denoted a low variance in comparison with the VAR networks. Furthermore, SCAU dependency connections not only were consistent with findings in the neuroscience literature, but it also provided further evidence on the directionality of the spatio-spectral dependencies such as the delta-originated and theta-induced links in the fronto-temporal brain network.

in arXiv: Quantitative Biology: Neurons and Cognition on May 14, 2021 01:30 AM.

• #### Loosely Conditioned Emulation of Global Climate Models With Generative Adversarial Networks. (arXiv:2105.06386v1 [physics.ao-ph])

Climate models encapsulate our best understanding of the Earth system, allowing research to be conducted on its future under alternative assumptions of how human-driven climate forces are going to evolve. An important application of climate models is to provide metrics of mean and extreme climate changes, particularly under these alternative future scenarios, as these quantities drive the impacts of climate on society and natural systems. Because of the need to explore a wide range of alternative scenarios and other sources of uncertainties in a computationally efficient manner, climate models can only take us so far, as they require significant computational resources, especially when attempting to characterize extreme events, which are rare and thus demand long and numerous simulations in order to accurately represent their changing statistics. Here we use deep learning in a proof of concept that lays the foundation for emulating global climate model output for different scenarios. We train two "loosely conditioned" Generative Adversarial Networks (GANs) that emulate daily precipitation output from a fully coupled Earth system model: one GAN modeling Fall-Winter behavior and the other Spring-Summer. Our GANs are trained to produce spatiotemporal samples: 32 days of precipitation over a 64x128 regular grid discretizing the globe. We evaluate the generator with a set of related performance metrics based upon KL divergence, and find the generated samples to be nearly as well matched to the test data as the validation data is to test. We also find the generated samples to accurately estimate the mean number of dry days and mean longest dry spell in the 32 day samples. Our trained GANs can rapidly generate numerous realizations at a vastly reduced computational expense, compared to large ensembles of climate models, which greatly aids in estimating the statistics of extreme events.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### Class-Incremental Learning for Wireless Device Identification in IoT. (arXiv:2105.06381v1 [cs.LG])

Deep Learning (DL) has been utilized pervasively in the Internet of Things (IoT). One typical application of DL in IoT is device identification from wireless signals, namely Non-cryptographic Device Identification (NDI). However, learning components in NDI systems have to evolve to adapt to operational variations, such a paradigm is termed as Incremental Learning (IL). Various IL algorithms have been proposed and many of them require dedicated space to store the increasing amount of historical data, and therefore, they are not suitable for IoT or mobile applications. However, conventional IL schemes can not provide satisfying performance when historical data are not available. In this paper, we address the IL problem in NDI from a new perspective, firstly, we provide a new metric to measure the degree of topological maturity of DNN models from the degree of conflict of class-specific fingerprints. We discover that an important cause for performance degradation in IL enabled NDI is owing to the conflict of devices' fingerprints. Second, we also show that the conventional IL schemes can lead to low topological maturity of DNN models in NDI systems. Thirdly, we propose a new Channel Separation Enabled Incremental Learning (CSIL) scheme without using historical data, in which our strategy can automatically separate devices' fingerprints in different learning stages and avoid potential conflict. Finally, We evaluated the effectiveness of the proposed framework using real data from ADS-B (Automatic Dependent Surveillance-Broadcast), an application of IoT in aviation. The proposed framework has the potential to be applied to accurate identification of IoT devices in a variety of IoT applications and services. Data and code available at IEEE Dataport (DOI: 10.21227/1bxc-ke87) and \url{https://github.com/pcwhy/CSIL}}

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### HeunNet: Extending ResNet using Heun's Methods. (arXiv:2105.06168v2 [cs.LG] UPDATED)

There is an analogy between the ResNet (Residual Network) architecture for deep neural networks and an Euler solver for an ODE. The transformation performed by each layer resembles an Euler step in solving an ODE. We consider the Heun Method, which involves a single predictor-corrector cycle, and complete the analogy, building a predictor-corrector variant of ResNet, which we call a HeunNet. Just as Heun's method is more accurate than Euler's, experiments show that HeunNet achieves high accuracy with low computational (both training and test) time compared to both vanilla recurrent neural networks and other ResNet variants.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### Negative Selection Algorithm Research and Applications in the last decade: A Review. (arXiv:2105.06109v1 [cs.NE])

The Negative selection Algorithm (NSA) is one of the important methods in the field of Immunological Computation (or Artificial Immune Systems). Over the years, some progress was made which turns this algorithm (NSA) into an efficient approach to solve problems in different domain. This review takes into account these signs of progress during the last decade and categorizes those based on different characteristics and performances. Our study shows that NSA's evolution can be labeled in four ways highlighting the most notable NSA variations and their limitations in different application domains. We also present alternative approaches to NSA for comparison and analysis. It is evident that NSA performs better for nonlinear representation than most of the other methods, and it can outperform neural-based models in computation time. We summarize NSA's development and highlight challenges in NSA research in comparison with other similar models.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### Dynamical Origin for Winner-Take-All Competition in A Biological Network of The Hippocampal Dentate Gyrus. (arXiv:2105.06057v1 [q-bio.NC])

We consider a biological network of the hippocampal dentate gyrus (DG). The DG is a pre-processor for pattern separation which facilitates pattern storage and retrieval in the CA3 area of the hippocampus. The main encoding cells in the DG are the granule cells (GCs) which receive the input from the entorhinal cortex (EC) and send their output to the CA3. The activation degree of GCs is so low (~ 5%). This sparsity has been thought to enhance the pattern separation. We investigate the dynamical origin for winner-take-all (WTA) competition which leads to sparse activation of the GCs. The whole GCs are grouped into lamellar clusters. In each GC cluster, there is one inhibitory (I) basket cell (BC) along with excitatory (E) GCs. There are three kinds of external inputs into the GCs; the direct excitatory EC input, the indirect inhibitory EC input, mediated by the HIPP (hilar perforant path-associated) cells, and the excitatory input from the hilar mossy cells (MCs). The firing activities of the GCs are determined via competition between the external E and I inputs. The E-I conductance ratio ${\cal{R}}_{\rm E-I}^{\rm (con)*}$ (given by the time average of the external E to I conductances) may represents well the degree of such external E-I input competition. GCs become active when their $\cal{R}_{\rm E-I}^{\rm (con)*}$ is larger than a threshold ${\cal{R}}_{th}^*$, and then the mean firing rates of the active GCs are strongly correlated with $\cal{R}_{\rm E-I}^{\rm (con)*}$. In each GC cluster, the feedback inhibition of the BC may select the winner GCs. GCs with larger $\cal{R}_{\rm E-I}^{\rm (con)*}$ than the threshold ${\cal{R}}_{th}^*$ survive, and they become winners; all the other GCs with smaller $\cal{R}_{\rm E-I}^{\rm (con)*}$ become silent. The WTA competition occurs via competition between the firing activity of the GCs and the feedback inhibition from the BC in each GC cluster.

in arXiv: Quantitative Biology: Neurons and Cognition on May 14, 2021 01:30 AM.

• #### Dynamical Isometry: The Missing Ingredient for Neural Network Pruning. (arXiv:2105.05916v1 [cs.LG])

Several recent works [40, 24] observed an interesting phenomenon in neural network pruning: A larger finetuning learning rate can improve the final performance significantly. Unfortunately, the reason behind it remains elusive up to date. This paper is meant to explain it through the lens of dynamical isometry [42]. Specifically, we examine neural network pruning from an unusual perspective: pruning as initialization for finetuning, and ask whether the inherited weights serve as a good initialization for the finetuning? The insights from dynamical isometry suggest a negative answer. Despite its critical role, this issue has not been well-recognized by the community so far. In this paper, we will show the understanding of this problem is very important -- on top of explaining the aforementioned mystery about the larger finetuning rate, it also unveils the mystery about the value of pruning [5, 30]. Besides a clearer theoretical understanding of pruning, resolving the problem can also bring us considerable performance benefits in practice.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### The Power of the Weisfeiler-Leman Algorithm for Machine Learning with Graphs. (arXiv:2105.05911v1 [cs.LG])

In recent years, algorithms and neural architectures based on the Weisfeiler-Leman algorithm, a well-known heuristic for the graph isomorphism problem, emerged as a powerful tool for (supervised) machine learning with graphs and relational data. Here, we give a comprehensive overview of the algorithm's use in a machine learning setting. We discuss the theoretical background, show how to use it for supervised graph- and node classification, discuss recent extensions, and its connection to neural architectures. Moreover, we give an overview of current applications and future directions to stimulate research.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### Coverage Guided Testing for Recurrent Neural Networks. (arXiv:1911.01952v3 [cs.LG] UPDATED)

Recurrent neural networks (RNNs) have been applied to a broad range of applications, including natural language processing, drug discovery, and video recognition. Their vulnerability to input perturbation is also known. Aligning with a view from software defect detection, this paper aims to develop a coverage guided testing approach to systematically exploit the internal behaviour of RNNs, with the expectation that such testing can detect defects with high possibility. Technically, the long short term memory network (LSTM), a major class of RNNs, is thoroughly studied. A family of three test metrics are designed to quantify not only the values but also the temporal relations (including both step-wise and bounded-length) exhibited when LSTM processing inputs. A genetic algorithm is applied to efficiently generate test cases. The test metrics and test case generation algorithm are implemented into a tool TestRNN, which is then evaluated on a set of LSTM benchmarks. Experiments confirm that TestRNN has advantages over the state-of-art tool DeepStellar and attack-based defect detection methods, owing to its working with finer temporal semantics and the consideration of the naturalness of input perturbation. Furthermore, TestRNN enables meaningful information to be collected and exhibited for users to understand the testing results, which is an important step towards interpretable neural network testing.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 14, 2021 01:30 AM.

• #### Remembering Mary Jeanne Kreek and her many contributions to addiction science

Nature Neuroscience, Published online: 14 May 2021; doi:10.1038/s41593-021-00863-z

Remembering Mary Jeanne Kreek and her many contributions to addiction science

in Nature Neuroscience on May 14, 2021 12:00 AM.

• #### Addendum: Topological superconductivity: Quantized, finally

Nature Physics, Published online: 14 May 2021; doi:10.1038/s41567-021-01261-9

in Nature Physics on May 14, 2021 12:00 AM.

• #### More speed out of the quantum gate

Nature Physics, Published online: 14 May 2021; doi:10.1038/s41567-021-01195-2

Quantum gates on trapped ions may be quicker and more reliable owing to squeezing of their vibrational motion. A threefold drop in operation time shows potential for applications in quantum technologies.

in Nature Physics on May 14, 2021 12:00 AM.

• #### Nanoantenna tunnelling currents record laser waves

Nature Photonics, Published online: 14 May 2021; doi:10.1038/s41566-021-00824-9

Tunnelling currents inside plasmonic nanostructures are fast enough to gain direct access to the oscillating electric field of near-infrared and visible light, opening up exciting routes towards attosecond metrology of light–matter interaction and unique approaches to spectroscopy.

in Nature Photomics on May 14, 2021 12:00 AM.

• #### Author Correction: Microscale Schottky superlubric generator with high direct-current density and ultralong life

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23563-5

Author Correction: Microscale Schottky superlubric generator with high direct-current density and ultralong life

in Nature Communications on May 14, 2021 12:00 AM.

• #### Publisher Correction: Structural characterization of ice XIX as the second polymorph related to ice VI

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23514-0

Publisher Correction: Structural characterization of ice XIX as the second polymorph related to ice VI

in Nature Communications on May 14, 2021 12:00 AM.

• #### Author Correction: Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23498-x

Author Correction: Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

in Nature Communications on May 14, 2021 12:00 AM.

• #### Author Correction: Direct observation of excitonic instability in Ta2NiSe5

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23476-3

Author Correction: Direct observation of excitonic instability in Ta2NiSe5

in Nature Communications on May 14, 2021 12:00 AM.

• #### Quality control of protein reagents for the improvement of research data reproducibility

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23167-z

Proteins and peptides are amongst the most widely used research reagents but often their quality is inadequate and can result in poor data reproducibility. Here we propose a simple set of guidelines that, when correctly applied to protein reagents should provide more reliable experimental data.

in Nature Communications on May 14, 2021 12:00 AM.

• #### Andreev reflection of fractional quantum Hall quasiparticles

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23160-6

Andreev reflection is normally known to occur at a metal-superconductor interface. Here, Hashisaka et al. observe an Andreev-like process in a narrow junction between fractional and integer quantum Hall states originating from a topological quantum many-body effect instead of superconductivity.

in Nature Communications on May 14, 2021 12:00 AM.

• #### Chemoselective catalytic hydrodefluorination of trifluoromethylalkenes towards mono-/gem-di-fluoroalkenes under metal-free conditions

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23101-3

Fluorine-containing moieties show significant effects in improving the properties of functional molecules. Here the authors show diazaphospholene-catalyzed hydrodefluorination of trifluoromethylalkenes to chemoselectively construct gem-difluoroalkenes and terminal monofluoroalkenes by simple adjustment of the reactant stoichiometry.

in Nature Communications on May 14, 2021 12:00 AM.

• #### Printable homocomposite hydrogels with synergistically reinforced molecular-colloidal networks

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23098-9

Composites which are made up of a single polymer, and yet allow modulation of the mechanical properties of the matrix without stress concentration, are challenging to fabricate. Here, the authors design a selfreinforced homocomposite alginate hydrogel with enhanced mechanical properties incorporating soft dendritic alginate colloids in the matrix and demonstrate its application in extrusion printing.

in Nature Communications on May 14, 2021 12:00 AM.

• #### Reply to “Re-evaluating the evidence for facilitation of stickleback speciation by admixture in the Lake Constance basin”

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23096-x

Reply to “Re-evaluating the evidence for facilitation of stickleback speciation by admixture in the Lake Constance basin”

in Nature Communications on May 14, 2021 12:00 AM.

• #### Re-evaluating the evidence for facilitation of stickleback speciation by admixture in the Lake Constance basin

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-23092-1

Re-evaluating the evidence for facilitation of stickleback speciation by admixture in the Lake Constance basin

in Nature Communications on May 14, 2021 12:00 AM.

• #### Author Correction: miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR–p-PI3K/AKT-c-JUN

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-22959-7

Author Correction: miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR–p-PI3K/AKT-c-JUN

in Nature Communications on May 14, 2021 12:00 AM.

• #### Degradation mechanism of hybrid tin-based perovskite solar cells and the critical role of tin (IV) iodide

Nature Communications, Published online: 14 May 2021; doi:10.1038/s41467-021-22864-z

Tin perovskites have emerged as promising alternatives to toxic lead perovskite in next-generation photovoltaics, but the poor environmental stability remains an obstacle for the application. Here, the authors study the degradation mechanism of tin perovskite films, and identify a cyclic degradation mechanism involving tin (IV) iodide.

in Nature Communications on May 14, 2021 12:00 AM.

• #### Daily briefing: Delayed second Pfizer dose boosts immune response

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01324-0

Delaying the second dose of the Pfizer–BioNTech COVID-19 vaccine could boost antibody responses in over-80s. Plus, China’s first rover on Mars and PLOS pushes to extend clout beyond biomedicine.

in Nature on May 14, 2021 12:00 AM.

• #### C. Austen Angell (1933–2021)

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01319-x

Visionary explorer of glasses and the limits of the liquid state.

in Nature on May 14, 2021 12:00 AM.

• #### Coronapod: The variant blamed for India's catastrophic second wave

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01308-0

Scientists race to understand the threat posed by SARS-CoV-2 variant B.1.617.

in Nature on May 14, 2021 12:00 AM.

• #### China has landed its first rover on Mars — here’s what happens next

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01301-7

The Zhurong landing was the biggest test yet of China’s deep-space exploration capabilities. Within days, the rover could start to make geological discoveries.

in Nature on May 14, 2021 12:00 AM.

• #### Kids with ‘bubble baby disease’ see gains after gene therapy

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01300-8

Stem cells carrying corrective genes offer hope for a devastating immune disorder.

in Nature on May 14, 2021 12:00 AM.

• #### India’s neighbours race to sequence genomes as COVID surges

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01287-2

From Sri Lanka to Nepal, scientists with limited resources are working feverishly to discover which variants are driving outbreaks.

in Nature on May 14, 2021 12:00 AM.

• #### Microbes in Neanderthals’ mouths reveal their carb-laden diet

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01260-z

Gunk on ancient teeth yields bacterial DNA, allowing scientists to trace the oral microbiome’s evolution.

in Nature on May 14, 2021 12:00 AM.

• #### Actin mixes up mitochondria for inheritance

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01115-7

In cells that divide symmetrically, a meshwork of actin cables is shown to maintain the uniform distribution of mitochondria around the mitotic spindle. Actin clouds and comet tails are assembled dynamically to shuffle mitochondria locally and ensure the equal and random inheritance of these organelles by the two daughter cells.

in Nature on May 14, 2021 12:00 AM.

• #### Breastfeeding influences the neonatal virome

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01112-w

The first viruses to colonize the infant gut are shown to arise from bacteria, with human-cell viruses colonizing the gut later, at around four months of age. Exclusive and partial breastfeeding were associated with fewer human viruses in the gut of infants compared with formula-feeding alone.

in Nature on May 14, 2021 12:00 AM.

• #### Mining the gaps of chromosome 8

Nature, Published online: 14 May 2021; doi:10.1038/d41586-021-01095-8

The first gapless, telomere-to-telomere sequence of a human autosome, chromosome 8, is complete. Sequencing and assembly of the corresponding centromere in the chimpanzee, orangutan and macaque reveals details of its rapid evolution over the past 25 million years.

in Nature on May 14, 2021 12:00 AM.

• #### Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

in Frontiers in Neuroscience: Neurodegeneration on May 14, 2021 12:00 AM.

• #### Detection and Grading of Gliomas Using a Novel Two-Phase Machine Learning Method Based on MRI Images

The early detection and grading of gliomas is important for treatment decision and assessment of prognosis. Over the last decade numerous automated computer analysis tools have been proposed, which can potentially lead to more reliable and reproducible brain tumor diagnostic procedures. In this paper, we used the gradient-based features extracted from structural magnetic resonance imaging (sMRI) images to depict the subtle changes within brains of patients with gliomas. Based on the gradient features, we proposed a novel two-phase classification framework for detection and grading of gliomas. In the first phase, the probability of each local feature being related to different types (e.g., diseased or healthy for detection, benign or malignant for grading) was calculated. Then the high-level feature representing the whole MRI image was generated by concatenating the membership probability of each local feature. In the second phase, the supervised classification algorithm was used to train a classifier based on the high-level features and patient labels of the training subjects. We applied this framework on the brain imaging data collected from Zhongnan Hospital of Wuhan University for glioma detection, and the public TCIA datasets including glioblastomas (WHO IV) and low-grade gliomas (WHO II and III) data for glioma grading. The experimental results showed that the gradient-based classification framework could be a promising tool for automatic diagnosis of brain tumors.

in Frontiers in Neuroscience: Brain Imaging Methods on May 14, 2021 12:00 AM.

• #### Neurostimulation for Stroke Rehabilitation

Neurological injuries such as strokes can lead to important loss in motor function. Thanks to neuronal plasticity, some of the lost functionality may be recovered over time. However, the recovery process is often slow and incomplete, despite the most effective conventional rehabilitation therapies. As we improve our understanding of the rules governing activity-dependent plasticity, neuromodulation interventions are being developed to harness neural plasticity to achieve faster and more complete recovery. Here, we review the principles underlying stimulation-driven plasticity as well as the most commonly used stimulation techniques and approaches. We argue that increased spatiotemporal precision is an important factor to improve the efficacy of neurostimulation and drive a more useful neuronal reorganization. Consequently, closed-loop systems and optogenetic stimulation hold theoretical promise as interventions to promote brain repair after stroke.

in Frontiers in Neuroscience: Neural Technology on May 14, 2021 12:00 AM.

• #### Prefrontal Cortex Activation During Motor Sequence Learning Under Interleaved and Repetitive Practice: A Two-Channel Near-Infrared Spectroscopy Study

Training under high interference conditions through interleaved practice (IP) results in performance suppression during training but enhances long-term performance relative to repetitive practice (RP) involving low interference. Previous neuroimaging work addressing this contextual interference effect of motor learning has relied heavily on the blood-oxygen-level-dependent (BOLD) response using functional magnetic resonance imaging (fMRI) methodology resulting in mixed reports of prefrontal cortex (PFC) recruitment under IP and RP conditions. We sought to clarify these equivocal findings by imaging bilateral PFC recruitment using functional near-infrared spectroscopy (fNIRS) while discrete key pressing sequences were trained under IP and RP schedules and subsequently tested following a 24-h delay. An advantage of fNIRS over the fMRI BOLD response is that the former measures oxygenated and deoxygenated hemoglobin changes independently allowing for assessment of cortical hemodynamics even when there is neurovascular decoupling. Despite slower sequence performance durations under IP, bilateral PFC oxygenated and deoxygenated hemoglobin values did not differ between practice conditions. During test, however, slower performance from those previously trained under RP coincided with hemispheric asymmetry in PFC recruitment. Specifically, following RP, test deoxygenated hemoglobin values were significantly lower in the right PFC. The present findings contrast with previous behavioral demonstrations of increased cognitive demand under IP to illustrate a more complex involvement of the PFC in the contextual interference effect. IP and RP incur similar levels of bilateral PFC recruitment, but the processes underlying the recruitment are dissimilar. PFC recruitment during IP supports action reconstruction and memory elaboration while RP relies on PFC recruitment to maintain task variation information in working memory from trial to trial. While PFC recruitment under RP serves to enhance immediate performance, it does not support long-term performance.

in Frontiers in Human Neuroscience on May 14, 2021 12:00 AM.

• #### Elevated Inter-Brain Coherence Between Subjects With Concordant Stances During Discussion of Social Issues

Social media platforms offer convenient, instantaneous social sharing on a mass scale with tremendous impact on public perceptions, opinions, and behavior. There is a need to understand why information spreads including the human motivations, cognitive processes, and neural dynamics of large-scale sharing. This study introduces a novel approach for investigating the effect social media messaging and in-person discussion has on the inter-brain dynamics within small groups of participants. The psychophysiological impact of information campaigns and narrative messaging within a closed social media environment was assessed using 24-channel wireless EEG. Data were acquired from three- or four-person groups while subjects debated contemporary social issues framed by four scenarios of varying controversy: (a) investing in ethical vs. unethical corporations, (b) selecting travel destination based on social awareness, (c) determining verdict in a murder trial and the punishment of life in prison or death penalty, and (d) decision to vaccinate. Pre-/post-scenario questionnaires assess the effects of the social media information. Inter-brain coherence between subject pairs on each social issue discussed by subjects was analyzed by concordance, agreement vs. disagreement, and by group unanimity, unanimous vs. not unanimous. Subject pairs that agreed on the social issues raised in the scenarios had significantly greater inter-brain coherence in gamma frequency range than disagreeing pairs over cortical regions known to be involved in social interactions. These effects were magnified when comparing groups where subject pairs were unanimous in their stance on the social issues for some but not all scenarios. While there was considerable overlap between scenarios in what EEG channels were significant, there was enough variability to indicate the possibility of scenario-specific effects on inter-brain coherence.

in Frontiers in Human Neuroscience on May 14, 2021 12:00 AM.

• #### Editorial: Homeostatic Synaptic Plasticity: From Synaptic Circuit Assembly to Neurological Disorders

in Frontiers in Cellular Neuroscience on May 14, 2021 12:00 AM.

• #### Corrigendum: VIP Modulation of Hippocampal Synaptic Plasticity: A Role for VIP Receptors as Therapeutic Targets in Cognitive Decline and Mesial Temporal Lobe Epilepsy

in Frontiers in Cellular Neuroscience on May 14, 2021 12:00 AM.

• #### Reversible Changes in BDNF Expression in MK-801-Induced Hippocampal Astrocytes Through NMDAR/PI3K/ERK Signaling

Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.

in Frontiers in Cellular Neuroscience on May 14, 2021 12:00 AM.

• #### Silencing of Long Noncoding RNA Growth Arrest–Specific 5 Alleviates Neuronal Cell Apoptosis and Inflammatory Responses Through Sponging microRNA-93 to Repress PTEN Expression in Spinal Cord Injury

A secondary injury induced by a spinal cord injury (SCI) remains the main cause of devastating neural dysfunction; therefore, it has been the subject of focused research for many years. Long noncoding RNA (lncRNA) has been found to participate in the SCI process, and this finding presents a high potential for diagnosis and treatment; however, the role of lncRNA in a secondary injury induced by SCI remains unclear. The aim of this study was to investigate the regulatory effect of lncRNA growth arrest–specific transcript 5 (GAS5) in secondary injury during SCI. The SCI mice model and hypoxic cellular model were established to research the roles of lncRNA GAS5 during SCI. Reverse transcription quantitative polymerase chain reaction (qRT-PCR) was conducted to determine the expression levels of microR-93 (miR-93) and lncRNA GAS5. Western blot analysis of the apoptosis regulator protein and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was conducted to evaluate neuron cell apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were calculated to assess neurological function. Flow cytometry was used to determine neuron cell apoptosis. The associations among GAS5, miR-93, and the phosphatase and tensin homolog (PTEN) were disclosed using RNA immunoprecipitation (RIP) assay, RNA pulldown assay, and dual-luciferase reporter assay. QRT-PCR demonstrated that GAS5 was significantly upregulated in both the SCI mice and hypoxic cellular models. GAS5 knockdown suppressed neuron cell apoptosis and inflammatory response in the SCI mice model. Further studies have indicated that GAS5 functions as a competing endogenous RNA (ceRNA) by sponging miR-93 in neuronal cells. In addition, PTEN was a target of miR-93, and GAS5 knockdown exhibited its anti-apoptotic and anti-inflammatory effects through the miR-93/PTEN axis. These findings suggest that the GAS5/miR-93/PTEN axis may be a promising therapeutic target for SCI.

in Frontiers in Cellular Neuroscience on May 14, 2021 12:00 AM.

• #### Acupuncture for Mild Cognitive Impairment and Dementia: An Overview of Systematic Reviews

Background: Dementia is a gradual decline in cognitive ability and is becoming more common in our elderly population. Mild cognitive impairment (MCI) is defined as a slight clinical deterioration of memory capacity, below the level of normal aging, but does not constitute a clinical diagnosis of dementia. To date, no interventions have been proven to cure MCI and dementia fully.

Purpose: To evaluate the potential effectiveness and safety of acupuncture for mild cognitive impairment (MCI) and dementia and evaluate the methodological quality of systematic reviews (SRs).

Methods: We conducted a literature search for SRs with meta-analyses in seven Chinese and international databases through October 1, 2020. The basic characteristics of the included SRs/meta-analyses and the basic information of the original included randomized controlled trials were extracted by three reviewers independently. A meta-analysis of the original randomized controlled trials from the included SRs/meta-analyses was performed using Stata 12.0 software. The Assessing the Methodological Quality of Systematic Reviews 2 was used to assess the methodological quality of the included SRs/meta-analyses, and the Grading of Recommendations, Assessment, Development, and Evaluation was used to rate the quality of evidence.

Results: A total of 35 SRs/meta-analyses were included, and the majority showed that acupuncture was more effective than western medicine or conventional therapy for MCI and dementia [odds ratio =1.39; 95% confidence interval (CI): 1.24, 1.56]. There was a statistically significant difference in the Mini-Mental State Examination score (weighted mean difference = 1.23; 95% CI: 0.78, 1.68; p < 0.00001), and there was no significant improvement in the activities of daily living score (weighted mean difference = 1.58; 95% CI: −0.02, 3.18; p = 0.053). The assessment results of Assessing the Methodological Quality of Systematic Reviews 2 showed that the methodological quality of most included SRs/meta-analyses was critically low; the lowest scores were items 2, 7, and 10. For Grading of Recommendations, Assessment, Development, and Evaluation, of the 73 outcomes, 50 (68.5%) outcomes were low or very low quality, and 23 (31.5%) outcomes were moderate quality.

Conclusions: Acupuncture can be considered as an alternative for the treatment of MCI and dementia when western medicine or other therapies are contraindicated. More high-quality evidence is needed to determine further the effectiveness of acupuncture.

in Frontiers in Ageing Neuroscience on May 14, 2021 12:00 AM.

• #### Endothelial Dysfunction and Impaired Neurovascular Coupling Responses Precede Cognitive Impairment in a Mouse Model of Geriatric Sepsis

Sepsis is a life-threatening condition, the incidence of which is significantly increased in elderly patients. One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function. Normal brain function is dependent on moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions. This homeostatic mechanism, termed neurovascular coupling (NVC, also known as functional hyperemia), is critically dependent on the production of vasodilator NO by microvascular endothelial cells in response to mediators released from activated astrocytes. The goal of this study was to test the hypothesis that sepsis in aging leads to impairment of NVC responses early after treatment and that this neurovascular dysfunction associates with impairments in cognitive performance and vascular endothelial dysfunction. To test this hypothesis, we used a commonly studied bacterial pathogen, Listeria monocytogenes, to induce sepsis in experimental animals (males, 24 months of age) and subjected experimental animals to a standard clinical protocol of 3 doses of ampicillin i.p. and 14 days of amoxicillin added to the drinking water. NVC responses, endothelial function and cognitive performance were measured in septic and age-matched control groups within 14 days after the final antibiotic treatment. Our data demonstrate that sepsis in aging significantly impairs NVC responses measured in somatosensory cortex during whisker stimulation, significantly impairs endothelial function in isolated and pressure cannulated aorta rings in response to acetylcholine stimulation. No significant impairment of cognitive function in post-sepsis aged animals has been observed when measured using the PhenoTyper homecage based system. Our findings suggest that sepsis-associated endothelial dysfunction and impairment of NVC responses may contribute to long-term cognitive deficits in older sepsis survivors.

in Frontiers in Ageing Neuroscience on May 14, 2021 12:00 AM.

• #### Low-dimensional learned feature spaces quantify individual and group differences in vocal repertoires

Increases in the scale and complexity of behavioral data pose an increasing challenge for data analysis. A common strategy involves replacing entire behaviors with small numbers of handpicked, domain-specific features, but this approach suffers from several crucial limitations. For example, handpicked features may miss important dimensions of variability, and correlations among them complicate statistical testing. Here, by contrast, we apply the variational autoencoder (VAE), an unsupervised learning method, to learn features directly from data and quantify the vocal behavior of two model species: the laboratory mouse and the zebra finch. The VAE converges on a parsimonious representation that outperforms handpicked features on a variety of common analysis tasks, enables the measurement of moment-by-moment vocal variability on the timescale of tens of milliseconds in the zebra finch, provides strong evidence that mouse ultrasonic vocalizations do not cluster as is commonly believed, and captures the similarity of tutor and pupil birdsong with qualitatively higher fidelity than previous approaches. In all, we demonstrate the utility of modern unsupervised learning approaches to the quantification of complex and high-dimensional vocal behavior.

in eLife on May 14, 2021 12:00 AM.

• #### Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

in eLife on May 14, 2021 12:00 AM.

• #### Distinct protocerebral neuropils associated with attractive and aversive female-produced odorants in the male moth brain

The pheromone system of heliothine moths is an optimal model for studying principles underlying higher-order olfactory processing. In Helicoverpa armigera, three male-specific glomeruli receive input about three female-produced signals, the primary pheromone component, serving as an attractant, and two minor constituents, serving a dual function, i.e. attraction versus inhibition of attraction. From the antennal-lobe glomeruli, the information is conveyed to higher olfactory centers, including the lateral protocerebrum, via three main paths – of which the medial tract is the most prominent. In this study, we traced physiologically identified medial-tract projection neurons from each of the three male‑specific glomeruli with the aim of mapping their terminal branches in the lateral protocerebrum. Our data suggest that the neurons’ wide-spread projections are organized according to behavioral significance, including a spatial separation of signals representing attraction versus inhibition – however, with a unique capacity of switching behavioral consequence based on the amount of the minor components.

in eLife on May 14, 2021 12:00 AM.

• #### Inbreeding in a dioecious plant has sex- and population origin-specific effects on its interactions with pollinators

We study the effects of inbreeding in a dioecious plant on its interaction with pollinating insects and test whether the magnitude of such effects is shaped by plant individual sex and the evolutionary histories of plant populations. We recorded spatial, scent, colour and rewarding flower traits as well as pollinator visitation rates in experimentally inbred and outbred, male and female Silene latifolia plants from European and North American populations differing in their evolutionary histories. We found that inbreeding specifically impairs spatial flower traits and floral scent. Our results support that sex-specific selection and gene expression may have partially magnified these inbreeding costs for females, and that divergent evolutionary histories altered the genetic architecture underlying inbreeding effects across population origins. Moreover, the results indicate that inbreeding effects on floral scent may have a huge potential to disrupt interactions among plants and nocturnal moth pollinators, which are mediated by elaborate chemical communication.

in eLife on May 14, 2021 12:00 AM.

• #### Exploring Uncharted Territory: Genetically Determined Sex Differences in Parkinson's Disease

Annals of Neurology, EarlyView.

in Annals of Neurology on May 13, 2021 02:23 PM.

• #### Secondary indoor air pollution and passive smoking associated with cannabis smoking using electric cigarette device–demonstrative <i>in silico</i> study

by Kazuki Kuga, Kazuhide Ito, Wenhao Chen, Ping Wang, Jeff Fowles, Kazukiyo Kumagai

With electronic (e)-liquids containing cannabis components easily available, many anecdotal examples of cannabis vaping using electronic cigarette devices have been reported. For electronic cigarette cannabis vaping, there are potential risks of secondary indoor air pollution from vapers. However, quantitative and accurate prediction of the inhalation and dermal exposure of a passive smoker in the same room is difficult to achieve due to the ethical constraints on subject experiments. The numerical method, i.e., in silico method, is a powerful tool to complement these experiments with real humans. In this study, we adopted a computer-simulated person that has been validated from multiple perspectives for prediction accuracy. We then conducted an in silico study to elucidate secondary indoor air pollution and passive smoking associated with cannabis vaping using an electronic cigarette device in an indoor environment. The aerosols exhaled by a cannabis vaper were confirmed to be a secondary emission source in an indoor environment; non-smokers were exposed to these aerosols via respiratory and dermal pathways. Tetrahydrocannabinol was used as a model chemical compound for the exposure study. Its uptake by the non-smoker through inhalation and dermal exposure under a worst-case scenario was estimated to be 5.9% and 2.6% of the exhaled quantity from an e-cigarette cannabis user, respectively.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Can molecular dynamics simulations improve the structural accuracy and virtual screening performance of GPCR models?

by Jon Kapla, Ismael Rodriguez Espigares, Flavio Ballante, Jana Selent, Jens Carlsson

The determination of G protein-coupled receptor (GPCR) structures at atomic resolution has improved understanding of cellular signaling and will accelerate the development of new drug candidates. However, experimental structures still remain unavailable for a majority of the GPCR family. GPCR structures and their interactions with ligands can also be modelled computationally, but such predictions have limited accuracy. In this work, we explored if molecular dynamics (MD) simulations could be used to refine the accuracy of in silico models of receptor-ligand complexes that were submitted to a community-wide assessment of GPCR structure prediction (GPCR Dock). Two simulation protocols were used to refine 30 models of the D3 dopamine receptor (D3R) in complex with an antagonist. Close to 60 μs of simulation time was generated and the resulting MD refined models were compared to a D3R crystal structure. In the MD simulations, the transmembrane helix region of the models generally drifted further away from the crystal structure conformation. However, MD refinement was able to improve the accuracy of the ligand binding mode and the second extracellular loop region. The best refinement protocol improved agreement with the experimentally observed ligand binding mode for a majority of the models. Receptor structures with improved virtual screening performance, which was assessed by molecular docking of ligands and decoys, could also be identified among the MD refined models. Application of weak restraints to the transmembrane helixes in the MD simulations further improved predictions of the ligand binding mode and second extracellular loop. These results provide guidelines for application of MD refinement in prediction of GPCR-ligand complexes and directions for further method development.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Red blood cell phenotyping from 3D confocal images using artificial neural networks

by Greta Simionato, Konrad Hinkelmann, Revaz Chachanidze, Paola Bianchi, Elisa Fermo, Richard van Wijk, Marc Leonetti, Christian Wagner, Lars Kaestner, Stephan Quint

The investigation of cell shapes mostly relies on the manual classification of 2D images, causing a subjective and time consuming evaluation based on a portion of the cell surface. We present a dual-stage neural network architecture for analyzing fine shape details from confocal microscopy recordings in 3D. The system, tested on red blood cells, uses training data from both healthy donors and patients with a congenital blood disease, namely hereditary spherocytosis. Characteristic shape features are revealed from the spherical harmonics spectrum of each cell and are automatically processed to create a reproducible and unbiased shape recognition and classification. The results show the relation between the particular genetic mutation causing the disease and the shape profile. With the obtained 3D phenotypes, we suggest our method for diagnostics and theragnostics of blood diseases. Besides the application employed in this study, our algorithms can be easily adapted for the 3D shape phenotyping of other cell types and extend their use to other applications, such as industrial automated 3D quality control.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Global importance analysis: An interpretability method to quantify importance of genomic features in deep neural networks

by Peter K. Koo, Antonio Majdandzic, Matthew Ploenzke, Praveen Anand, Steffan B. Paul

Deep neural networks have demonstrated improved performance at predicting the sequence specificities of DNA- and RNA-binding proteins compared to previous methods that rely on k-mers and position weight matrices. To gain insights into why a DNN makes a given prediction, model interpretability methods, such as attribution methods, can be employed to identify motif-like representations along a given sequence. Because explanations are given on an individual sequence basis and can vary substantially across sequences, deducing generalizable trends across the dataset and quantifying their effect size remains a challenge. Here we introduce global importance analysis (GIA), a model interpretability method that quantifies the population-level effect size that putative patterns have on model predictions. GIA provides an avenue to quantitatively test hypotheses of putative patterns and their interactions with other patterns, as well as map out specific functions the network has learned. As a case study, we demonstrate the utility of GIA on the computational task of predicting RNA-protein interactions from sequence. We first introduce a convolutional network, we call ResidualBind, and benchmark its performance against previous methods on RNAcompete data. Using GIA, we then demonstrate that in addition to sequence motifs, ResidualBind learns a model that considers the number of motifs, their spacing, and sequence context, such as RNA secondary structure and GC-bias.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Incorporating the speciation process into species delimitation

by Jeet Sukumaran, Mark T. Holder, L. Lacey Knowles

The “multispecies” coalescent (MSC) model that underlies many genomic species-delimitation approaches is problematic because it does not distinguish between genetic structure associated with species versus that of populations within species. Consequently, as both the genomic and spatial resolution of data increases, a proliferation of artifactual species results as within-species population lineages, detected due to restrictions in gene flow, are identified as distinct species. The toll of this extends beyond systematic studies, getting magnified across the many disciplines that rely upon an accurate framework of identified species. Here we present the first of a new class of approaches that addresses this issue by incorporating an extended speciation process for species delimitation. We model the formation of population lineages and their subsequent development into independent species as separate processes and provide for a way to incorporate current understanding of the species boundaries in the system through specification of species identities of a subset of population lineages. As a result, species boundaries and within-species lineages boundaries can be discriminated across the entire system, and species identities can be assigned to the remaining lineages of unknown affinities with quantified probabilities. In addition to the identification of species units in nature, the primary goal of species delimitation, the incorporation of a speciation model also allows us insights into the links between population and species-level processes. By explicitly accounting for restrictions in gene flow not only between, but also within, species, we also address the limits of genetic data for delimiting species. Specifically, while genetic data alone is not sufficient for accurate delimitation, when considered in conjunction with other information we are able to not only learn about species boundaries, but also about the tempo of the speciation process itself.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Fostering accessible online education using Galaxy as an e-learning platform

by Beatriz Serrano-Solano, Melanie C. Föll, Cristóbal Gallardo-Alba, Anika Erxleben, Helena Rasche, Saskia Hiltemann, Matthias Fahrner, Mark J. Dunning, Marcel H. Schulz, Beáta Scholtz, Dave Clements, Anton Nekrutenko, Bérénice Batut, Björn A. Grüning

The COVID-19 pandemic is shifting teaching to an online setting all over the world. The Galaxy framework facilitates the online learning process and makes it accessible by providing a library of high-quality community-curated training materials, enabling easy access to data and tools, and facilitates sharing achievements and progress between students and instructors. By combining Galaxy with robust communication channels, effective instruction can be designed inclusively, regardless of the students’ environments.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### A constructivist-based proposal for bioinformatics teaching practices during lockdown

by Cristóbal Gallardo-Alba, Björn Grüning, Beatriz Serrano-Solano

The Coronavirus Disease 2019 (COVID-19) outbreaks have caused universities all across the globe to close their campuses and forced them to initiate online teaching. This article reviews the pedagogical foundations for developing effective distance education practices, starting from the assumption that promoting autonomous thinking is an essential element to guarantee full citizenship in a democracy and for moral decision-making in situations of rapid change, which has become a pressing need in the context of a pandemic. In addition, the main obstacles related to this new context are identified, and solutions are proposed according to the existing bibliography in learning sciences.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Ten steps to investigate a cellular system with mathematical modeling

by Jasia King, Kerbaï Saïd Eroumé, Roman Truckenmüller, Stefan Giselbrecht, Ann E. Cowan, Leslie Loew, Aurélie Carlier

Cellular and intracellular processes are inherently complex due to the large number of components and interactions, which are often nonlinear and occur at different spatiotemporal scales. Because of this complexity, mathematical modeling is increasingly used to simulate such systems and perform experiments in silico, many orders of magnitude faster than real experiments and often at a higher spatiotemporal resolution. In this article, we will focus on the generic modeling process and illustrate it with an example model of membrane lipid turnover.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Ten simple rules to cultivate transdisciplinary collaboration in data science

by Faryad Sahneh, Meghan A. Balk, Marina Kisley, Chi-kwan Chan, Mercury Fox, Brian Nord, Eric Lyons, Tyson Swetnam, Daniela Huppenkothen, Will Sutherland, Ramona L. Walls, Daven P. Quinn, Tonantzin Tarin, David LeBauer, David Ribes, Dunbar P. Birnie III, Carol Lushbough, Eric Carr, Grey Nearing, Jeremy Fischer, Kevin Tyle, Luis Carrasco, Meagan Lang, Peter W. Rose, Richard R. Rushforth, Samapriya Roy, Thomas Matheson, Tina Lee, C. Titus Brown, Tracy K. Teal, Monica Papeș, Stephen Kobourov, Nirav Merchant

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Hierarchical semantic composition of biosimulation models using bond graphs

by Niloofar Shahidi, Michael Pan, Soroush Safaei, Kenneth Tran, Edmund J. Crampin, David P. Nickerson

Simulating complex biological and physiological systems and predicting their behaviours under different conditions remains challenging. Breaking systems into smaller and more manageable modules can address this challenge, assisting both model development and simulation. Nevertheless, existing computational models in biology and physiology are often not modular and therefore difficult to assemble into larger models. Even when this is possible, the resulting model may not be useful due to inconsistencies either with the laws of physics or the physiological behaviour of the system. Here, we propose a general methodology for composing models, combining the energy-based bond graph approach with semantics-based annotations. This approach improves model composition and ensures that a composite model is physically plausible. As an example, we demonstrate this approach to automated model composition using a model of human arterial circulation. The major benefit is that modellers can spend more time on understanding the behaviour of complex biological and physiological systems and less time wrangling with model composition.

in PLoS Computational Biology on May 13, 2021 02:00 PM.

• #### Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

by Pau B. Esparza-Moltó, Inés Romero-Carramiñana, Cristina Núñez de Arenas, Marta P. Pereira, Noelia Blanco, Beatriz Pardo, Georgina R. Bates, Carla Sánchez-Castillo, Rafael Artuch, Michael P. Murphy, José A. Esteban, José M. Cuezva

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.

in PLoS Biology on May 13, 2021 02:00 PM.

• #### Cryptic surface-associated multicellularity emerges through cell adhesion and its regulation

by Jordi van Gestel, Andreas Wagner

The repeated evolution of multicellularity leads to a wide diversity of organisms, many of which are sessile, including land plants, many fungi, and colonial animals. Sessile organisms adhere to a surface for most of their lives, where they grow and compete for space. Despite the prevalence of surface-associated multicellularity, little is known about its evolutionary origin. Here, we introduce a novel theoretical approach, based on spatial lineage tracking of cells, to study this origin. We show that multicellularity can rapidly evolve from 2 widespread cellular properties: cell adhesion and the regulatory control of adhesion. By evolving adhesion, cells attach to a surface, where they spontaneously give rise to primitive cell collectives that differ in size, life span, and mode of propagation. Selection in favor of large collectives increases the fraction of adhesive cells until a surface becomes fully occupied. Through kin recognition, collectives then evolve a central-peripheral polarity in cell adhesion that supports a division of labor between cells and profoundly impacts growth. Despite this spatial organization, nascent collectives remain cryptic, lack well-defined boundaries, and would require experimental lineage tracking technologies for their identification. Our results suggest that cryptic multicellularity could readily evolve and originate well before multicellular individuals become morphologically evident.

in PLoS Biology on May 13, 2021 02:00 PM.

• #### ANA Investigates: Tenecteplase

Annals of Neurology, EarlyView.

in Annals of Neurology on May 13, 2021 12:51 PM.

• #### Mechanisms underlying vaccination protocols that may optimally elicit broadly neutralizing antibodies against highly mutable pathogens

Author(s): Raman S. Ganti and Arup K. Chakraborty

Researchers use nonequilibrium statistical physics methods to guide the design of vaccines that are effective against many strains of a virus, a holy grail of immunology.

[Phys. Rev. E 103, 052408] Published Thu May 13, 2021

in Physical Review E: Biological physics on May 13, 2021 10:00 AM.

• #### Exploring the Similarity of Representations in Model-Agnostic Meta-Learning. (arXiv:2105.05757v1 [cs.LG])

In past years model-agnostic meta-learning (MAML) has been one of the most promising approaches in meta-learning. It can be applied to different kinds of problems, e.g., reinforcement learning, but also shows good results on few-shot learning tasks. Besides their tremendous success in these tasks, it has still not been fully revealed yet, why it works so well. Recent work proposes that MAML rather reuses features than rapidly learns. In this paper, we want to inspire a deeper understanding of this question by analyzing MAML's representation. We apply representation similarity analysis (RSA), a well-established method in neuroscience, to the few-shot learning instantiation of MAML. Although some part of our analysis supports their general results that feature reuse is predominant, we also reveal arguments against their conclusion. The similarity-increase of layers closer to the input layers arises from the learning task itself and not from the model. In addition, the representations after inner gradient steps make a broader change to the representation than the changes during meta-training.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 13, 2021 01:30 AM.

• #### Directional GAN: A Novel Conditioning Strategy for Generative Networks. (arXiv:2105.05712v2 [cs.CV] UPDATED)

Image content is a predominant factor in marketing campaigns, websites and banners. Today, marketers and designers spend considerable time and money in generating such professional quality content. We take a step towards simplifying this process using Generative Adversarial Networks (GANs). We propose a simple and novel conditioning strategy which allows generation of images conditioned on given semantic attributes using a generator trained for an unconditional image generation task. Our approach is based on modifying latent vectors, using directional vectors of relevant semantic attributes in latent space. Our method is designed to work with both discrete (binary and multi-class) and continuous image attributes. We show the applicability of our proposed approach, named Directional GAN, on multiple public datasets, with an average accuracy of 86.4% across different attributes.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 13, 2021 01:30 AM.

• #### Image interpretation by iterative bottom-up top-down processing. (arXiv:2105.05592v1 [cs.CV])

Scene understanding requires the extraction and representation of scene components together with their properties and inter-relations. We describe a model in which meaningful scene structures are extracted from the image by an iterative process, combining bottom-up (BU) and top-down (TD) networks, interacting through a symmetric bi-directional communication between them (counter-streams structure). The model constructs a scene representation by the iterative use of three components. The first model component is a BU stream that extracts selected scene elements, properties and relations. The second component (cognitive augmentation) augments the extracted visual representation based on relevant non-visual stored representations. It also provides input to the third component, the TD stream, in the form of a TD instruction, instructing the model what task to perform next. The TD stream then guides the BU visual stream to perform the selected task in the next cycle. During this process, the visual representations extracted from the image can be combined with relevant non-visual representations, so that the final scene representation is based on both visual information extracted from the scene and relevant stored knowledge of the world. We describe how a sequence of TD-instructions is used to extract from the scene structures of interest, including an algorithm to automatically select the next TD-instruction in the sequence. The extraction process is shown to have favorable properties in terms of combinatorial generalization, generalizing well to novel scene structures and new combinations of objects, properties and relations not seen during training. Finally, we compare the model with relevant aspects of the human vision, and suggest directions for using the BU-TD scheme for integrating visual and cognitive components in the process of scene understanding.

in arXiv: Quantitative Biology: Neurons and Cognition on May 13, 2021 01:30 AM.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 13, 2021 01:30 AM.

• #### CCN GAC Workshop: Issues with learning in biological recurrent neural networks. (arXiv:2105.05382v1 [q-bio.NC])

This perspective piece came about through the Generative Adversarial Collaboration (GAC) series of workshops organized by the Computational Cognitive Neuroscience (CCN) conference in 2020. We brought together a number of experts from the field of theoretical neuroscience to debate emerging issues in our understanding of how learning is implemented in biological recurrent neural networks. Here, we will give a brief review of the common assumptions about biological learning and the corresponding findings from experimental neuroscience and contrast them with the efficiency of gradient-based learning in recurrent neural networks commonly used in artificial intelligence. We will then outline the key issues discussed in the workshop: synaptic plasticity, neural circuits, theory-experiment divide, and objective functions. Finally, we conclude with recommendations for both theoretical and experimental neuroscientists when designing new studies that could help to bring clarity to these issues.

in arXiv: Quantitative Biology: Neurons and Cognition on May 13, 2021 01:30 AM.

• #### Burst-dependent synaptic plasticity can coordinate learning in hierarchical circuits

Nature Neuroscience, Published online: 13 May 2021; doi:10.1038/s41593-021-00857-x

The authors propose a synaptic plasticity rule for pyramidal neurons based on postsynaptic bursting that captures experimental data and solves the credit assignment problem for deep networks.

in Nature Neuroscience on May 13, 2021 12:00 AM.

• #### Correlations enhance the behavioral readout of neural population activity in association cortex

Nature Neuroscience, Published online: 13 May 2021; doi:10.1038/s41593-021-00845-1

Correlations in neural activity in association cortex can benefit behavioral performance in perceptual tasks, even when decreasing sensory information, by facilitating the propagation and the readout of information carried by population activity.

in Nature Neuroscience on May 13, 2021 12:00 AM.

• #### Bursting potentiates the neuro–AI connection

Nature Neuroscience, Published online: 13 May 2021; doi:10.1038/s41593-021-00844-2

For decades, researchers have wondered whether algorithms used by artificial neural networks might be implemented by biological networks. Payeur et al. have strengthened the connection between neuroscience and artificial intelligence by showing that biologically plausible mechanisms can approximate key features of an essential artificial intelligence learning algorithm.

in Nature Neuroscience on May 13, 2021 12:00 AM.

• #### TRUST4: immune repertoire reconstruction from bulk and single-cell RNA-seq data

Nature Methods, Published online: 13 May 2021; doi:10.1038/s41592-021-01142-2

TRUST4 is a computational tool for reconstructing T-cell and B-cell receptor repertoires using bulk and single-cell RNA-seq data.

in Nature Methods on May 13, 2021 12:00 AM.

• #### Challenges in benchmarking metagenomic profilers

Nature Methods, Published online: 13 May 2021; doi:10.1038/s41592-021-01141-3

Many computational tools for metagenomic profiling have been developed, with different algorithms and features. This analysis shows that, when comparing these tools, the distinction of different types of relative sequence abundance should be taken into consideration.

in Nature Methods on May 13, 2021 12:00 AM.

• #### Oscillations of the thermal conductivity in the spin-liquid state of α-RuCl3

Nature Physics, Published online: 13 May 2021; doi:10.1038/s41567-021-01243-x

Transport measurements on the Kitaev quantum spin liquid candidate α-RuCl3 subjected to a magnetic field reveal oscillating behaviour in its thermal conductivity, reminiscent of Shubnikov de Haas oscillations in metals.

in Nature Physics on May 13, 2021 12:00 AM.

• #### Quantum amplification of boson-mediated interactions

Nature Physics, Published online: 13 May 2021; doi:10.1038/s41567-021-01237-9

Many applications of quantum systems require them to be joined by strong, controllable interactions. Exploiting the physics of quantum squeezing can amplify the strength of boson-mediated interactions, yielding higher performance.

in Nature Physics on May 13, 2021 12:00 AM.

• #### Topological Shiba bands in artificial spin chains on superconductors

Nature Physics, Published online: 13 May 2021; doi:10.1038/s41567-021-01234-y

Chains of magnetic atoms on the surface of a superconductor are shown to have topologically non-trivial bands that could host Majorana bound states.

in Nature Physics on May 13, 2021 12:00 AM.

• #### Cascaded particle accelerators reach new energy

Nature Photonics, Published online: 13 May 2021; doi:10.1038/s41566-021-00822-x

The successful demonstration of two-stage acceleration driven by terahertz pulses bodes well for the future development of compact, efficient particle accelerators.

in Nature Photomics on May 13, 2021 12:00 AM.

• #### Subcycle contact-free nanoscopy of ultrafast interlayer transport in atomically thin heterostructures

Nature Photonics, Published online: 13 May 2021; doi:10.1038/s41566-021-00813-y

Subcycle nano-videography of charge-transfer dynamics in WSe2/WS2 heterostructures is obtained by using a terahertz near-field microscopy. The central idea is to probe the local polarizability of electron–hole pairs with evanescent terahertz fields.

in Nature Photomics on May 13, 2021 12:00 AM.

• #### Author Correction: Reovirus directly engages integrin to recruit clathrin for entry into host cells

Nature Communications, Published online: 13 May 2021; doi:10.1038/s41467-021-23537-7

Author Correction: Reovirus directly engages integrin to recruit clathrin for entry into host cells

in Nature Communications on May 13, 2021 12:00 AM.

• #### Daily briefing: Voyager 1 detects ‘eerie’ hum of interstellar space

Nature, Published online: 13 May 2021; doi:10.1038/d41586-021-01304-4

NASA’s Voyager 1 spacecraft captures the ripples in interstellar plasma, a brain implant turns thoughts into text and how nature-based solutions can help cool the planet — if we act now.

in Nature on May 13, 2021 12:00 AM.

• #### Delaying a COVID vaccine’s second dose boosts immune response

Nature, Published online: 13 May 2021; doi:10.1038/d41586-021-01299-y

Older people who waited 11–12 weeks for their second jab had higher peak antibody levels than did those who waited only 3 weeks.

in Nature on May 13, 2021 12:00 AM.

• #### Corrigendum: Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

in Frontiers in Molecular Neuroscience on May 13, 2021 12:00 AM.

• #### Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with TDP-43 mislocalization and aggregation. Genetic forms of FTLD and ALS are caused by pathogenic variants in various genes, such as PGRN (progranulin). To date, depletion of parkin E3 ubiquitin protein ligase, a key mitophagy regulator, has been reported in sporadic ALS patients and ALS mice models with TDP-43 proteinopathy. In this work, we show parkin downregulation also in fibroblasts derived from FTLD patients with four different PGRN pathogenic variants. We corroborate this finding in control fibroblasts upon PGRN silencing, demonstrating additionally the decrease of parkin downstream targets, mitofusin 2 (MFN2) and voltage dependent anion channel 1 (VDAC1). Importantly, we show that TDP-43 overexpression rescues PRKN levels upon transient PGRN silencing, but not in FTLD fibroblasts with PGRN pathogenic variants, despite upregulating PGRN levels in both cases. Further observation of PRKN downregulation upon TDP-43 silencing, suggests that TDP-43 loss-of-function contributes to PRKN decrease. Our results provide further evidence that parkin downregulation might be a common and systemic phenomenon in neurodegenerative diseases with TDP- 43 loss-of-function.

in Frontiers in Molecular Neuroscience on May 13, 2021 12:00 AM.

• #### Autism Spectrum Disorder Risk Factor Met Regulates the Organization of Inhibitory Synapses

A common hypothesis explains autism spectrum disorder (ASD) as a neurodevelopmental disorder linked to excitatory/inhibitory (E/I) imbalance in neuronal network connectivity. Mutation of genes including Met and downstream signaling components, e.g., PTEN, Tsc2 and, Rheb are involved in the control of synapse formation and stabilization and were all considered as risk genes for ASD. While the impact of Met on glutamatergic synapses was widely appreciated, its contribution to the stability of inhibitory, GABAergic synapses is poorly understood. The stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin. Here, we show in vivo and in vitro that Met is necessary and sufficient for the stabilization of GABAergic synapses via induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering via activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.

in Frontiers in Molecular Neuroscience on May 13, 2021 12:00 AM.

• #### Dephosphorylation Passivates the Seeding Activity of Oligomeric Tau Derived From Alzheimer’s Brain

Accumulation of intracellular neurofibrillary tangles (NFTs), which are constituted of abnormally phosphorylated tau, is one of the neuropathological hallmarks of Alzheimer’s disease (AD). The oligomeric aggregates of tau in AD brain (AD O-tau) are believed to trigger NFT spreading by seeding normal tau aggregation as toxic seeds, in a prion-like fashion. Here, we revealed the features of AD O-tau by Western blots using antibodies against various epitopes and determined the effect of dephosphorylation on the seeding activity of AD O-tau by capture and seeded aggregation assays. We found that N-terminal truncated and C-terminalhyperphosphorylated tau species were enriched in AD O-tau. Dephosphorylation of AD O-tau by alkaline phosphatasediminished its activity in capturing tau in vitro and ininducing insoluble aggregates in cultured cells. Our resultssuggested that dephosphorylation passivated the seeding activity ofAD O-tau. Inhibition of phosphorylation may be a potentstrategy to prevent the spreading of tau patho3logy.

in Frontiers in Molecular Neuroscience on May 13, 2021 12:00 AM.

• #### An Improvement of Survival Stratification in Glioblastoma Patients via Combining Subregional Radiomics Signatures

Purpose

To investigate whether combining multiple radiomics signatures derived from the subregions of glioblastoma (GBM) can improve survival prediction of patients with GBM.

Methods

In total, 129 patients were included in this study and split into training (n = 99) and test (n = 30) cohorts. Radiomics features were extracted from each tumor region then radiomics scores were obtained separately using least absolute shrinkage and selection operator (LASSO) COX regression. A clinical nomogram was also constructed using various clinical risk factors. Radiomics nomograms were constructed by combing a single radiomics signature from the whole tumor region with clinical risk factors or combining three radiomics signatures from three tumor subregions with clinical risk factors. The performance of these models was assessed by the discrimination, calibration and clinical usefulness metrics, and was compared with that of the clinical nomogram.

Results

Incorporating the three radiomics signatures, i.e., Radscores for ET, NET, and ED, into the radiomics-based nomogram improved the performance in estimating survival (C-index: training/test cohort: 0.717/0.655) compared with that of the clinical nomogram (C-index: training/test cohort: 0.633/0.560) and that of the radiomics nomogram based on single region radiomics signatures (C-index: training/test cohort: 0.656/0.535).

Conclusion

The multiregional radiomics nomogram exhibited a favorable survival stratification accuracy.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### Multi-Source Co-adaptation for EEG-Based Emotion Recognition by Mining Correlation Information

Since each individual subject may present completely different encephalogram (EEG) patterns with respect to other subjects, existing subject-independent emotion classifiers trained on data sampled from cross-subjects or cross-dataset generally fail to achieve sound accuracy. In this scenario, the domain adaptation technique could be employed to address this problem, which has recently got extensive attention due to its effectiveness on cross-distribution learning. Focusing on cross-subject or cross-dataset automated emotion recognition with EEG features, we propose in this article a robust multi-source co-adaptation framework by mining diverse correlation information (MACI) among domains and features with l2,1−norm as well as correlation metric regularization. Specifically, by minimizing the statistical and semantic distribution differences between source and target domains, multiple subject-invariant classifiers can be learned together in a joint framework, which can make MACI use relevant knowledge from multiple sources by exploiting the developed correlation metric function. Comprehensive experimental evidence on DEAP and SEED datasets verifies the better performance of MACI in EEG-based emotion recognition.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### Machine Learning for Predicting Individual Severity of Blepharospasm Using Diffusion Tensor Imaging

Accumulating diffusion tensor imaging (DTI) evidence suggests that white matter abnormalities evaluated by local diffusion homogeneity (LDH) or fractional anisotropy (FA) occur in patients with blepharospasm (BSP), both of which are significantly correlated with disease severity. However, whether the individual severity of BSP can be identified using these DTI metrics remains unknown. We aimed to investigate whether a combination of machine learning techniques and LDH or FA can accurately identify the individual severity of BSP. Forty-one patients with BSP were assessed using the Jankovic Rating Scale and DTI. The patients were assigned to non-functionally and functionally limited groups according to their Jankovic Rating Scale scores. A machine learning scheme consisting of beam search and support vector machines was designed to identify non-functionally versus functionally limited outcomes, with the input features being LDH or FA in 68 white matter regions. The proposed machine learning scheme with LDH or FA yielded an overall accuracy of 88.67 versus 85.19% in identifying non-functionally limited versus functionally limited outcomes. The scheme also identified a sensitivity of 91.40 versus 85.87% in correctly identifying functionally limited outcomes, a specificity of 83.33 versus 83.67% in accurately identifying non-functionally limited outcomes, and an area under the curve of 93.7 versus 91.3%. These findings suggest that a combination of LDH or FA measurements and a sophisticated machine learning scheme can accurately and reliably identify the individual disease severity in patients with BSP.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### Imaging Voltage in Complete Neuronal Networks Within Patterned Microislands Reveals Preferential Wiring of Excitatory Hippocampal Neurons

Voltage imaging with fluorescent dyes affords the opportunity to map neuronal activity in both time and space. One limitation to imaging is the inability to image complete neuronal networks: some fraction of cells remains outside of the observation window. Here, we combine voltage imaging, post hoc immunocytochemistry, and patterned microisland hippocampal culture to provide imaging of complete neuronal ensembles. The patterned microislands completely fill the field of view of our high-speed (500 Hz) camera, enabling reconstruction of the spiking patterns of every single neuron in the network. Cultures raised on microislands are similar to neurons grown on coverslips, with parallel developmental trajectories and composition of inhibitory and excitatory cell types (CA1, CA3, and dentate granule cells, or DGC). We calculate the likelihood that action potential firing in one neuron triggers action potential firing in a downstream neuron in a spontaneously active network to construct a functional connection map of these neuronal ensembles. Importantly, this functional map indicates preferential connectivity between DGC and CA3 neurons and between CA3 and CA1 neurons, mimicking the neuronal circuitry of the intact hippocampus. We envision that patterned microislands, in combination with voltage imaging and methods to classify cell types, will be a powerful method for exploring neuronal function in both healthy and disease states. Additionally, because the entire neuronal network is sampled simultaneously, this strategy has the power to go further, revealing all functional connections between all cell types.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### Optical Spike Detection and Connectivity Analysis With a Far-Red Voltage-Sensitive Fluorophore Reveals Changes to Network Connectivity in Development and Disease

The ability to optically record dynamics of neuronal membrane potential promises to revolutionize our understanding of neurobiology. In this study, we show that the far-red voltage sensitive fluorophore, Berkeley Red Sensor of Transmembrane potential-1, or BeRST 1, can be used to monitor neuronal membrane potential changes across dozens of neurons at a sampling rate of 500 Hz. Notably, voltage imaging with BeRST 1 can be implemented with affordable, commercially available illumination sources, optics, and detectors. BeRST 1 is well-tolerated in cultures of rat hippocampal neurons and provides exceptional optical recording fidelity, as judged by dual fluorescence imaging and patch-clamp electrophysiology. We developed a semi-automated spike-picking program to reduce user bias when calling action potentials and used this in conjunction with BeRST 1 to develop an optical spike and connectivity analysis (OSCA) for high-throughput dissection of neuronal activity dynamics. The high temporal resolution of BeRST 1 enables dissection of firing rate changes in response to acute, pharmacological interventions with commonly used inhibitors like gabazine and picrotoxin. Over longer periods of time, BeRST 1 also tracks chronic perturbations to neurons exposed to amyloid beta 1–42 (Aβ 1–42), revealing modest changes to spiking frequency but profound changes to overall network connectivity. Finally, we use OSCA to track changes in neuronal connectivity during maturation in culture, providing a functional readout of network assembly. We envision that use of BeRST 1 and OSCA described here will be of use to the broad neuroscience community.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### In-vitro Recordings of Neural Magnetic Activity From the Auditory Brainstem Using Color Centers in Diamond: A Simulation Study

Magnetometry based on nitrogen-vacancy (NV) centers in diamond is a novel technique capable of measuring magnetic fields with high sensitivity and high spatial resolution. With the further advancements of these sensors, they may open up novel approaches for the 2D imaging of neural signals in vitro. In the present study, we investigate the feasibility of NV-based imaging by numerically simulating the magnetic signal from the auditory pathway of a rodent brainstem slice (ventral cochlear nucleus, VCN, to the medial trapezoid body, MNTB) as stimulated by both electric and optic stimulation. The resulting signal from these two stimulation methods are evaluated and compared. A realistic pathway model was created based on published data of the neural morphologies and channel dynamics of the globular bushy cells in the VCN and their axonal projections to the principal cells in the MNTB. The pathway dynamics in response to optic and electric stimulation and the emitted magnetic fields were estimated using the cable equation. For simulating the optic stimulation, the light distribution in brain tissue was numerically estimated and used to model the optogenetic neural excitation based on a four state channelrhodopsin-2 (ChR2) model. The corresponding heating was also estimated, using the bio-heat equation and was found to be low (<2°C) even at excessively strong optic signals. A peak magnetic field strength of ∼0.5 and ∼0.1 nT was calculated from the auditory brainstem pathway after electrical and optical stimulation, respectively. By increasing the stimulating light intensity four-fold (far exceeding commonly used intensities) the peak magnetic signal strength only increased to 0.2 nT. Thus, while optogenetic stimulation would be favorable to avoid artefacts in the recordings, electric stimulation achieves higher peak fields. The present simulation study predicts that high-resolution magnetic imaging of the action potentials traveling along the auditory brainstem pathway will only be possible for next generation NV sensors. However, the existing sensors already have sufficient sensitivity to support the magnetic sensing of cumulated neural signals sampled from larger parts of the pathway, which might be a promising intermediate step toward further maturing this novel technology.

in Frontiers in Neuroscience: Neural Technology on May 13, 2021 12:00 AM.

• #### Iterative Restoration of the Fringe Phase (REFRASE) for QSM

In quantitative susceptibility mapping (QSM), reconstructed results can be critically biased by misinterpreted or missing phase data near the edges of the brain support originating from the non-local relationship between field and susceptibility. These data either have to be excluded or corrected before further processing can take place. To address this, our iterative restoration of the fringe phase (REFRASE) approach simultaneously enhances the accuracy of multi-echo phase data QSM maps and the extent of the area available for evaluation. Data loss caused by strong local phase gradients near the surface of the brain support is recovered within the original phase data using harmonic and dipole-based fields extrapolated from a robust support region toward an extended brain mask. Over several iterations, phase data are rectified prior to the application of further QSM processing steps. The concept is successfully validated on numerical phantoms and brain scans from a cohort of volunteers. The increased extent of the mask and improved numerical stability within the segmented globus pallidus confirm the efficacy of the presented method in comparison to traditional evaluation.

in Frontiers in Neuroscience: Brain Imaging Methods on May 13, 2021 12:00 AM.

• #### Editorial: APPNING: Animal Population Imaging

in Frontiers in Neuroinformatics on May 13, 2021 12:00 AM.

• #### Antiepileptic Efficacy and Network Connectivity Modulation of Repetitive Transcranial Magnetic Stimulation by Vertex Suppression

A core feature of drug-resistant epilepsy is hyperexcitability in the motor cortex, and low-frequency repetitive transcranial magnetic stimulation (rTMS) is a suitable treatment for seizures. However, the antiepileptic effect causing network reorganization has rarely been studied. Here, we assessed the impact of rTMS on functional network connectivity (FNC) in resting functional networks (RSNs) and their relation to treatment response. Fourteen patients with medically intractable epilepsy received inhibitive rTMS with a figure-of-eight coil over the vertex for 10 days spread across two weeks. We designed a 6-week follow-up phase divided into four time points to investigate FNC and rTMS-induced timing-dependent plasticity, such as seizure frequency and abnormal interictal discharges on electroencephalography (EEG). For psychiatric comorbidities, the Hamilton Depression Scale (HAM-D) and the Hamilton Anxiety Scale (HAM-A) were applied to measure depression and anxiety before and after rTMS. FNC was also compared to that of a cohort of 17 healthy control subjects. The after-effects of rTMS included all subjects that achieved the significant decrease rate of more than 50% in interictal epileptiform discharges and seizure frequency, 12 (14) patients with the reduction rate above 50% compared to the baseline, as well as emotional improvements in depression and anxiety (p < 0.05). In the analysis of RSNs, we found a higher synchronization between the sensorimotor network (SMN) and posterior default-mode network (pDMN) in epileptic patients than in healthy controls. In contrast to pre-rTMS, the results demonstrated a weaker FNC between the anterior DMN (aDMN) and SMN after rTMS, while the FNC between the aDMN and dorsal attention network (DAN) was greater (p < 0.05, FDR corrected). Importantly, the depressive score was anticorrelated with the FNC of the aDMN-SMN (r = −0.67, p = 0.0022), which was markedly different in the good and bad response groups treated with rTMS (p = 0.0115). Based on the vertex suppression by rTMS, it is possible to achieve temporary clinical efficacy by modulating network reorganization in the DMN and SMN for patients with refractory epilepsy.

in Frontiers in Human Neuroscience on May 13, 2021 12:00 AM.

• #### Occupational Injuries and Use of Benzodiazepines: A Systematic Review and Metanalysis

Background: Benzodiazepines have been widely used in clinical practice for over four decades and continue to be one of the most consumed and highly prescribed class of drugs available in the treatment of anxiety, depression, and insomnia. The literature indicates that Benzodiazepine users at a significantly increased risk of Motor Vehicle accidents compared to non-users but the impact on injuries at workplace is not well-defined. We aimed to investigate whether use of benzodiazepine is associated with increased risk of occupational injuries (OI).

Methods: PubMed, Embase, and Scopus databases were searched. A meta-analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI) among case controls, cross-sectional studies, either questionnaire or laboratory exams based.

Results: A total of 13 studies met inclusion criteria, involving 324,168 OI from seven different countries, with an estimated occurrence of benzodiazepine positivity of 2.71% (95% CI 1.45–4.98). A total of 14 estimates were retrieved. Of them, 10 were based on laboratory analyses, three on institutional databases, while one study was based on questionnaires. Regarding the occupational groups, three estimates focused on commercial drivers (0.73%, 95% CI 0.12–4.30), that exhibited a reduced risk ratio for benzodiazepine positivity compared to other occupational groups (RR 0.109, 95% CI 0.063–0.187). Eventually, no increased risk for benzodiazepine positivity was identified, either from case control studies (OR 1.520, 95% CI 0.801–2.885, I2 76%), or cross sectional studies, when only laboratory based estimates were taken in account (OR 0.590, 95% CI 0.253–1.377, I2 63%).

Conclusions: Even though benzodiazepines have the potential to increase injury rates among casual and chronic users, available evidence are insufficient to sustain this hypothesis, particularly when focusing on laboratory-based studies (i.e., studies the characterized the benzodiazepine immediately before the event).

in Frontiers in Human Neuroscience on May 13, 2021 12:00 AM.

• #### Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

The claustrum is a thin sheet of neurons that is densely connected to many cortical regions and has been implicated in numerous high-order brain functions. Such brain functions arise from brain states that are influenced by neuromodulatory pathways from the cholinergic basal forebrain, dopaminergic substantia nigra and ventral tegmental area, and serotonergic raphe. Recent revelations that the claustrum receives dense input from these structures have inspired investigation of state-dependent control of the claustrum. Here, we review neuromodulation in the claustrum—from anatomical connectivity to behavioral manipulations—to inform future analyses of claustral function.

in Frontiers in Neural Circuits on May 13, 2021 12:00 AM.

• #### Optical Imaging-Based Guidance of Viral Microinjections and Insertion of a Laminar Electrophysiology Probe Into a Predetermined Barrel in Mouse Area S1BF

Wide-field Optical Imaging of Intrinsic Signals (OI-IS; Grinvald et al., 1986) is a method for imaging functional brain hemodynamic responses, mainly used to image activity from the surface of the cerebral cortex. It localizes small functional modules – such as cortical columns – with great spatial resolution and spatial specificity relative to the site of increases in neuronal activity. OI-IS is capable of imaging responses either through an intact or thinned skull or following a craniotomy. Therefore, it is minimally invasive, which makes it ideal for survival experiments. Here we describe OI-IS-based methods for guiding microinjections of optogenetics viral vectors in proximity to small functional modules (S1 barrels) of the cerebral cortex and for guiding the insertion of electrodes for electrophysiological recording into such modules. We validate our proposed methods by tissue processing of the cerebral barrel field area, revealing the track of the electrode in a predetermined barrel. In addition, we demonstrate the use of optical imaging to visualize the spatial extent of the optogenetics photostimulation, making it possible to estimate one of the two variables that conjointly determine which region of the brain is stimulated. Lastly, we demonstrate the use of OI-IS at high-magnification for imaging the upper recording contacts of a laminar probe, making it possible to estimate the insertion depth of all contacts relative to the surface of the cortex. These methods support the precise positioning of microinjections and recording electrodes, thus overcoming the variability in the spatial position of fine-scale functional modules.

in Frontiers in Neural Circuits on May 13, 2021 12:00 AM.

• #### Developmental Characterization of Schizophrenia-Associated Gene Zswim6 in Mouse Forebrain

Schizophrenia is a devastating neuropsychiatric disease with a globally 1% life-long prevalence. Clinical studies have linked Zswim6 mutations to developmental and neurological diseases, including schizophrenia. Zswim6’s function remains largely unknown. Given the involvement of Zswim6 in schizophrenia and schizophrenia as a neurodevelopmental disease, it is important to understand the spatiotemporal expression pattern of Zswim6 in the developing brain. Here, we performed a comprehensive analysis of the spatiotemporal expression pattern of Zswim6 in the mouse forebrain by in situ hybridization with radioactive and non-radioactive-labeled riboprobes. Zswim6 mRNA was detected as early as E11.5 in the ventral forebrain. At E11.5–E13.5, Zswim6 was highly expressed in the lateral ganglionic eminence (LGE). The LGE consisted of two progenitor populations. Dlx+;Er81+ cells in dorsal LGE comprised progenitors of olfactory bulb interneurons, whereas Dlx+;Isl1+ progenitors in ventral LGE gave rise to striatal projection neurons. Zswim6 was not colocalized with Er81 in the dorsal LGE. In the ventral LGE, Zswim6 was colocalized with striatal progenitor marker Nolz-1. Zswim6 was highly expressed in the subventricular zone (SVZ) of LGE in which progenitors undergo the transition from proliferation to differentiation. Double labeling showed that Zswim6 was not colocalized with proliferation marker Ki67 but was colocalized with differentiation marker Tuj1 in the SVZ, suggesting Zswim6 expression in early differentiating neurons. Zswim6 was also expressed in the adjacent structures of medial and caudal ganglionic eminences (MGE, CGE) that contained progenitors of cortical interneurons. At E15.5 and E17.5, Zswim6 was expressed in several key brain regions that were involved in the pathogenesis of schizophrenia, including the striatum, cerebral cortex, hippocampus, and medial habenular nucleus. Zswim6 was persistently expressed in the postnatal brain. Cell type analysis indicated that Zswim6 mRNA was colocalized with D1R-expressing striatonigral and D2R-expressing striatopallidal neurons of the adult striatum with a higher colocalization in striatopallidal neurons. These findings are of particular interest as striatal dopamine D2 receptors are known to be involved in the pathophysiology of schizophrenia. In summary, the comprehensive analysis provides an anatomical framework for the study of Zswim6 function and Zswim6-associated neurological disorders.

in Frontiers in Neuroanatomy on May 13, 2021 12:00 AM.

• #### Posterior Cortical Cognitive Deficits Are Associated With Structural Brain Alterations in Mild Cognitive Impairment in Parkinson’s Disease

Context: Cognitive impairments are common in patients with Parkinson’s disease (PD) and are heterogeneous in their presentation. The “dual syndrome hypothesis” suggests the existence of two distinct subtypes of mild cognitive impairment (MCI) in PD: a frontostriatal subtype with predominant attentional and/or executive deficits and a posterior cortical subtype with predominant visuospatial, memory, and/or language deficits. The latter subtype has been associated with a higher risk of developing dementia.

Objective: The objective of this study was to identify structural modifications in cortical and subcortical regions associated with each PD-MCI subtype.

Methods: One-hundred and fourteen non-demented PD patients underwent a comprehensive neuropsychological assessment as well as a 3T magnetic resonance imaging scan. Patients were categorized as having no cognitive impairment (n = 41) or as having a frontostriatal (n = 16), posterior cortical (n = 25), or a mixed (n = 32) MCI subtype. Cortical regions were analyzed using a surface-based Cortical thickness (CTh) method. In addition, the volumes, shapes, and textures of the caudate nuclei, hippocampi, and thalami were studied. Tractometric analyses were performed on associative and commissural white matter (WM) tracts.

Results: There were no between-group differences in volumetric measurements and cortical thickness. Shape analyses revealed more abundant and more extensive deformations fields in the caudate nuclei, hippocampi, and thalami in patients with posterior cortical deficits compared to patients with no cognitive impairment. Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) were also observed in the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the striato-parietal tract, and the anterior and posterior commissural tracts. Texture analyses showed a significant difference in the right hippocampus of patients with a mixed MCI subtype.

Conclusion: PD-MCI patients with posterior cortical deficits have more abundant and more extensive structural alterations independently of age, disease duration, and severity, which may explain why they have an increased risk of dementia.

in Frontiers in Ageing Neuroscience on May 13, 2021 12:00 AM.

• #### Dual-Phase β-Amyloid PET Captures Neuronal Injury and Amyloidosis in Corticobasal Syndrome

Objectives: In recent years several 18F-labeled amyloid PET (Aβ-PET) tracers have been developed and have obtained clinical approval. There is evidence that Aβ-PET perfusion can provide surrogate information about neuronal injury in neurodegenerative diseases when compared to conventional blood flow and glucose metabolism assessment. However, this paradigm has not yet been tested in neurodegenerative disorders with cortical and subcortical affection. Therefore, we investigated the performance of early acquisition 18F-flutemetamol Aβ-PET in comparison to 18F-fluorodeoxyglucose (FDG)-PET in corticobasal syndrome (CBS).

Methods: Subjects with clinically possible or probable CBS were recruited within the prospective Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer’s Disease (ActiGliA) observational study and all CBS cases with an available FDG-PET prior to Aβ-PET were selected. Aβ-PET was acquired 0–10 min p.i. (early-phase) and 90–110 min p.i. (late-phase) whereas FDG-PET was recorded statically from 30 to 50 min p.i. Semiquantitative regional values and asymmetry indices (AI) were compared between early-phase Aβ-PET and FDG-PET. Visual assessments of hypoperfusion and hypometabolism were compared between both methods. Late-phase Aβ-PET was evaluated visually for assessment of Aβ-positivity.

Results: Among 20 evaluated patients with CBS, 5 were Aβ-positive. Early-phase Aβ-PET and FDG-PET SUVr correlated highly in cortical (mean R = 0.86, range 0.77–0.92) and subcortical brain regions (mean R = 0.84, range 0.79–0.90). Strong asymmetry was observed in FDG-PET for the motor cortex (mean |AI| = 2.9%), the parietal cortex (mean |AI| = 2.9%), and the thalamus (mean |AI| = 5.5%), correlating well with AI of early-phase Aβ-PET (mean R = 0.87, range 0.62–0.98). Visual assessments of hypoperfusion and hypometabolism were highly congruent.

Conclusion: Early-phase Aβ-PET facilitates assessment of neuronal injury in CBS for cortical and subcortical areas. Known asymmetries in CBS are captured by this method, enabling assessment of Aβ-status and neuronal injury with a single radiation exposure at a single visit.

in Frontiers in Ageing Neuroscience on May 13, 2021 12:00 AM.

• #### Effects of Aging on Levo-Dihydroxyphenylalanine- Induced Dyskinesia in a Rat Model of Parkinson’s Disease

Background

It remains unclear why patients with young-onset Parkinson’s disease more often develop levo-dihydroxyphenylalanine (L-dopa)-induced dyskinesia (LID) and have a more severe form than patients with old-onset Parkinson’s disease. Previous studies using animal models have failed to show young-onset Parkinson’s disease enhances LID.

Objectives

To evaluate the association of age at dopaminergic denervation (onset age) and initiation of L-dopa treatment (treatment age) with LID development in model rats.

Methods

We established rat models of young- and old-lesioned Parkinson’s disease (6-hydroxydopamine lesions at 10 and 88 weeks of age, respectively). Dopaminergic denervation was confirmed by the rotational behavior test using apomorphine. Rats in the young-lesioned group were allocated to either L-dopa treatment at a young or old age, or saline treatment. Rats in the old-lesioned group were allocated to either L-dopa treatment or saline group. We evaluated L-dopa-induced abnormal involuntary movements during the 14-day treatment period. We also examined preprodynorphin mRNA expression in the striatum (a neurochemical hallmark of LID) and the volume of the medial globus pallidus (a pathological hallmark of LID).

Results

LID-like behavior was enhanced in L-dopa-treated young-lesioned rats compared with L-dopa-treated old-lesioned rats. Preprodynorphin mRNA expression was higher in L-dopa-treated young-lesioned rats than in in L-dopa-treated old-lesioned rats. The volume of the medial globus pallidus was greater in L-dopa-treated young-lesioned rats than in L-dopa-treated old-lesioned rats. Treatment age did not affect LID-like behavior or the degree of medial globus pallidus hypertrophy in the young-lesioned model.

Conclusion

Both dopaminergic denervation and L-dopa initiation at a young age contributed to the development of LID; however, the former may be a more important factor.

in Frontiers in Ageing Neuroscience on May 13, 2021 12:00 AM.

• #### Association Between Childhood Neighborhood Quality and the Risk of Cognitive Dysfunction in Chinese Middle-Aged and Elderly Population: The Moderation Effect of Body Mass Index

Background: Identification of early modifiable factors is crucial to delay or prevent the development of cognitive impairment and reduce the social and economic burden.

Objective: This study aimed to examine the longitudinal associations of childhood neighborhood quality (CNQ) with the risk of later-life cognitive dysfunction and the role of body mass index (BMI) in this association.

Methods: A total of 8,289 community-dwelling middle-aged and elderly population from wave 2011, wave 2013, and wave 2015 of the China Health and Retirement Longitudinal Study (CHARLS) were included. Cognitive function and CNQ were measured by standardized questionnaires. Multilevel linear regression models were used to estimate the associations of CNQ and cognitive function. The interactions of BMI with CNQ in the progress of cognitive function were also estimated.

Results: The participants with higher CNQ had a significantly low risk of cognitive impairment than those with lower CNQ score (β = 0.067, 95% CI: 0.031, 0.103), and the results remained similar (β = 0.039, 95% CI: 0.004, 0.075) after controlling other confounding variables. Furthermore, there was an interaction between BMI with CNQ score (P < 0.001) for the risk of cognitive impairment. In BMI-stratified analysis, we found that the association of CNQ and cognitive function was not statistically significant in overweight or obese population (β = 0.019, 95% CI: −0.032, 0.070), but was statistically significant in people with lower BMI (β = 0.059, 95% CI: 0.010, 0.107).

Conclusions: Higher CNQ score is significantly associated with the lower risk of cognitive dysfunction in adulthood. BMI may moderate the associations of CNQ with the risk of cognitive function.

in Frontiers in Ageing Neuroscience on May 13, 2021 12:00 AM.

• #### Increased Plasma Level of 24S-Hydroxycholesterol and Polymorphism of CYP46A1 SNP (rs754203) Are Associated With Mild Cognitive Impairment in Patients With Type 2 Diabetes

Background

Abnormal cholesterol metabolism is common in type 2 diabetes mellitus (T2DM) and causes dementia. Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol (24-OHC) and maintains cholesterol homeostasis in the brain.

Objective

This study aimed to investigate the roles of 24-OHC and the CYP46A1 (rs754203) polymorphism in patients with T2DM and mild cognitive impairment (MCI).

Methods

A total of 193 Chinese patients with T2DM were recruited into two groups according to the Montreal Cognitive Assessment (MoCA). Demographic and clinical data were collected, and neuropsychological tests were conducted. Enzyme-linked immunosorbent assay (ELISA) and Seqnome method were used to detect the concentration of plasma 24-OHC and the CYP46A1 rs754203 genotype, respectively.

Results

Compared with 118 healthy cognition participants, patients with MCI (n = 75) displayed a higher plasma level of 24-OHC and total cholesterol concentration (all p = 0.031), while no correlation was found between them. In the overall diabetes population, the plasma level of 24-OHC was negatively correlated with MoCA (r = −0.150, p = 0.039), and it was further proved to be an independent risk factor of diabetic MCI (OR = 1.848, p = 0.001). Additionally, patients with MCI and the CC genotype of CYP46A1 rs754203 showed the highest plasma level of 24-OHC even though the difference was not statistically significant, and they obtained low scores in both the verbal fluency test and Stroop color and word test A (p = 0.008 and p = 0.029, respectively).

Conclusion

In patients with T2DM, high plasma level of 24-OHC and the CC genotype carrier of CYP46A1 rs754203 may portend a high risk of developing early cognitive impairment, including attention and executive deficits.

in Frontiers in Ageing Neuroscience on May 13, 2021 12:00 AM.

• #### Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

by Nikolina ŠoŠtarić, Vera van Noort

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

in PLoS Computational Biology on May 12, 2021 02:00 PM.

• #### Swarm: A federated cloud framework for large-scale variant analysis

by Amir Bahmani, Kyle Ferriter, Vandhana Krishnan, Arash Alavi, Amir Alavi, Philip S. Tsao, Michael P. Snyder, Cuiping Pan

Genomic data analysis across multiple cloud platforms is an ongoing challenge, especially when large amounts of data are involved. Here, we present Swarm, a framework for federated computation that promotes minimal data motion and facilitates crosstalk between genomic datasets stored on various cloud platforms. We demonstrate its utility via common inquiries of genomic variants across BigQuery in the Google Cloud Platform (GCP), Athena in the Amazon Web Services (AWS), Apache Presto and MySQL. Compared to single-cloud platforms, the Swarm framework significantly reduced computational costs, run-time delays and risks of security breach and privacy violation.

in PLoS Computational Biology on May 12, 2021 02:00 PM.

• #### Balanced networks under spike-time dependent plasticity

by Alan Eric Akil, Robert Rosenbaum, Krešimir Josić

The dynamics of local cortical networks are irregular, but correlated. Dynamic excitatory–inhibitory balance is a plausible mechanism that generates such irregular activity, but it remains unclear how balance is achieved and maintained in plastic neural networks. In particular, it is not fully understood how plasticity induced changes in the network affect balance, and in turn, how correlated, balanced activity impacts learning. How do the dynamics of balanced networks change under different plasticity rules? How does correlated spiking activity in recurrent networks change the evolution of weights, their eventual magnitude, and structure across the network? To address these questions, we develop a theory of spike–timing dependent plasticity in balanced networks. We show that balance can be attained and maintained under plasticity–induced weight changes. We find that correlations in the input mildly affect the evolution of synaptic weights. Under certain plasticity rules, we find an emergence of correlations between firing rates and synaptic weights. Under these rules, synaptic weights converge to a stable manifold in weight space with their final configuration dependent on the initial state of the network. Lastly, we show that our framework can also describe the dynamics of plastic balanced networks when subsets of neurons receive targeted optogenetic input.

in PLoS Computational Biology on May 12, 2021 02:00 PM.

• #### Patterns of selection against centrosome amplification in human cell lines

by Marco António Dias Louro, Mónica Bettencourt-Dias, Claudia Bank

The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.

in PLoS Computational Biology on May 12, 2021 02:00 PM.

• #### Individuals with autism spectrum disorder have altered visual encoding capacity

by Jean-Paul Noel, Ling-Qi Zhang, Alan A. Stocker, Dora E. Angelaki

Perceptual anomalies in individuals with autism spectrum disorder (ASD) have been attributed to an imbalance in weighting incoming sensory evidence with prior knowledge when interpreting sensory information. Here, we show that sensory encoding and how it adapts to changing stimulus statistics during feedback also characteristically differs between neurotypical and ASD groups. In a visual orientation estimation task, we extracted the accuracy of sensory encoding from psychophysical data by using an information theoretic measure. Initially, sensory representations in both groups reflected the statistics of visual orientations in natural scenes, but encoding capacity was overall lower in the ASD group. Exposure to an artificial (i.e., uniform) distribution of visual orientations coupled with performance feedback altered the sensory representations of the neurotypical group toward the novel experimental statistics, while also increasing their total encoding capacity. In contrast, neither total encoding capacity nor its allocation significantly changed in the ASD group. Across both groups, the degree of adaptation was correlated with participants’ initial encoding capacity. These findings highlight substantial deficits in sensory encoding—independent from and potentially in addition to deficits in decoding—in individuals with ASD.

in PLoS Biology on May 12, 2021 02:00 PM.

• #### Glyphosate inhibits melanization and increases susceptibility to infection in insects

by Daniel F. Q. Smith, Emma Camacho, Raviraj Thakur, Alexander J. Barron, Yuemei Dong, George Dimopoulos, Nichole A. Broderick, Arturo Casadevall

Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanin’s broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate—the most widely used herbicide globally—inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in 2 evolutionary distant species, Galleria mellonella (Lepidoptera: Pyralidae) and Anopheles gambiae (Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival of G. mellonella caterpillars following infection with the fungus Cryptococcus neoformans and decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria-causing parasite Plasmodium falciparum in A. gambiae mosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosate’s mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation–reduction balance. Overall, these findings suggest that glyphosate’s environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.

in PLoS Biology on May 12, 2021 02:00 PM.

• #### The molecular and metabolic program by which white adipocytes adapt to cool physiologic temperatures

by Hiroyuki Mori, Colleen E. Dugan, Akira Nishii, Ameena Benchamana, Ziru Li, Thomas S. Cadenhead IV, Arun K. Das, Charles R. Evans, Katherine A. Overmyer, Steven M. Romanelli, Sydney K. Peterson, Devika P. Bagchi, Callie A. Corsa, Julie Hardij, Brian S. Learman, Mahmoud El Azzouny, Joshua J. Coon, Ken Inoki, Ormond A. MacDougald

in PLoS Biology on May 12, 2021 02:00 PM.

• #### A theory of capacity and sparse neural encoding

Publication date: Available online 12 May 2021

Source: Neural Networks

Author(s): Pierre Baldi, Roman Vershynin

in Neural Networks on May 12, 2021 01:00 PM.

• #### Experimental stability analysis of neural networks in classification problems with confidence sets for persistence diagrams

Publication date: Available online 12 May 2021

Source: Neural Networks

Author(s): Naoki Akai, Takatsugu Hirayama, Hiroshi Murase

in Neural Networks on May 12, 2021 01:00 PM.

• #### <math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="d1e259" altimg="si3.svg" class="math"><msub><mrow><mi>H</mi></mrow><mrow><mi>∞</mi></mrow></msub>[/itex] synchronization of delayed neural networks via event-triggered dynamic output control

Publication date: Available online 11 May 2021

Source: Neural Networks

Author(s): Yachun Yang, Zhengwen Tu, Liangwei Wang, Jinde Cao, Lei Shi, Wenhua Qian

in Neural Networks on May 12, 2021 01:00 PM.

• #### Efficient learning with augmented spikes: A case study with image classification

Publication date: Available online 12 May 2021

Source: Neural Networks

Author(s): Shiming Song, Chenxiang Ma, Wei Sun, Junhai Xu, Jianwu Dang, Qiang Yu

in Neural Networks on May 12, 2021 01:00 PM.

• #### Polymer-induced microcolony compaction in early biofilms: A computer simulation study

Author(s): Francisco Javier Lobo-Cabrera, Alessandro Patti, Fernando Govantes, and Alejandro Cuetos

Microscopic organisms, such as bacteria, have the ability of colonizing surfaces and developing biofilms that can determine diseases and infections. Most bacteria secrete a significant amount of extracellular polymer substances that are relevant for biofilm stabilization and growth. In this work, we...

[Phys. Rev. E 103, 052407] Published Wed May 12, 2021

in Physical Review E: Biological physics on May 12, 2021 10:00 AM.

• #### Mapping Reward Mechanisms by Intracerebral Self Stimulation in the Rhesus Monkey (Macaca mulatta)

in Journal of Comparative Neurology on May 12, 2021 09:54 AM.

• #### Robot navigation as hierarchical active inference

Publication date: Available online 10 May 2021

Source: Neural Networks

Author(s): Ozan Çatal, Tim Verbelen, Toon Van de Maele, Bart Dhoedt, Adam Safron

in Neural Networks on May 12, 2021 07:00 AM.

• #### α4β2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait‐Balance Disorders

in Annals of Neurology on May 12, 2021 06:05 AM.

• #### Two novel feature selection algorithms based on crowding distance. (arXiv:2105.05212v3 [cs.LG] UPDATED)

In this paper, two novel algorithms for features selection are proposed. The first one is a filter method while the second is wrapper method. Both the proposed algorithms use the crowding distance used in the multiobjective optimization as a metric in order to sort the features. The less crowded features have great effects on the target attribute (class). The experimental results have shown the effectiveness and the robustness of the proposed algorithms.

in arXiv: Computer Science: Neural and Evolutionary Computing on May 12, 2021 01:30 AM.

• #### Ion implanation success

Nature Photonics, Published online: 12 May 2021; doi:10.1038/s41566-021-00825-8

A new way to define the shape of tiny light-emitting semiconductor pixels provides a means to fabricate arrays of InGaN blue micro-LEDs with a resolution as high as 8,500 pixels per inch.

in Nature Photomics on May 12, 2021 12:00 AM.

• #### Corrigendum: Changes in Resting-State Functional Connectivity of Cerebellum in Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Case-Control Study

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

• #### Targeted Blood Brain Barrier Opening With Focused Ultrasound Induces Focal Macrophage/Microglial Activation in Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS). EAE reflects important histopathological hallmarks, dissemination, and diversity of the disease, but has only moderate reproducibility of clinical and histopathological features. Focal lesions are less frequently observed in EAE than in MS, and can neither be constrained to specific locations nor timed to occur at a pre-specified moment. This renders difficult any experimental assessment of the pathogenesis of lesion evolution, including its inflammatory, degenerative (demyelination and axonal degeneration), and reparatory (remyelination, axonal sprouting, gliosis) component processes. We sought to develop a controlled model of inflammatory, focal brain lesions in EAE using focused ultrasound (FUS). We hypothesized that FUS induced focal blood brain barrier disruption (BBBD) will increase the likelihood of transmigration of effector cells and subsequent lesion occurrence at the sonicated location. Lesion development was monitored with conventional magnetic resonance imaging (MRI) as well as with magnetic resonance elastography (MRE) and further analyzed by histopathological means. EAE was induced in 12 6–8 weeks old female C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide. FUS-induced BBBD was performed 6, 7, and 9 days after immunization in subgroups of four animals and in an additional control group. MRI and MRE were performed on a 7T horizontal bore small animal MRI scanner. Imaging was conducted longitudinally 2 and 3 weeks after disease induction and 1 week after sonication in control animals, respectively. The scan protocol comprised contrast-enhanced T1-weighted and T2-weighted sequences as well as MRE with a vibration frequency of 1 kHz. Animals were sacrificed for histopathology after the last imaging time point. The overall clinical course of EAE was mild. A total of seven EAE animals presented with focal T2w hyperintense signal alterations in the sonicated hemisphere. These were most frequent in the group of animals sonicated 9 days after immunization. Histopathology revealed foci of activated microglia/macrophages in the sonicated right hemisphere of seven EAE animals. Larger cellular infiltrates or apparent demyelination were not seen. Control animals showed no abnormalities on MRI and did not have clusters of activated microglia/macrophages at the sites targeted with FUS. None of the animals had hemorrhages or gross tissue damage as potential side effects of FUS. EAE-animals tended to have lower values of viscoelasticity and elasticity in the sonicated compared to the contralateral parenchyma. This trend was significant when comparing the right sonicated to the left normal hemisphere and specifically the right sonicated compared to the left normal cortex in animals that underwent FUS-BBBD 9 days after immunization (right vs. left hemisphere: mean viscoelasticity 6.1 vs. 7.2 kPa; p = 0.003 and mean elasticity 4.9 vs. 5.7 kPa, p = 0.024; right vs. left cortex: mean viscoelasticity 5.8 vs. 7.5 kPa; p = 0.004 and mean elasticity 5 vs. 6.5 kPa; p = 0.008). A direct comparison of the biomechanical properties of focal T2w hyperintensities with normal appearing brain tissue did not yield significant results. Control animals showed no differences in viscoelasticity between sonicated and contralateral brain parenchyma. We here provide first evidence for a controlled lesion induction model in EAE using FUS-induced BBBD. The observed lesions in EAE are consistent with foci of activated microglia that may be interpreted as targeted initial inflammatory activity and which have been described as pre-active lesions in MS. Such foci can be identified and monitored with MRI. Moreover, the increased inflammatory activity in the sonicated brain parenchyma seems to have an effect on overall tissue matrix structure as reflected by changes of biomechanical parameters.

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

• #### Tapping the Potential of Multimodal Non-invasive Brain Stimulation to Elucidate the Pathophysiology of Movement Disorders

This mini-review provides a detailed outline of studies that have used multimodal approaches in non-invasive brain stimulation to investigate the pathophysiology of the three common movement disorders, namely, essential tremor, Parkinson’s disease, and dystonia. Using specific search terms and filters in the PubMed® database, we finally shortlisted 27 studies in total that were relevant to this review. While two-thirds (Brittain et al., 2013) of these studies were performed on Parkinson’s disease patients, we could find only three studies that were conducted in patients with essential tremor. We clearly show that although multimodal non-invasive brain stimulation holds immense potential in unraveling the physiological mechanisms that are disrupted in movement disorders, the technical challenges and pitfalls of combining these methods may hinder their widespread application by movement disorder specialists. A multidisciplinary team with clinical and technical expertise may be crucial in reaping the fullest benefits from such novel multimodal approaches.

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

• #### An Adolescent Sensitive Period for Social Dominance Hierarchy Plasticity Is Regulated by Cortical Plasticity Modulators in Mice

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

• #### Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

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

• #### Therapeutic Development for CGG Repeat Expansion-Associated Neurodegeneration

Non-coding repeat expansions, such as CGG, GGC, CUG, CCUG, and GGGGCC, have been shown to be involved in many human diseases, particularly neurological disorders. Of the diverse pathogenic mechanisms proposed in these neurodegenerative diseases, dysregulated RNA metabolism has emerged as an important contributor. Expanded repeat RNAs that form particular structures aggregate to form RNA foci, sequestering various RNA binding proteins and consequently altering RNA splicing, transport, and other downstream biological processes. One of these repeat expansion-associated diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), is caused by a CGG repeat expansion in the 5’UTR region of the fragile X mental retardation 1 (FMR1) gene. Moreover, recent studies have revealed abnormal GGC repeat expansion within the 5’UTR region of the NOTCH2NLC gene in both essential tremor (ET) and neuronal intranuclear inclusion disease (NIID). These CGG repeat expansion-associated diseases share genetic, pathological, and clinical features. Identification of the similarities at the molecular level could lead to a better understanding of the disease mechanisms as well as developing novel therapeutic strategies. Here, we highlight our current understanding of the molecular pathogenesis of CGG repeat expansion-associated diseases and discuss potential therapeutic interventions for these neurological disorders.

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

• #### Gait Impairment and Upper Extremity Disturbance Are Associated With Total Magnetic Resonance Imaging Cerebral Small Vessel Disease Burden

Background and Purpose: Cerebral small vessel disease (cSVD)—including white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), lacunes, and enlarged perivascular spaces (EPVS)—is related to gait impairment. However, the association between the total magnetic resonance imaging (MRI) cSVD burden and gait and upper extremity function remains insufficiently investigated. This study aimed to assess the correlation between the total MRI cSVD burden score and gait impairment as well as upper extremity impairment.

Method: A total of 224 participants underwent MRI scans, and the presence of lacunes, WMHs, CMBs, and EPVS was evaluated and recorded as a total MRI cSVD burden score (range 0–4). Gait was assessed by 4-m walkway, Tinetti, Timed Up and Go (TUG), and Short Physical Performance Battery (SPPB) tests. Upper extremity function was assessed by 10-repeat hand pronation-supination time, 10-repeat finger-tapping time, and 10-repeat hand opening and closing time.

Result: The mean age of the 224 participants was 60.6 ± 10.5 years, and 64.3% were men. Independent of age, sex, height, and vascular risk factors, multivariable linear regression analyses showed that a higher total MRI cSVD burden score was related to a shorter stride length, wider step width, higher cadence, and poorer performance on the Tinetti, TUG, and SPPB tests and upper extremity tests (all P < 0.05).

Conclusion: Total MRI cSVD burden was associated with gait impairment and upper extremity disturbances, suggesting that total MRI cSVD burden might contribute to motor function decline. Longitudinal studies are required to determine whether there is a causal relationship between total MRI cSVD burden and motor function decline.

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

• #### Altered Neurovascular Coupling in Subcortical Ischemic Vascular Disease

Patients with subcortical ischemic vascular disease (SIVD) exhibit a high risk of cognitive impairment that might be caused by neurologic deficits and vascular injuries. However, the mechanism remains unknown. In current study, 24 normal controls (NC) and 54 SIVD patients, including 26 SIVD patients with no cognitive impairment (SIVD-NCI) and 28 SIVD patients with mild cognitive impairment (SIVD-MCI) underwent the resting-state functional MRI (rs-fMRI) and neuropsychological assessments. We combined regional homogeneity (ReHo) and cerebral blood flow (CBF) by using the global ReHo-CBF correlations coefficient and the ReHo/CBF ratio to detect the inner link between neuronal activity and vascular responses. Correlations between the ReHo/CBF ratio and neuropsychological assessments were explored in patients with SIVD. As a result, we identified significantly decreased global ReHo-CBF coupling in the SIVD-NCI group and SIVD- MCI group with respect to the NC. The SIVD-MCI group showed more serious decoupling of the global ReHo-CBF correlation. We also found a significantly abnormal ReHo/CBF ratio predominantly located in cognitive-related brain regions, including the left insula, right middle temporal gyrus, right precuneus, left precentral gyrus, and left inferior parietal lobule but not the supramarginal and angular gyri. The SIVD-MCI group showed more severe disorders of neurovascular coupling than the other two groups. Moreover, the ReHo/CBF ratio in the left precentral gyrus of the SIVD-NCI group exhibited a positive correlation with the MMSE scores. These findings suggested that patients with SIVD show abnormal neurovascular coupling at the early stage of the disease and during disease development. It might be associated with disease severity and cognitive impairment. Neurovascular decoupling in brain may be a possible neuropathological mechanism of SIVD.

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

• #### Impairments in brain perfusion, executive control network, topological characteristics, and neurocognition in adult patients with asymptomatic Moyamoya disease

Asymptomatic Moyamoya disease (MMD) impairs hemodynamic and cognitive function. The relationship between these changes, cerebral blood flow (CBF), and network connectivity remains largely unknown. The aim of t...

in BMC Neuroscience on May 12, 2021 12:00 AM.

• #### Neuronal replacement: Concepts, achievements, and call for caution

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Magdalena Götz, Riccardo Bocchi

in Current Opinion in Neurobiology on May 11, 2021 06:00 PM.

• #### Concerns Regarding Therapeutic Implications of Very Low‐Level Dystrophin

Annals of Neurology, EarlyView.

in Annals of Neurology on May 11, 2021 04:01 PM.

• #### Point‐of‐Care Noninvasive Assessments of Cerebrovascular Reactivity in Traumatic Brain Injury: Integrating the Physiome with Clinical Phenotype

Annals of Neurology, EarlyView.

in Annals of Neurology on May 11, 2021 03:59 PM.

• #### NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity: Insights through multilayer network analysis

by Marko Šterk, Lidija Križančić Bombek, Maša Skelin Klemen, Marjan Slak Rupnik, Marko Marhl, Andraž Stožer, Marko Gosak

NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems.

in PLoS Computational Biology on May 11, 2021 02:00 PM.

• #### The growth factor <i>BMP11</i> is required for the development and evolution of a male exaggerated weapon and its associated fighting behavior in a water strider

by William Toubiana, David Armisén, Séverine Viala, Amélie Decaras, Abderrahman Khila

Exaggerated sexually selected traits, often carried by males, are characterized by the evolution of hyperallometry, resulting in their disproportionate growth relative to the rest of the body among individuals of the same population. While the evolution of allometry has attracted much attention for centuries, our understanding of the developmental genetic mechanisms underlying its emergence remains fragmented. Here we conduct comparative transcriptomics of the legs followed by an RNA interference (RNAi) screen to identify genes that play a role in the hyperallometric growth of the third legs in the males of the water strider Microvelia longipes. We demonstrate that a broadly expressed growth factor, Bone Morphogenetic Protein 11 (BMP11, also known as Growth Differentiation Factor 11), regulates leg allometries through increasing the allometric slope and mean body size in males. In contrast, BMP11 RNAi reduced mean body size but did not affect slope either in the females of M. longipes or in the males and females of other closely related Microvelia species. Furthermore, our data show that a tissue-specific factor, Ultrabithorax (Ubx), increases intercept without affecting mean body size. This indicates a genetic correlation between mean body size and variation in allometric slope, but not intercept. Strikingly, males treated with BMP11 RNAi exhibited a severe reduction in fighting frequency compared to both controls and Ubx RNAi-treated males. Therefore, male body size, the exaggerated weapon, and the intense fighting behavior associated with it are genetically correlated in M. longipes. Our results support a possible role of pleiotropy in the evolution of allometric slope.

in PLoS Biology on May 11, 2021 02:00 PM.

• #### Neuropeptides as potential modulators of behavioral transitions in the ant Cataglyphis nodus

We highlighted the spatial distribution of the neuropeptides allatostatin‐A, corazonin, and tachykinin in the brain of Cataglyphis nodus desert ants. We further show behavioral‐stage‐related changes in allatostatin‐A and corazonin expression patterns. The results suggest that these neuropeptides are highly promising candidate modulators for major behavioral transitions of the ants. Abstract Age‐related behavioral plasticity is a major prerequisite for the ecological success of insect societies. Although ecological aspects of behavioral flexibility have been targeted in many studies, the underlying intrinsic mechanisms controlling the diverse changes in behavior along the individual life history of social insects are not completely understood. Recently, the neuropeptides allatostatin‐A, corazonin, and tachykinin have been associated with the regulation of behavioral transitions in social insects. Here, we investigated changes in brain localization and expression of these neuropeptides following major behavioral transitions in Cataglyphis nodus ants. Our immunohistochemical analyses in the brain revealed that the overall branching pattern of neurons immunoreactive (ir) for the three neuropeptides is largely independent of the behavioral stages. Numerous allatostatin‐A‐ and tachykinin‐ir neurons innervate primary sensory neuropils and high‐order integration centers of the brain. In contrast, the number of corazonergic neurons is restricted to only four neurons per brain hemisphere with cell bodies located in the pars lateralis and axons extending to the medial protocerebrum and the retrocerebral complex. Most interestingly, the cell‐body volumes of these neurons are significantly increased in foragers compared to freshly eclosed ants and interior workers. Quantification of mRNA expression levels revealed a stage‐related change in the expression of allatostatin‐A and corazonin mRNA in the brain. Given the presence of the neuropeptides in major control centers of the brain and the neurohemal organs, these mRNA‐changes strongly suggest an important modulatory role of both neuropeptides in the behavioral maturation of Cataglyphis ants.

in Journal of Comparative Neurology on May 11, 2021 09:49 AM.

• #### A moment for muons

Nature Physics, Published online: 11 May 2021; doi:10.1038/s41567-021-01251-x

The recent measurement of the muon’s anomalous magnetic moment increases the tension with predictions from theory. Or does it?

in Nature Physics on May 11, 2021 12:00 AM.

• #### Detect, don’t destroy

Nature Physics, Published online: 11 May 2021; doi:10.1038/s41567-021-01250-y

Detect, don’t destroy

in Nature Physics on May 11, 2021 12:00 AM.

• #### Don’t bet on it

Nature Physics, Published online: 11 May 2021; doi:10.1038/s41567-021-01248-6

Don’t bet on it

in Nature Physics on May 11, 2021 12:00 AM.

• #### A constant by any other name

Nature Physics, Published online: 11 May 2021; doi:10.1038/s41567-021-01242-y

As the namesake of a variety of constants, distributions and equations, Ludwig Boltzmann has earned his place in the physics hall of fame. But as Ankita Anirban reveals, he cannot take sole credit for the most famous constant bearing his name.

in Nature Physics on May 11, 2021 12:00 AM.

• #### A love letter to Black feminist physicists

Nature Physics, Published online: 11 May 2021; doi:10.1038/s41567-021-01241-z

A love letter to Black feminist physicists

in Nature Physics on May 11, 2021 12:00 AM.

• #### Author Correction: Hard X-ray transient grating spectroscopy on bismuth germanate

Nature Photonics, Published online: 11 May 2021; doi:10.1038/s41566-021-00826-7

Author Correction: Hard X-ray transient grating spectroscopy on bismuth germanate

in Nature Photomics on May 11, 2021 12:00 AM.

• #### Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure

In Alzheimer’s disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss.

in Frontiers in Synaptic Neuroscience on May 11, 2021 12:00 AM.

• #### Semaphorins in Adult Nervous System Plasticity and Disease

Semaphorins, originally discovered as guidance cues for developing axons, are involved in many processes that shape the nervous system during development, from neuronal proliferation and migration to neuritogenesis and synapse formation. Interestingly, the expression of many Semaphorins persists after development. For instance, Semaphorin 3A is a component of perineuronal nets, the extracellular matrix structures enwrapping certain types of neurons in the adult CNS, which contribute to the closure of the critical period for plasticity. Semaphorin 3G and 4C play a crucial role in the control of adult hippocampal connectivity and memory processes, and Semaphorin 5A and 7A regulate adult neurogenesis. This evidence points to a role of Semaphorins in the regulation of adult neuronal plasticity. In this review, we address the distribution of Semaphorins in the adult nervous system and we discuss their function in physiological and pathological processes.

in Frontiers in Synaptic Neuroscience on May 11, 2021 12:00 AM.

• #### Reciprocal Relationship Between Calcium Signaling and Circadian Clocks: Implications for Calcium Homeostasis, Clock Function, and Therapeutics

in Frontiers in Molecular Neuroscience on May 11, 2021 12:00 AM.

• #### Microglial Exosomes in Neurodegenerative Disease

Microglia play an important role in neurodegenerative disease [i.e., Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS)]. These diseases share some similar pathological changes and several microglia-associated processes, including immune response, neuroinflammation, phagocytosis, elimination of synapses et al. Microglia in the central nervous system (CNS) has been described as having both destructive and protective effects in neurological disorders. Besides, considerable evidence also indicates that microglia play a significant role in neurogenesis, neuronal cell death, and synaptic interactions. The communication between microglia and neurons is of vital role in regulating complex functions which are key to appropriate the activity of the brain. Accumulating studies have also demonstrated that exosomes with sizes ranging from 40–100 nm, released by microglia, could serve as key mediators in intercellular signaling. These exosomes, identified in terms of cellular origin in many kinds of biological fluids, exert their effects by delivering specific cargos such as proteins, microRNAs (miRNAs), and mRNAs. It was shown that microglial exosomes could transport to and be uptake by neurons, which may either be beneficial or instead, detrimental to CNS diseases. The focus of this review is to summarize the involvement of microglial exosomes in critical pathologies associated with neurodegenerative disease and how they contribute to these disorders, including PD, AD, and ALS. We also review the application of microglia exosomes as potential biomarkers in monitoring disease progression, as well as focusing on their roles as drug delivery vehicles in treating neurodegenerative disorders.

in Frontiers in Molecular Neuroscience on May 11, 2021 12:00 AM.

• #### A Novel Statistical Model for Predicting the Efficacy of Vagal Nerve Stimulation in Patients With Epilepsy (Pre-X-Stim) Is Applicable to Different EEG Systems

Background: Identifying patients with intractable epilepsy who would benefit from therapeutic chronic vagal nerve stimulation (VNS) preoperatively remains a major clinical challenge. We have developed a statistical model for predicting VNS efficacy using only routine preimplantation electroencephalogram (EEG) recorded with the TruScan EEG device (Brazdil et al., 2019). It remains to be seen, however, if this model can be applied in different clinical settings.

Objective: To validate our model using EEG data acquired with a different recording system.

Methods: We identified a validation cohort of eight patients implanted with VNS, whose preimplantation EEG was recorded on the BrainScope device and who underwent the EEG recording according to the protocol. The classifier developed in our earlier work, named Pre-X-Stim, was then employed to classify these patients as predicted responders or non-responders based on the dynamics in EEG power spectra. Predicted and real-world outcomes were compared to establish the applicability of this classifier. In total, two validation experiments were performed using two different validation approaches (single classifier or classifier voting).

Results: The classifier achieved 75% accuracy, 67% sensitivity, and 100% specificity. Only two patients, both real-life responders, were classified incorrectly in both validation experiments.

Conclusion: We have validated the Pre-X-Stim model on EEGs from a different recording system, which indicates its application under different technical conditions. Our approach, based on preoperative EEG, is easily applied and financially undemanding and presents great potential for real-world clinical use.

in Frontiers in Neuroscience: Neural Technology on May 11, 2021 12:00 AM.

• #### Tiered Neuroscience and Mental Health Professional Development in Liberia Improves Teacher Self-Efficacy, Self-Responsibility, and Motivation

After acquiring knowledge of the neuroscience of learning, memory, stress and emotions, teachers incorporate more cognitive engagement and student-centered practices into their lessons. However, the role understanding neuroscience plays in teachers own affective and motivational competencies has not yet been investigated. The goal of this study was to investigate how learning neuroscience effected teachers’ self-efficacy, beliefs in their ability to teach effectively, self-responsibility and other components of teacher motivation. A pilot training-of-trainers program was designed and delivered in Liberia combining basic neuroscience with information on social, emotional, behavioral and mental health issues faced by students. Tier I of the professional development was a 2 weeks workshop led by a visiting neuroscientist. A subset of the 24 Tier I secondary science teachers formed a Leadership Team who adapted the content to the Liberian context and subsequently led additional workshops and follow-up sessions for the Tier II secondary science teachers. Science teachers in both tiers completed the affective-motivational scales from the internationally vetted, multiscale Innovative Teaching for Effective Learning Teacher Knowledge Survey from the OECD. Tier II teachers completed the survey in a pre-post-delayed post design. Tier I teachers completed the survey after the workshop with their attitudes at that time and separately with retrospective projections of their pre-workshop attitudes. Ten of the 92 Tier II teachers participated in structured interviews at follow-up. Statistical analysis of survey data demonstrated improved teacher self-efficacy, self-responsibility for student outcomes, and motivation to teach. Qualitatively, teachers expressed more confidence in their ability to motivate students, engage them through active learning, and manage the class through positive rather than negative reinforcement. Teachers’ own self-regulation improved as they made efforts to build supporting relationships with students. Together, these results demonstrated that (i) teacher affective-motivational attitudes can be altered with professional development, (ii) basic neuroscience, as knowledge of how students learn, can improve teacher competency, and (iii) a training-of-trainers model can be effective in a low and middle income country for disseminating neuroscience knowledge, increasing teachers’ knowledge of students’ social and emotional needs, and promoting educational improvement.

in Frontiers in Human Neuroscience on May 11, 2021 12:00 AM.

• #### Values Evolution in Human Machine Relations: Grounding Computationalism and Neural Dynamics in a Physical a Priorism of Nature

in Frontiers in Human Neuroscience on May 11, 2021 12:00 AM.

• #### Colors and Handles: How Action Primes Perception

How deeply does action influence perception? Does action performance affect the perception of object features directly related to action only? Or does it concern also object features such as colors, which are not held to directly afford action? The present study aimed at answering these questions. We asked participants to repeatedly grasp a handled mug hidden from their view before judging whether a visually presented mug was blue rather than cyan. The motor training impacted on their perceptual judgments, by speeding participants’ responses, when the handle of the presented mug was spatially aligned with the trained hand. The priming effect did not occur when participants were trained to merely touch the mug with their hand closed in a fist. This indicates that action performance may shape the perceptual judgment on object features, even when these features are colors and do not afford any action. How we act on surrounding objects is therefore not without consequence for how we experience them.

in Frontiers in Human Neuroscience on May 11, 2021 12:00 AM.

• #### Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

in Frontiers in Ageing Neuroscience on May 11, 2021 12:00 AM.

• #### Application of Functional Magnetic Resonance Imaging in the Diagnosis of Parkinson’s Disease: A Histogram Analysis

This study aimed to investigate the value of amplitude of low-frequency fluctuation (ALFF)-based histogram analysis in the diagnosis of Parkinson’s disease (PD) and to investigate the regions of the most important discriminative features and their contribution to classification discrimination. Patients with PD (n = 59) and healthy controls (HCs; n = 41) were identified and divided into a primary set (80 cases, including 48 patients with PD and 32 HCs) and a validation set (20 cases, including 11 patients with PD and nine HCs). The Automated Anatomical Labeling (AAL) 116 atlas was used to extract the histogram features of the regions of interest in the brain. Machine learning methods were used in the primary set for data dimensionality reduction, feature selection, model construction, and model performance evaluation. The model performance was further validated in the validation set. After feature data dimension reduction and feature selection, 23 of a total of 1,276 features were entered in the model. The brain regions of the selected features included the frontal, temporal, parietal, occipital, and limbic lobes, as well as the cerebellum and the thalamus. In the primary set, the area under the curve (AUC) of the model was 0.974, the sensitivity was 93.8%, the specificity was 90.6%, and the accuracy was 93.8%. In the validation set, the AUC, sensitivity, specificity, and accuracy were 0.980, 90.9%, 88.9%, and 90.0%, respectively. ALFF-based histogram analysis can be used to classify patients with PD and HCs and to effectively identify abnormal brain function regions in PD patients.

in Frontiers in Ageing Neuroscience on May 11, 2021 12:00 AM.

• #### Time spent on the smartphone does not relate to manual dexterity in young adults

The Grooved Pegboard Test (GPT) is widely adopted to evaluate manual dexterity, it presents normative data but the test is influenced by different factors. The influence of time spent on smartphones has not be...

in BMC Neuroscience on May 11, 2021 12:00 AM.

• #### Cover Image, Volume 529, Issue 10

The cover image is based on the Research Article Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn by Stephanie I. Shiers., https://doi.org/10.1002/cne.25122.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### The Journal of Comparative Neurology, Table of Content, Vol. 529, No. 10, July 2021

Journal of Comparative Neurology, Volume 529, Issue 10, Page 2405-2406, July 1, 2021.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

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

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Cortical connections of the functional domain for climbing or running in posterior parietal cortex of galagos

A domain for combined forelimb and hindlimb movements in posterior parietal cortex (PPC) of galagos was identified. This domain had dense intrinsic connections within PPC and reciprocal connections with frontal and parietal sensorimotor areas of the ipsilateral cortex. It also had connections with the homotopic region of the contralateral cortex. Abstract Previous studies in prosimian galagos (Otolemur garnetti) have demonstrated that posterior parietal cortex (PPC) is subdivided into several functionally distinct domains, each of which mediates a specific type of complex movements (e.g., reaching, grasping, hand‐to‐mouth) and has a different pattern of cortical connections. Here we identified a medially located domain in PPC where combined forelimb and hindlimb movements, as if climbing or running, were evoked by long‐train intracortical microstimulation. We injected anatomical tracers in this climbing/running domain of PPC to reveal its cortical connections. Our results showed the PPC climbing domain had dense intrinsic connections within rostral PPC and reciprocal connections with forelimb and hindlimb region in primary motor cortex (M1) of the ipsilateral hemisphere. Fewer connections were with dorsal premotor cortex (PMd), supplementary motor (SMA), and cingulate motor (CMA) areas, as well as somatosensory cortex including areas 3a, 3b, and 1–2, secondary somatosensory (S2), parietal ventral (PV), and retroinsular (Ri) areas. The rostral portion of the climbing domain had more connections with primary somatosensory cortex than the caudal portion. Cortical projections were found in functionally matched domains in M1 and premotor cortex (PMC). Similar patterns of connections with fewer labeled neurons and terminals were seen in the contralateral hemisphere. These connection patterns are consistent with the proposed role of the climbing/running domain as part of a parietal‐frontal network for combined use of the limbs in locomotion as in climbing and running. The cortical connections identify this action‐specific domain in PPC as a more somatosensory driven domain.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Convergence of peptidergic and non‐peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn

Calcitonin gene‐related peptide (CGRP) and the purinergic receptor P2X3 (P2X3R) label relatively distinct populations of nociceptors in the rodent dorsal root ganglion (DRG). These two unique populations, known as the peptidergic and non‐peptidergic nociceptors, innervate different lamina of the rodent spinal dorsal horn. However, contrary to previous reports in rodent, we find that CGRP and P2X3R are highly co‐expressed in the human DRG and terminate in the same laminae (laminae 1–2) of the spinal dorsal horn. Additionally, we find that other markers such as TrpV1 and Nav1.7 are more widely expressed in human and innervate laminae 1–2 of the spinal dorsal horn. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that sensory neurons and their central projections are different between mice and humans. Abstract Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non‐peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long‐standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non‐peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co‐expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1, and Nav1.7 proteins stained the entirety of lamina 1–2, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Fractional anisotropy from diffusion tensor imaging correlates with acute astrocyte and myelin swelling in neonatal swine models of excitotoxic and hypoxic‐ischemic brain injury

In neonatal piglets with encephalopathy from excitotoxic brain injury, fractional anisotropy from diffusion tensor imaging correlates with swollen astrocytes immunophenotyped by glutamate transporter‐1 (GLT‐1) and normal neurons with perineuronal GLT‐1+ astrocyte decorations in the striatum. Abstract The specific cytopathology that causes abnormal fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) after neonatal hypoxia‐ischemia (HI) is not completely understood. The panoply of cell types in the brain might contribute differentially to changes in DTI metrics. Because glia are the predominant cell type in brain, we hypothesized that changes in FA and MD would signify perturbations in glial microstructure. Using a 3‐Tesla clinical scanner, we conducted in vivo DTI MRI in nine neonatal piglets at 20–96 h after excitotoxic brain injury from striatal quinolinic acid injection or global HI. FA and MD from putamen, caudate, and internal capsule in toto were correlated with astrocyte swelling, neuronal excitotoxicity, and white matter injury. Low FA correlated with more swollen astrocytes immunophenotyped by aquaporin‐4 (AQP4), glial fibrillary acidic protein (GFAP), and glutamate transporter‐1 (GLT‐1). Low FA was also related to the loss of neurons with perineuronal GLT‐1+ astrocyte decorations, large myelin swellings, lower myelin density, and oligodendrocyte cell death identified by 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase, bridging integrator‐1, and nuclear morphology. MD correlated with degenerating oligodendrocytes and depletion of normal GFAP+ astrocytes but not with astrocyte or myelin swelling. We conclude that FA is associated with cytotoxic edema in astrocytes and oligodendrocyte processes as well as myelin injury at the cellular level. MD can detect glial cell death and loss, but it may not discern subtle pathology in swollen astrocytes, oligodendrocytes, or myelin. This study provides a cytopathologic basis for interpreting DTI in the neonatal brain after HI.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Identification of retinal ganglion cell types expressing the transcription factor Satb2 in three primate species

Morphology of Satb2 expressing ganglion cells in macaque, human, and marmoset retinas. The study shows that Satb2 expression in retinal ganglion cells is not conserved across Old World and New World primate species. Abstract In primates, the retinal ganglion cells contributing to high acuity spatial vision (midget cells and parasol cells), and blue‐yellow color vision (small bistratified cells) are well understood. Many other ganglion cell types with large dendritic fields (named wide‐field ganglion cells) have been identified, but their spatial density and distribution are largely unknown. Here we took advantage of the recently established molecular diversity of ganglion cells to study wide‐field ganglion cell populations in three primate species. We used antibodies against the transcription factor Special AT‐rich binding protein 2 (Satb2) to explore its expression in macaque (Macaca fascicularis, M. nemestrina), human and marmoset (Callithrix jacchus) retinas. In all three species, Satb2 cells make up a low proportion (1.5–4%) of the ganglion cell population, with a slight increase from central to peripheral retina. Intracellular dye injections revealed that in macaque and human retinas, the large majority (over 80%) of Satb2 cells are inner and outer stratifying large sparse cells. By contrast, in marmoset retina the majority (over 60%) of Satb2 expressing cells were broad thorny cells, with smaller proportions of recursive bistratified (putative direction‐selective), large bistratified, and outer stratifying narrow thorny cells. Our findings imply that Satb2 expression has undergone rapid species specific adaptations during primate evolution, because expression is not conserved across Old World (macaque, human) and New World (marmoset) suborders.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Anatomical projections to the dorsal tegmental nucleus and abducens nucleus arise from separate cell populations in the nucleus prepositus hypoglossi, but overlapping cell populations in the medial vestibular nucleus

Retrograde tracers were utilized to examine projections to the dorsal tegmental nucleus (DTN), a critical component of the head direction cell circuitry, and the abducens nucleus, an oculomotor structure. We found that the medial vestibular nucleus contains individual neurons that project to both the DTN and abducens nucleus. In contrast, neurons in the nucleus prepositus hypoglossi project to either the DTN or abducens nucleus, but rarely to both structures simultaneously. Additionally, we describe interhemispheric connections between the left and right DTN, and projections from the supragenual nucleus, interpeduncular nucleus, and retrosplenial cortex to the DTN. Abstract Specialized circuitry in the brain processes spatial information to provide a sense of direction used for navigation. The dorsal tegmental nucleus (DTN) is a core component of this circuitry and utilizes vestibular inputs to generate neural activity encoding the animal's directional heading. Projections arising from the nucleus prepositus hypoglossi (NPH) and the medial vestibular nucleus (MVe) are thought to transmit critical vestibular signals to the DTN and other brain areas, including the abducens nucleus (ABN), a component of eye movement circuitry. Here, we utilized a dual retrograde tracer approach in rats to investigate whether overlapping or distinct populations of neurons project from the NPH or MVe to the DTN and ABN. We report that individual MVe neurons project to both the DTN and ABN. In contrast, we observed individual NPH neurons that project to either the DTN or ABN, but rarely to both structures simultaneously. We also examined labeling patterns in other structures located in the brainstem and posterior cortex and observed (1) complex patterns of interhemispheric connectivity between the left and right DTN, (2) projections from the supragenual nucleus, interpeduncular nucleus, and retrosplenial cortex to the DTN, (3) projections from the lateral superior olive to the ABN, and (4) a unique population of cerebrospinal fluid‐contacting neurons in the dorsal raphe nucleus. Collectively, our experiments provide valuable new information that extends our understanding of the anatomical organization of the brain's spatial processing circuitry.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Astrocytes in rare neurological conditions: Morphological and functional considerations

Astrocytes are essential cells of the CNS with several functions relating to neuronal and overall homeostasis. As a result, astrocytic dysfunction can cause widespread detrimental effects. There still exist numerous rare neurological conditions in which astrocytic involvement is only beginning to be explored. Accordingly, we will detail the role of astrocytes in over 40+ rare neurological conditions through the lens of function and morphology and highlight remaining neuropathologies where astrocytic involvement has yet to be investigated. Abstract Astrocytes are a population of central nervous system (CNS) cells with distinctive morphological and functional characteristics that differ within specific areas of the brain and are widely distributed throughout the CNS. There are mainly two types of astrocytes, protoplasmic and fibrous, which differ in morphologic appearance and location. Astrocytes are important cells of the CNS that not only provide structural support, but also modulate synaptic activity, regulate neuroinflammatory responses, maintain the blood–brain barrier, and supply energy to neurons. As a result, astrocytic disruption can lead to widespread detrimental effects and can contribute to the pathophysiology of several neurological conditions. The characteristics of astrocytes in more common neuropathologies such as Alzheimer's and Parkinson's disease have significantly been described and continue to be widely studied. However, there still exist numerous rare neurological conditions in which astrocytic involvement is unknown and needs to be explored. Accordingly, this review will summarize functional and morphological changes of astrocytes in various rare neurological conditions based on current knowledge thus far and highlight remaining neuropathologies where astrocytic involvement has yet to be investigated.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Morpho‐physiological properties and connectivity of vasoactive intestinal polypeptide‐expressing interneurons in the mouse hippocampal dentate gyrus

Wei et al. characterized morpho‐physiological properties and connectivity of VIP+ interneurons in the mouse dentate gyrus. VIP+ interneurons comprise four morphologically distinct subtypes with variable physiological properties and preferentially innervate GABAergic interneurons over glutamatergic principal cells. Abstract The hippocampus is a key brain structure for cognitive and emotional functions. Among the hippocampal subregions, the dentate gyrus (DG) is the first station that receives multimodal sensory information from the cortex. Local‐circuit inhibitory GABAergic interneurons (INs) regulate the excitation–inhibition balance in the DG principal neurons (PNs) and therefore are critical for information processing. Similar to PNs, GABAergic INs also receive distinct inhibitory inputs. Among various classes of INs, vasoactive intestinal polypeptide‐expressing (VIP+) INs preferentially target other INs in several brain regions and thereby directly modulate the GABAergic system. However, the morpho‐physiological characteristics and postsynaptic targets of VIP+ INs in the DG are poorly understood. Here, we report that VIP+ INs in the mouse DG are highly heterogeneous based on their morpho‐physiological characteristics. In approximately two‐thirds of morphologically reconstructed cells, their axons ramify in the hilus. The remaining cells project their axons exclusively to the molecular layer (15%), to both the molecular layer and hilus (10%), or throughout the entire DG layers (8%). Generally, VIP+ INs display variable intrinsic properties and discharge patterns without clear correlation with their morphologies. Finally, VIP+ INs are recruited with a long latency in response to theta‐band cortical inputs and preferentially innervate GABAergic INs over glutamatergic PNs. In summary, VIP+ INs in the DG are composed of highly diverse subpopulations and control the DG output via disinhibition.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Chronic stress differentially alters mRNA expression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

US females compared to US males had: (1) more PENK‐expressing granule cells; (2) fewer OPRD1 expressing granule cells; and (3) more OPRM1‐expressing interneurons in CA3b. CIS females compared to CIS males had less: (1) PDYN expression in granule cells; (2) OPRD1 expression in interneurons in CA3b; (3) OPRM1 probe expression in CA2/3a and granule cell expression; and (4) OPRK1 expression in interneurons in CA2/3a and the hilus of the dentate gyrus. US females compared to US males had: (1) more PENK‐expressing granule cells; (2) fewer OPRD1 expressing granule cells; and (3) more OPRM1‐expressing interneurons in CA3b. CIS females compared to CIS males had less: (1) PDYN expression in granule cells; (2) OPRD1 expression in interneurons in CA3b; (3) OPRM1 probe expression in CA2/3a and granule cell expression; and (4) OPRK1 expression in interneurons in CA2/3a and the hilus of the dentate gyrus. Abstract Chronic immobilization stress (CIS) results in sex‐dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus, which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (∼2.5 months old ) Sprague Dawley rats. In all groups, dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1‐was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK‐expressing and fewer OPRD1‐expressing granule cells and more OPRM1‐expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: (1) PENK‐expressing dentate granule cells and interneurons in CA1 and CA2/3a; (2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the dentate gyrus; and (3) OPRK1‐expressing interneurons in the dentate hilus. Also, CIS males compared to US males had elevated: (1) PDYN expression in granule cells; (2) OPRD1 probe and interneuron expression in CA2/3a; (3) OPRM1 in granule cells; and (4) OPRK1 interneuron expression in CA2/3a. The sex‐specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Functional alterations of retinal neurons and vascular involvement progress simultaneously in the Psammomys obesus model of diabetic retinopathy

The diabetic retinopathy in the diurnal rodent Psammomys obesus is manifested by a functional and structural dysfunction. The functional alteration detected by the decrease in the amplitude of the ERG components over time following the diabetic induction. Whereas the structural dysfunction is evinced by the disruption of retinal architecture and the appearance of exudates at an advanced stage of the disease progression as well as the decrease of the retinal thinness. Abstract To investigate the progression of diabetic retinopathy (DR) in a new diurnal animal model, we monitored clinically the DR in Psammomys obesus (P. obesus) during 7 months using electroretinography (ERG) and imaging techniques. After the onset of DR, all ERG components decreased progressively. In scotopic conditions, by 3‐months of disease progression, the diabetic P. obesus displayed a significant decrease in amplitude of b‐max, b‐wave responses, and mixed b‐waves. While mixed a‐wave decreased between 4 and 7 months. Significant differences of OP2 appeared following 1 month of disease. In photopic conditions, we noticed a decrease in the a‐wave at 2 months, while it took more than 5 months in b‐wave amplitude. The photopic negative response (PhNR) and the i‐wave amplitudes decreased following 4 and 5 months. OP1 and OP2 were the first to be altered and a significant decrease in the amplitude started after 3 months. Finally, 30 Hz‐flicker and photopic S‐cone were impaired after 2 and 3 months, respectively. The assessment of the eye fundus of the retina revealed an abnormal vascular architecture appeared at Months 6 and 7. In addition, we noticed exudates in the superior periphery of the retina at the same stage. The retina thickness showed a significant reduction at Month 7. Our results indicate that the clinical correlates of human DR are present in diabetic P. obesus. The depressed of ERGs, disruption of retinal architecture, and the appearance of exudates may reflect vascular and neuronal damage throughout the retina as are seen in the advanced stages of human DR.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Expression patterns and evolution of urocortin and corticotropin‐releasing hormone genes in a cichlid fish

Expression patterns of all CRH/UCN family genes have not been thoroughly described in any fish species. In a highly social cichlid fish, Astatotilapia burtoni, we used in situ hybridization to map mRNA expression patterns of crhb, uts1, ucn2, and ucn3. Phylogenetic analyses revealed evolutionary relationships and novel urocortin orthologs. Abstract The corticotropin‐releasing hormone and urocortin family of peptides consists of five members in many vertebrates: CRH (crha/crhb in teleosts), CRH2, UCN/UTS1, UCN2, and UCN3. These genes differ in expression pattern, as well as receptor affinity, allowing them to serve a wide range of functions in a variety of species. To better understand the roles of these genes in a single species, we examined their expression patterns in the cichlid fish Astatotilapia burtoni. In situ hybridization to map mRNA expression patterns of crhb, uts1, ucn2, and ucn3 in the brain revealed conserved and distinct spatial features of expression. crhb‐ and uts1‐expressing cells were the most broadly distributed, with several areas of co‐regionalization. ucn3 was less abundant but was found in discrete regions throughout the extent of the brain, with high expression in the cerebellum, while ucn2 was restricted to only a few areas. RT‐PCR showed that while crhb, uts1, and ucn3 are found in several body tissues and widespread throughout the brain, ucn2 is quite restricted in the brain, and crha is only expressed in the eye. Bayesian phylogenetic analyses identified detailed relationships and novel orthologs in the urocortin family. We found evidence for a UCN2 gene loss in some reptiles. Our detailed description of the complete family of genes in the central nervous system of a model organism will inform future studies on the function of these genes in A. burtoni and provides a foundation for comparative studies with teleosts and other vertebrates.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### A histological study of the song system of the carrion crow (Corvus corone)

The song system of songbirds (oscines) is one of the best explored neuroethological model systems. The study presents a histological investigation of the nuclei of the extended song system of the carrion crow (Corvus corone), a songbird of the corvid family that has become an interesting model system for cognitive neuroscience. Abstract The song system of songbirds (oscines) is one of the best studied neuroethological model systems. So far, it has been treated as a relatively constrained sensorimotor system. Songbirds such as crows, however, are also known for their capability to cognitively control their audio‐vocal system. Yet, the neuroanatomy of the corvid song system has never been explored systematically. We aim to close this scientific gap by presenting a stereotactic investigation of the extended song system of the carrion crow (Corvus corone), an oscine songbird of the corvid family that has become an interesting model system for cognitive neuroscience. In order to identify and delineate the song nuclei, the ascending auditory nuclei, and the descending vocal‐motor nuclei, four stains were applied. In addition to the classical Nissl‐, myelin‐, and a combination of Nissl‐and‐myelin staining, staining for tyrosine hydroxylase was used to reveal the distribution of catecholaminergic neurons (dopaminergic, noradrenergic, and adrenergic) in the song system. We show that the crow brain contains the important song‐related nuclei, including auditory input and motor output structures, and map them throughout the brain. Fiber‐stained sections reveal putative connection patterns between the crow's song nuclei comparable to other songbirds.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Immunocytochemical and ultrastructural organization of the taste thalamus of the tree shrew (Tupaia belangeri)

The synaptic circuitry of primary sensory thalamic nuclei has been well characterized and shows striking similarities both in terminal morphology and chemical characteristics. The exception to this is the taste thalamus, the VPMP. A past study of synaptic circuitry in the rat taste thalamus (VPMpc) revealed marked differences from other nuclei like the LGN and MGN. Our data demonstrate that the tree shrew VPMP shares synaptic characteristics common to primary sensory thalamic nuclei including presynaptic interneuron dendrites, large VGluT2 positive terminals, and triadic arrangements in glomeruli. Abstract Ventroposterior medialis parvocellularis (VPMP) nucleus of the primate thalamus receives direct input from the nucleus of the solitary tract, whereas the homologous thalamic structure in the rodent does not. To reveal whether the synaptic circuitries in these nuclei lend evidence for conservation of design principles in the taste thalamus across species or across sensory thalamus in general, we characterized the ultrastructural and molecular properties of the VPMP in a close relative of primates, the tree shrew (Tupaia belangeri), and compared these to known properties of the taste thalamus in rodent, and the visual thalamus in mammals. Electron microscopy analysis to categorize the synaptic inputs in the VPMP revealed that the largest‐size terminals contained many vesicles and formed large synaptic zones with thick postsynaptic density on multiple, medium‐caliber dendrite segments. Some formed triads within glomerular arrangements. Smaller‐sized terminals contained dark mitochondria; most formed a single asymmetric or symmetric synapse on small‐diameter dendrites. Immuno‐EM experiments revealed that the large‐size terminals contained VGLUT2, whereas the small‐size terminal populations contained VGLUT1 or ChAT. These findings provide evidence that the morphological and molecular characteristics of synaptic circuitry in the tree shrew VPMP are similar to that in nonchemical sensory thalamic nuclei. Furthermore, the results indicate that all primary sensory nuclei of the thalamus in higher mammals share a structural template for processing thalamocortical sensory information. In contrast, substantial morphological and molecular differences in rodent versus tree shrew taste nuclei suggest a fundamental divergence in cellular processing mechanisms of taste input in these two species.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Conservation and dimorphism in androgen receptor distribution in Alston's singing mouse (Scotinomys teguina)

We used immunohistochemistry to qualitatively and quantitatively characterize the nuclear androgen receptor (AR) in the brain of the Alston's singing mouse (Scotinomys teguina). Abstract Because of their roles in courtship and intrasexual competition, sexual displays are often sexually dimorphic, but we know little about the mechanisms that produce such dimorphism. Among mammals, one example is the vocalization of Alston's singing mouse (Scotinomys teguina), which consists of a series of rapidly repeated, frequency‐modulated notes. The rate and duration of songs is sexually dimorphic and androgen responsive. To understand the neuronal mechanisms underlying this sexual dimorphism, we map the sites of androgen sensitivity throughout the brain, focusing analysis along a pathway that spans from limbic structures to vocal motor regions. We find widespread expression of AR immunoreactivity (AR‐ir) throughout limbic structures important for social behavior and vocalization, including the lateral septum, extended amygdala, preoptic area and hypothalamus. We also find extensive AR staining along previously documented vocal motor pathways, including the periaqueductal gray, parabrachial nucleus, and nucleus ambiguus, the last of which innervates intrinsic laryngeal muscles. Lastly, AR‐ir is also evident in sensory areas such as the medial geniculate, inferior, and superior colliculi. A quantitative analysis revealed that males exhibited more AR‐ir than females, a pattern that was most pronounced in the hypothalamus. Despite the elaboration of vocalization in singing mice, comparison with prior literature suggests that the broad pattern of AR‐ir may be conserved across a wide range of rodents. Together these data identify brain nuclei well positioned to shape the sexually dimorphic vocalization of S. teguina and suggest that such androgen modulation of vocalization is evolutionary conserved among rodents.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Axon guidance at the spinal cord midline—A live imaging perspective

We describe a novel method to culture the intact spinal cord of the chicken embryo for live imaging of axon guidance at the midline. The stability of this ex vivo method allowed us to characterize key aspects of midline crossing, such as axonal growth, timing of crossing, dynamic morphological changes of the growth cones, and growth cone‐floor plate cell interactions. Abstract During neural circuit formation, axons navigate several choice points to reach their final target. At each one of these intermediate targets, growth cones need to switch responsiveness from attraction to repulsion in order to move on. Molecular mechanisms that allow for the precise timing of surface expression of a new set of receptors that support the switch in responsiveness are difficult to study in vivo. Mostly, mechanisms are inferred from the observation of snapshots of many different growth cones analyzed in different preparations of tissue harvested at distinct time points. However, to really understand the behavior of growth cones at choice points, a single growth cone should be followed arriving at and leaving the intermediate target. Existing ex vivo preparations, like cultures of an “open‐book” preparation of the spinal cord have been successfully used to study floor plate entry and exit, but artifacts prevent the analysis of growth cone behavior at the floor plate exit site. Here, we describe a novel spinal cord preparation that allows for live imaging of individual axons during navigation in their intact environment. When comparing growth cone behavior in our ex vivo system with snapshots from in vivo navigation, we do not see any differences. The possibility to observe the dynamics of single growth cones navigating their intermediate target allows for measuring growth speed, changes in morphology, or aberrant behavior, like stalling and wrong turning. Moreover, observation of the intermediate target—the floor plate—revealed its active participation and interaction with commissural axons during midline crossing.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### The Opsin 3/Teleost multiple tissue opsin system: mRNA localization in the retina and brain of medaka (Oryzias latipes)

Opsin 3 (Opn3)/Teleost multiple tissue (Tmt) opsins are putative blue‐light‐sensitive photoreceptor protein found in animals. The distributions of mRNA of opn3/tmt‐opsins in the retina and brain of medaka were investigated by in situ hybridization. These opsins are differentially expressed in the multiple retinal and brain regions. Abstract The photoreceptor protein, opsin, is one of the major components for vision and photoreceptive function in animals. Although many opsins have been discovered from animal genomes, only a few nonimage‐forming functions mediated by opsins have been identified. Understanding the mRNA distribution of photoreceptor proteins is one crucial step in uncovering their photoreceptive function in animals. Here, we focus on the medaka fish (Oryzias latipes) Opsin 3 (Opn3)/Teleost multiple opsin (Tmt) system, which constitutes a separate phylogenetic group, having putative blue light photoreceptors for nonimage‐forming functions. In medaka, there is one opn3 and five tmt‐opsin orthologs. The expression pattern of the opn3/tmt‐opsins in the retina and brain was investigated by in situ hybridization. mRNAs for opn3/tmt‐opsins were distributed in the retinal ganglion cells as well as interneurons and specific brain nuclei. Specifically, hybridization signals were observed in the glutamate decarboxylase 1 (gad1)‐expressing amacrine cells for opn3, tmt1a, tmt1b, and tmt2, in the caudal lobe of the cerebellum for tmt1b and tmt2, in the cranial nerve nuclei for opn3, tmt1a, tmt1b, tmt2, and in the rostral pars distalis (adenohypophysis) for opn3. These expression patterns suggest that blue light sensing in the fish retina and brain may be involved in the integration of visual inputs, vestibular function, somatosensation, motor outputs, and pituitary endocrine regulation.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Astrocyte regional heterogeneity revealed through machine learning‐based glial neuroanatomical assays

Traditional image analysis techniques fail to determine the morphological changes astrocytes undergo following inflammation. Developing an automated segmentation workflow allowed us to extract morphological data of GFAP or ALDH1L1 positive objects. Using principal component analysis and random forests, we were able to determine the features most important for identifying whether an astrocyte was baseline or reactive. To further determine the changes, different segmented cellular astrocyte components underwent (i.e., the body or process), we performed k‐means clustering. Multiple, well‐validated machine learning approaches allowed us to determine astrocytes undergo a region‐specific heterogenous morphological change following inflammation by lipopolysaccharide (LPS). Abstract Evaluation of reactive astrogliosis by neuroanatomical assays represents a common experimental outcome for neuroanatomists. The literature demonstrates several conflicting results as to the accuracy of such measures. We posited that the diverging results within the neuroanatomy literature were due to suboptimal analytical workflows in addition to astrocyte regional heterogeneity. We therefore generated an automated segmentation workflow to extract features of glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase family 1, member L1 (ALDH1L1) labeled astrocytes with and without neuroinflammation. We achieved this by capturing multiplexed immunofluorescent confocal images of mouse brains treated with either vehicle or lipopolysaccharide (LPS) followed by implementation of our workflows. Using classical image analysis techniques focused on pixel intensity only, we were unable to identify differences between vehicle‐treated and LPS‐treated animals. However, when utilizing machine learning–based algorithms, we were able to (1) accurately predict which objects were derived from GFAP or ALDH1L1‐stained images indicating that GFAP and ALDH1L1 highlight distinct morphological aspects of astrocytes, (2) we could predict which neuroanatomical region the segmented GFAP or ALDH1L1 object had been derived from, indicating that morphological features of astrocytes change as a function of neuroanatomical location. (3) We discovered a statistically significant, albeit not highly accurate, prediction of which objects had come from LPS versus vehicle‐treated animals, indicating that although features exist capable of distinguishing LPS‐treated versus vehicle‐treated GFAP and ALDH1L1‐segmented objects, that significant overlap between morphologies exists. We further determined that for most classification scenarios, nonlinear models were required for improved treatment class designations. We propose that unbiased automated image analysis techniques coupled with well‐validated machine learning tools represent highly useful models capable of providing insights into neuroanatomical assays.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Neuronal localization of m1 muscarinic receptor immunoreactivity in the monkey basolateral amygdala

Using antibodies to calcium/calmodulin‐dependent protein kinase II (CaMK) as a marker for pyramidal neurons (PNs) in the monkey basolateral amygdala (BNC) it was shown that virtually all PNs in the BNC express type 1 muscarinic receptors (m1Rs). Additional studies indicated that one‐third of inhibitory interneurons (INs) expressing glutamic acid decarboxylase (GAD), and 60% of parvalbumin immunoreactive INs (PV) were also m1R+. These results indicate that expression of m1Rs in BNC INs is greater in the monkey versus the rat. Abstract The basolateral nuclear complex (BNC) of the amygdala plays an important role in the generation of emotional/motivational behavior and the consolidation of emotional memories. Activation of M1 cholinergic receptors (M1Rs) in the BNC is critical for memory consolidation. Previous receptor binding studies in the monkey amygdala demonstrated that the BNC has a high density of M1Rs, but did not have sufficient resolution to identify which neurons in the BNC expressed them. This was accomplished in the present immunohistochemical investigation using an antibody for the m1 receptor (m1R). Analysis of m1Rs in the monkey BNC using immunoperoxidase techniques revealed that their expression was very dense in the BNC, and suggested that virtually all of the pyramidal projection neurons (PNs) in all of the BNC nuclei were m1R‐immunoreactive (m1R+). This was confirmed with dual‐labeling immunofluorescence using staining for calcium/calmodulin‐dependent protein kinase II (CaMK) as a marker for BNC PNs. However, additional dual‐labeling studies indicated that one‐third of inhibitory interneurons (INs) expressing glutamic acid decarboxylase (GAD) were also m1R+. Moreover, the finding that 60% of parvalbumin (PV) immunoreactive neurons were m1R+ indicated that this IN subpopulation was the main GAD+ subpopulation exhibiting m1R expression. The cholinergic innervation of the amygdala is greatly reduced in Alzheimer's disease and there is currently considerable interest in developing selective M1R positive allosteric modulators (PAMs) to treat the symptoms. The results of the present study indicate that M1Rs in both PNs and INs in the primate BNC would be targeted by M1R PAMs.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### A novel telencephalon‐opto‐hypothalamic morphogenetic domain coexpressing Foxg1 and Otp produces most of the glutamatergic neurons of the medial extended amygdala

This study shows that most glutamatergic neurons of the mouse medial extended amygdala originate in a novel telencephalon‐opto‐hypothalamic embryonic domain (TOH), which produces Otp‐lineage neurons expressing the telencephalic marker Foxg1 during development. These glutamatergic cells include a subpopulation of projection neurons, which activation has been previously shown to promote autistic‐like behavior. Our data open new venues for studying the implication of these neurons in neurodevelopmental disorders producing social deficits. Abstract Deficits in social cognition and behavior are a hallmark of many psychiatric disorders. The medial extended amygdala, including the medial amygdala and the medial bed nucleus of the stria terminalis, is a key component of functional networks involved in sociality. However, this nuclear complex is highly heterogeneous and contains numerous GABAergic and glutamatergic neuron subpopulations. Deciphering the connections of different neurons is essential in order to understand how this structure regulates different aspects of sociality, and it is necessary to evaluate their differential implication in distinct mental disorders. Developmental studies in different vertebrates are offering new venues to understand neuronal diversity of the medial extended amygdala and are helping to establish a relation between the embryonic origin and molecular signature of distinct neurons with the functional subcircuits in which they are engaged. These studies have provided many details on the distinct GABAergic neurons of the medial extended amygdala, but information on the glutamatergic neurons is still scarce. Using an Otp‐eGFP transgenic mouse and multiple fluorescent labeling, we show that most glutamatergic neurons of the medial extended amygdala originate in a distinct telencephalon‐opto‐hypothalamic embryonic domain (TOH), located at the transition between telencephalon and hypothalamus, which produces Otp‐lineage neurons expressing the telencephalic marker Foxg1 but not Nkx2.1 during development. These glutamatergic cells include a subpopulation of projection neurons of the medial amygdala, which activation has been previously shown to promote autistic‐like behavior. Our data open new venues for studying the implication of this neuron subtype in neurodevelopmental disorders producing social deficits.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Gamma‐protocadherin localization at the synapse is associated with parameters of synaptic maturation

Serial section immuno‐electron microscopy of gamma protocadherins (Pcdh‐γs), a subset of clustered protocadherins, at synapses in CA1. We characterized synaptic diameter and perforation status for synapses labeled with antibodies to Pcdh‐γs and found that they were larger with more frequent perforations. Results were confirmed by light level imaging of immunolabeled synapses. The results suggest that clustered protocadherins may mediate a late event in synaptic development. Bar = 500 nm. Abstract Clustered protocadherins (Pcdhs) are a family of ~60 cadherin‐like proteins (divided into subclasses α, β, and γ) that regulate dendrite morphology and neural connectivity. Their expression is controlled through epigenetic regulation at a gene cluster encoding the molecules. During neural development, Pcdhs mediate dendrite self‐avoidance in some neuronal types through an uncharacterized anti‐adhesive mechanism. Pcdhs are also important for dendritic complexity in cortical neurons likely through a pro‐adhesive mechanism. Pcdhs have also been postulated to participate in synaptogenesis and connectivity. Some synaptic defects were noted in knockout animals, including synaptic number and physiology, but the role of these molecules in synaptic development is not understood. The effect of Pcdh knockout on dendritic patterning may present a confound to studying synaptogenesis. We showed previously that Pcdh‐γs are highly enriched in intracellular compartments in dendrites and spines with localization at only a few synaptic clefts. To gain insight into how Pcdh‐γs might affect synapses, we compared synapses that harbored Pcdh‐γs versus those that did not for parameters of synaptic maturation including pre‐ and postsynaptic size, postsynaptic perforations, and spine morphology by light microscopy in cultured hippocampal neurons and by serial section immuno‐electron microscopy in hippocampal CA1. In mature neurons, synapses immunopositive for Pcdh‐γs were larger in diameter with more frequent perforations. Analysis of spines in cultured neurons revealed that mushroom spines were more frequently immunopositive for Pcdh‐γs at their tips than thin spines. These results suggest that Pcdh‐γ function at the synapse may be related to promotion of synaptic maturation and stabilization.

in Journal of Comparative Neurology on May 10, 2021 07:03 PM.

• #### Finding functions of phase separation in the presynapse

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Nathan A. McDonald, Kang Shen

in Current Opinion in Neurobiology on May 10, 2021 06:00 PM.

• #### Predicting mean ribosome load for 5’UTR of any length using deep learning

by Alexander Karollus, Žiga Avsec, Julien Gagneur

The 5’ untranslated region plays a key role in regulating mRNA translation and consequently protein abundance. Therefore, accurate modeling of 5’UTR regulatory sequences shall provide insights into translational control mechanisms and help interpret genetic variants. Recently, a model was trained on a massively parallel reporter assay to predict mean ribosome load (MRL)—a proxy for translation rate—directly from 5’UTR sequence with a high degree of accuracy. However, this model is restricted to sequence lengths investigated in the reporter assay and therefore cannot be applied to the majority of human sequences without a substantial loss of information. Here, we introduced frame pooling, a novel neural network operation that enabled the development of an MRL prediction model for 5’UTRs of any length. Our model shows state-of-the-art performance on fixed length randomized sequences, while offering better generalization performance on longer sequences and on a variety of translation-related genome-wide datasets. Variant interpretation is demonstrated on a 5’UTR variant of the gene HBB associated with beta-thalassemia. Frame pooling could find applications in other bioinformatics predictive tasks. Moreover, our model, released open source, could help pinpoint pathogenic genetic variants.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### Active head rolls enhance sonar-based auditory localization performance

by Lakshitha P. Wijesinghe, Melville J. Wohlgemuth, Richard H. Y. So, Jochen Triesch, Cynthia F. Moss, Bertram E. Shi

Animals utilize a variety of active sensing mechanisms to perceive the world around them. Echolocating bats are an excellent model for the study of active auditory localization. The big brown bat (Eptesicus fuscus), for instance, employs active head roll movements during sonar prey tracking. The function of head rolls in sound source localization is not well understood. Here, we propose an echolocation model with multi-axis head rotation to investigate the effect of active head roll movements on sound localization performance. The model autonomously learns to align the bat’s head direction towards the target. We show that a model with active head roll movements better localizes targets than a model without head rolls. Furthermore, we demonstrate that active head rolls also reduce the time required for localization in elevation. Finally, our model offers key insights to sound localization cues used by echolocating bats employing active head movements during echolocation.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression

by Felipe Dalvi-Garcia, Luis L. Fonseca, Ana Tereza R. Vasoncelos, Cecilia Hedin-Pereira, Eberhard O. Voit

A major factor contributing to the etiology of depression is a neurochemical imbalance of the dopaminergic and serotonergic systems, which is caused by persistently high levels of circulating stress hormones. Here, a computational model is proposed to investigate the interplay between dopaminergic and serotonergic-kynurenine metabolism under cortisolemia and its consequences for the onset of depression. The model was formulated as a set of nonlinear ordinary differential equations represented with power-law functions. Parameter values were obtained from experimental data reported in the literature, biological databases, and other general information, and subsequently fine-tuned through optimization. Model simulations predict that changes in the kynurenine pathway, caused by elevated levels of cortisol, can increase the risk of neurotoxicity and lead to increased levels of 3,4-dihydroxyphenylaceltahyde (DOPAL) and 5-hydroxyindoleacetaldehyde (5-HIAL). These aldehydes contribute to alpha-synuclein aggregation and may cause mitochondrial fragmentation. Further model analysis demonstrated that the inhibition of both serotonin transport and kynurenine-3-monooxygenase decreased the levels of DOPAL and 5-HIAL and the neurotoxic risk often associated with depression. The mathematical model was also able to predict a novel role of the dopamine and serotonin metabolites DOPAL and 5-HIAL in the ethiology of depression, which is facilitated through increased cortisol levels. Finally, the model analysis suggests treatment with a combination of inhibitors of serotonin transport and kynurenine-3-monooxygenase as a potentially effective pharmacological strategy to revert the slow-down in monoamine neurotransmission that is often triggered by inflammation.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### Computational phenotyping of brain-behavior dynamics underlying approach-avoidance conflict in major depressive disorder

by Mads L. Pedersen, Maria Ironside, Ken-ichi Amemori, Callie L. McGrath, Min S. Kang, Ann M. Graybiel, Diego A. Pizzagalli, Michael J. Frank

Adaptive behavior requires balancing approach and avoidance based on the rewarding and aversive consequences of actions. Imbalances in this evaluation are thought to characterize mood disorders such as major depressive disorder (MDD). We present a novel application of the drift diffusion model (DDM) suited to quantify how offers of reward and aversiveness, and neural correlates thereof, are dynamically integrated to form decisions, and how such processes are altered in MDD. Hierarchical parameter estimation from the DDM demonstrated that the MDD group differed in three distinct reward-related parameters driving approach-based decision making. First, MDD was associated with reduced reward sensitivity, measured as the impact of offered reward on evidence accumulation. Notably, this effect was replicated in a follow-up study. Second, the MDD group showed lower starting point bias towards approaching offers. Third, this starting point was influenced in opposite directions by Pavlovian effects and by nucleus accumbens activity across the groups: greater accumbens activity was related to approach bias in controls but avoid bias in MDD. Cross-validation revealed that the combination of these computational biomarkers were diagnostic of patient status, with accumbens influences being particularly diagnostic. Finally, within the MDD group, reward sensitivity and nucleus accumbens parameters were differentially related to symptoms of perceived stress and depression. Collectively, these findings establish the promise of computational psychiatry approaches to dissecting approach-avoidance decision dynamics relevant for affective disorders.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### Agent-based model provides insight into the mechanisms behind failed regeneration following volumetric muscle loss injury

by Amanda M. Westman, Shayn M. Peirce, George J. Christ, Silvia S. Blemker

Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation

by Christopher J. Arthurs, Rostislav Khlebnikov, Alex Melville, Marija Marčan, Alberto Gomez, Desmond Dillon-Murphy, Federica Cuomo, Miguel Silva Vieira, Jonas Schollenberger, Sabrina R. Lynch, Christopher Tossas-Betancourt, Kritika Iyer, Sara Hopper, Elizabeth Livingston, Pouya Youssefi, Alia Noorani, Sabrina Ben Ahmed, Foeke J. H. Nauta, Theodorus M. J. van Bakel, Yunus Ahmed, Petrus A. J. van Bakel, Jonathan Mynard, Paolo Di Achille, Hamid Gharahi, Kevin D. Lau, Vasilina Filonova, Miquel Aguirre, Nitesh Nama, Nan Xiao, Seungik Baek, Krishna Garikipati, Onkar Sahni, David Nordsletten, C. Alberto Figueroa

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization.

in PLoS Computational Biology on May 10, 2021 02:00 PM.

• #### How hype and hyperbole distort the neuroscience of sex differences

by Gina Rippon, Lise Eliot, Sarah Genon, Daphna Joel

Sex/gender differences in the human brain attract attention far beyond the neuroscience community. Given the interest of nonspecialists, it is important that researchers studying human female–male brain difference assume greater responsibility for the accurate communication of their findings. Mind your language! This Perspective article points out that the source of misreporting in the field of sex/gender differences can often be found in the unjustified overstatements used by researchers themselves in reporting their findings; caution is needed when addressing differences between human beings, and hype and hyperbole should be avoided.

in PLoS Biology on May 10, 2021 02:00 PM.

• #### Expression of Concern: The Communication Factor EDF and the Toxin–Antitoxin Module <i>mazEF</i> Determine the Mode of Action of Antibiotics

by The PLOS Biology Editors

in PLoS Biology on May 10, 2021 02:00 PM.

• #### Sensitivity to expression levels underlies differential dominance of a putative null allele of the <i>Drosophila t</i>ß<i>h</i> gene in behavioral phenotypes

by Christine Damrau, Julien Colomb, Björn Brembs

The biogenic amine octopamine (OA) and its precursor tyramine (TA) are involved in controlling a plethora of different physiological and behavioral processes. The tyramine-ß-hydroxylase (tßh) gene encodes the enzyme catalyzing the last synthesis step from TA to OA. Here, we report differential dominance (from recessive to overdominant) of the putative null tßhnM18 allele in 2 behavioral measures in Buridan’s paradigm (walking speed and stripe deviation) and in proboscis extension (sugar sensitivity) in the fruit fly Drosophila melanogaster. The behavioral analysis of transgenic tßh expression experiments in mutant and wild-type flies as well as of OA and TA receptor mutants revealed a complex interaction of both aminergic systems. Our analysis suggests that the different neuronal networks responsible for the 3 phenotypes show differential sensitivity to tßh gene expression levels. The evidence suggests that this sensitivity is brought about by a TA/OA opponent system modulating the involved neuronal circuits. This conclusion has important implications for standard transgenic techniques commonly used in functional genetics.

in PLoS Biology on May 10, 2021 02:00 PM.

• #### Analytic determination of lung microgeometry with gas diffusion magnetic resonance

Author(s): Niels Buhl

Through inhalation of, e.g., hyperpolarized ${}^{3}\mathrm{He}$, it is possible to acquire gas diffusion magnetic resonance measurements that depend on the local geometry in the vast network of microscopic airways that form the respiratory zone of the human lung. Here, we demonstrate that this can be used to determ...

[Phys. Rev. E 103, 052406] Published Mon May 10, 2021

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

• #### Reaction coupling in ADH1A alcohol dehydrogenase enzyme by exciplex formation with adenosine diphosphate moderated by low-energy electronic excited states

Author(s): Igor Khmelinskii and Vladimir I. Makarov

Two commonly accepted theories about enzymes were revisited. The first states that adenosine triphosphate (ATP)–stored energy is only released when the substrate is in place, because the substrate changes the enzyme structure when it is bound to the enzyme. In fact, as demonstrated and discussed pre...

[Phys. Rev. E 103, 052405] Published Mon May 10, 2021

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

• #### In vivo CRISPR screening for novel noncoding RNA functional targets in glioblastoma models

Lentivirally packaged clustered regularly interspaced short palindromic repeat interference (CRISPRi) library is transduced into glioblastoma cells (1,000 cells transduced/single guide RNA after drug selection), with transduced cells injected into the mouse cortex, and resected under fluorescence guidance after 2‐week growth. Fluorescence‐activated cell sorting isolates viable, transduced cells, and sequencing of tagged cells identifies specific gene knockdowns associated with in vivo growth. Abstract CRISPR (clustered regularly interspaced short palindromic repeat)‐based genetic screens offer unbiased and powerful tools for systematic and specific evaluation of phenotypes associated with specific target genes. CRISPR screens have been utilized heavily in vitro to identify functional coding and noncoding genes in a large number of cell types, including glioblastoma (GB), though no prior study has described the evaluation of CRISPR screening in GB in vivo. Here, we describe a protocol for targeting and transcriptionally repressing GB‐specific long noncoding RNAs (lncRNAs) by CRISPR interference (CRISPRi) system in vivo, with tumor growth in the mouse cerebral cortex. Given the target‐specific parameters of each individual screen, we list general steps involved in transducing guide RNA libraries into GB tumor lines, maintaining sufficient coverage, as well as cortically injecting and subsequently isolating transduced screen tumor cell populations for analysis. Finally, in order to demonstrate the use of this technique to discern an essential lncRNA, HOTAIR, from a nonessential lncRNA, we injected a 1:1 (HOTAIR:control nonessential lncRNA knockdown) mixture of fluorescently tagged U87 GB cells into the cortex of eight mice, evaluating selective depletion of HOTAIR‐tagged cells at 2 weeks of growth. Fluorescently tagged populations were analyzed via flow cytometry for hiBFP (control knockdown) and green fluorescent protein (HOTAIR knockdown), revealing 17% (p = 0.007) decrease in fluorescence associated with HOTAIR knockdown relative to control. The described in vivo CRISPR screening methodology thus appears to be an effective option for identifying noncoding (and coding) genes affecting GB growth within the mouse cortex.

in Journal of Neuroscience Research on May 10, 2021 07:32 AM.

• #### Hunger or thirst state uncertainty is resolved by outcome evaluation in medial prefrontal cortex to guide decision-making

Nature Neuroscience, Published online: 10 May 2021; doi:10.1038/s41593-021-00850-4

Eiselt et al. report conditions under which mice confuse thirst for hunger, similar to some human decisions that lead to over-eating. Evaluation of physiological need state requires consuming food or water and depends on the prefrontal cortex.

in Nature Neuroscience on May 10, 2021 12:00 AM.

• #### Wireless multilateral devices for optogenetic studies of individual and social behaviors

Nature Neuroscience, Published online: 10 May 2021; doi:10.1038/s41593-021-00849-x

The authors introduce advanced technology for controlled wireless light delivery in optogenetics applications with real-time user programming capacity. The utility of the platform is highlighted by induction of neural synchrony to modify social behavior in mice.

in Nature Neuroscience on May 10, 2021 12:00 AM.

• #### Integrating barcoded neuroanatomy with spatial transcriptional profiling enables identification of gene correlates of projections

Nature Neuroscience, Published online: 10 May 2021; doi:10.1038/s41593-021-00842-4

Sun et al. present BARseq2, a high-throughput method combining in situ sequencing of endogenous mRNAs with barcode-based axonal projection mapping, and apply it to identify cadherins that correlate with similar projections in two cortical areas.

in Nature Neuroscience on May 10, 2021 12:00 AM.

• #### Ultra-high-performance liquid chromatography high-resolution mass spectrometry variants for metabolomics research

Nature Methods, Published online: 10 May 2021; doi:10.1038/s41592-021-01116-4

This Review surveys ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC–HRMS), a highly sensitive, high-throughput technique that is used for analyzing a broad range of metabolites.

in Nature Methods on May 10, 2021 12:00 AM.

• #### Tunable quantum interference using a topological source of indistinguishable photon pairs

Nature Photonics, Published online: 10 May 2021; doi:10.1038/s41566-021-00810-1

Indistinguishable photon pairs are generated via four-wave mixing in a two-dimensional array of ring resonators that exhibit topological edge states. They show tunable spectral−temporal correlations and robustness against fabrication disorders.

in Nature Photomics on May 10, 2021 12:00 AM.

• #### Temporal solitons in a coherently driven active resonator

Nature Photonics, Published online: 10 May 2021; doi:10.1038/s41566-021-00807-w

By adding a carefully designed amplification section in a passive resonator, but pumping it below the lasing threshold, ultra-stable high-power cavity solitons can be formed, effectively removing the important barrier of having to work in low-loss environments.

in Nature Photomics on May 10, 2021 12:00 AM.

• #### Impact of Perineuronal Nets on Electrophysiology of Parvalbumin Interneurons, Principal Neurons, and Brain Oscillations: A Review

Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround specific neurons in the brain and spinal cord, appear during critical periods of development, and restrict plasticity during adulthood. Removal of PNNs can reinstate juvenile-like plasticity or, in cases of PNN removal during early developmental stages, PNN removal extends the critical plasticity period. PNNs surround mainly parvalbumin (PV)-containing, fast-spiking GABAergic interneurons in several brain regions. These inhibitory interneurons profoundly inhibit the network of surrounding neurons via their elaborate contacts with local pyramidal neurons, and they are key contributors to gamma oscillations generated across several brain regions. Among other functions, these gamma oscillations regulate plasticity associated with learning, decision making, attention, cognitive flexibility, and working memory. The detailed mechanisms by which PNN removal increases plasticity are only beginning to be understood. Here, we review the impact of PNN removal on several electrophysiological features of their underlying PV interneurons and nearby pyramidal neurons, including changes in intrinsic and synaptic membrane properties, brain oscillations, and how these changes may alter the integration of memory-related information. Additionally, we review how PNN removal affects plasticity-associated phenomena such as long-term potentiation (LTP), long-term depression (LTD), and paired-pulse ratio (PPR). The results are discussed in the context of the role of PV interneurons in circuit function and how PNN removal alters this function.

in Frontiers in Synaptic Neuroscience on May 10, 2021 12:00 AM.

• #### Specialty Grand Challenge for Brain Disease Mechanisms

in Frontiers in Molecular Neuroscience on May 10, 2021 12:00 AM.

• #### Comparative Effectiveness of Intracerebroventricular, Intrathecal, and Intranasal Routes of AAV9 Vector Administration for Genetic Therapy of Neurologic Disease in Murine Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). The two current treatments [hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT)], are insufficiently effective in addressing neurologic disease, in part due to the inability of lysosomal enzyme to cross the blood brain barrier. With a goal to more effectively treat neurologic disease, we have investigated the effectiveness of AAV-mediated IDUA gene delivery to the brain using several different routes of administration. Animals were treated by either direct intracerebroventricular (ICV) injection, by intrathecal (IT) infusion into the cerebrospinal fluid, or by intranasal (IN) instillation of AAV9-IDUA vector. AAV9-IDUA was administered to IDUA-deficient mice that were either immunosuppressed with cyclophosphamide (CP), or immunotolerized at birth by weekly injections of human iduronidase. In animals treated by ICV or IT administration, levels of IDUA enzyme ranged from 3- to 1000-fold that of wild type levels in all parts of the microdissected brain. In animals administered vector intranasally, enzyme levels were 100-fold that of wild type in the olfactory bulb, but enzyme expression was close to wild type levels in other parts of the brain. Glycosaminoglycan levels were reduced to normal in ICV and IT treated mice, and in IN treated mice they were normalized in the olfactory bulb, or reduced in other parts of the brain. Immunohistochemical analysis showed extensive IDUA expression in all parts of the brain of ICV treated mice, while IT treated animals showed transduction that was primarily restricted to the hind brain with some sporadic labeling seen in the mid- and fore brain. At 6 months of age, animals were tested for spatial navigation, memory, and neurocognitive function in the Barnes maze; all treated animals were indistinguishable from normal heterozygous control animals, while untreated IDUA deficient animals exhibited significant learning and spatial navigation deficits. We conclude that IT and IN routes are acceptable and alternate routes of administration, respectively, of AAV vector delivery to the brain with effective IDUA expression, while all three routes of administration prevent the emergence of neurocognitive deficiency in a mouse MPS I model.

in Frontiers in Molecular Neuroscience on May 10, 2021 12:00 AM.

• #### Validation of Affect-tag Affective and Cognitive Indicators

The Affect-tag solution measures physiological signals to deliver indicators derived from cognitive science. To provide the most accurate and effective results, a database of electrodermal activity (EDA) signals acquired using the Affect-tag A1 band was created. An experimental paradigm was designed to measure action-taking, autonomic regulation, cognitive load (CL), emotions, and stress, affects, and social stress. The Affect-tag emotional power (EP), emotional density (ED), and CL affective and cognitive indicators were refined based on the physiological responses of 48 participants during these tasks. Statistical significance was obtained for all indicators in tasks they were designed to measure, resulting in a total accuracy score of 89% for the combined indicators. Data obtained during this study will be further analyzed to define emotional and affective states.

in Frontiers in Neuroinformatics on May 10, 2021 12:00 AM.

• #### Stochasticity, Nonlinear Value Functions, and Update Rules in Learning Aesthetic Biases

A theoretical framework for the reinforcement learning of aesthetic biases was recently proposed based on brain circuitries revealed by neuroimaging. A model grounded on that framework accounted for interesting features of human aesthetic biases. These features included individuality, cultural predispositions, stochastic dynamics of learning and aesthetic biases, and the peak-shift effect. However, despite the success in explaining these features, a potential weakness was the linearity of the value function used to predict reward. This linearity meant that the learning process employed a value function that assumed a linear relationship between reward and sensory stimuli. Linearity is common in reinforcement learning in neuroscience. However, linearity can be problematic because neural mechanisms and the dependence of reward on sensory stimuli were typically nonlinear. Here, we analyze the learning performance with models including optimal nonlinear value functions. We also compare updating the free parameters of the value functions with the delta rule, which neuroscience models use frequently, vs. updating with a new Phi rule that considers the structure of the nonlinearities. Our computer simulations showed that optimal nonlinear value functions resulted in improvements of learning errors when the reward models were nonlinear. Similarly, the new Phi rule led to improvements in these errors. These improvements were accompanied by the straightening of the trajectories of the vector of free parameters in its phase space. This straightening meant that the process became more efficient in learning the prediction of reward. Surprisingly, however, this improved efficiency had a complex relationship with the rate of learning. Finally, the stochasticity arising from the probabilistic sampling of sensory stimuli, rewards, and motivations helped the learning process narrow the range of free parameters to nearly optimal outcomes. Therefore, we suggest that value functions and update rules optimized for social and ecological constraints are ideal for learning aesthetic biases.

in Frontiers in Human Neuroscience on May 10, 2021 12:00 AM.

• #### Muscle Synergies in Children Walking and Running on a Treadmill

Muscle synergies reflect the presence of a common neural input to multiple muscles. Steering small sets of synergies is commonly believed to simplify the control of complex motor tasks like walking and running. When these locomotor patterns emerge, it is likely that synergies emerge as well. We hence hypothesized that in children learning to run the number of accompanying synergies increases and that some of the synergies’ activities display a temporal shift related to a reduced stance phase as observed in adults. We investigated the development of locomotion in 23 children aged 2–9 years of age and compared them with seven young adults. Muscle activity of 15 bilateral leg, trunk, and arm muscles, ground reaction forces, and kinematics were recorded during comfortable treadmill walking and running, followed by a muscle synergy analysis. We found that toddlers (2–3.5 years) and preschoolers (3.5–6.5 years) utilize a “walk-run strategy” when learning to run: they managed the fastest speeds on the treadmill by combining double support (DS) and flight phases (FPs). In particular the activity duration of the medial gastrocnemius muscle was weakly correlated with age. The number of synergies across groups and conditions needed to cover sufficient data variation ranged between four and eight. The number of synergies tended to be smaller in toddlers than it did in preschoolers and school-age children but the adults had the lowest number for both conditions. Against our expectations, the age groups did not differ significantly in the timing or duration of synergies. We believe that the increase in the number of muscle synergies in older children relates to motor learning and exploration. The ability to run with a FP is clearly associated with an increase in the number of muscle synergies.

in Frontiers in Human Neuroscience on May 10, 2021 12:00 AM.

• #### Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations

The serotonin transporter (SERT) terminates neurotransmission by transporting serotonin from the synapse into the pre-synaptic nerve terminal. Altered SERT function leads to several neurological diseases including depression, anxiety, mood disorders, and attention deficit hyperactivity disorders (ADHD). Accordingly SERT is the target for their pharmacological treatments, but also targeted by multiple drugs of abuse. Transport of serotonin by SERT is energized by the transmembrane electrochemical gradient of sodium. We used extensive molecular dynamics simulations to investigate the process of sodium binding to SERT, which is the first step in the transport cycle that leads to serotonin uptake. Comparing data from 51 independent simulations, we find a remarkably well-defined path for sodium entry and could identify two transient binding sites, while observing binding kinetics that are comparable to experimental data. Importantly, the structure and dynamics of the sodium binding sites indicate that sodium binding is accompanied by an induced-fit mechanism that leads to new conformations and reduces local dynamics.

in Frontiers in Cellular Neuroscience on May 10, 2021 12:00 AM.

• #### The Role of NF-κB Triggered Inflammation in Cerebral Ischemia

Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death. However, there is presently a matter of controversy over whether inflammation could either be involved in brain damage or be a necessary part of brain repair. The inflammatory response is triggered by inflammasomes, key multiprotein complexes that promote secretion of pro-inflammatory cytokines. An early event in post-ischemic brain tissue is the release of certain molecules and reactive oxygen species (ROS) from injured neurons which induce the expression of the nuclear factor-kappaB (NF-κB), a transcription factor involved in the activation of the inflammasome. There are conflicting observations related to the role of NF-κB. While some observe that NF-κB plays a damaging role, others suggest it to be neuroprotective in the context of cerebral ischemia, indicating the need for additional investigation. Here we discuss the dual role of the major inflammatory signaling pathways and provide a review of the latest research aiming to clarify the relationship between NF-κB mediated inflammation and neuronal death in cerebral ischemia.

in Frontiers in Cellular Neuroscience on May 10, 2021 12:00 AM.

• #### Women Neuroscientist Disciples of Pío del Río-Hortega: the Cajal School Spreads in Europe and South America

Pio del Rio-Hortega was not only the discoverer of the microglia and oligodendroglia but also possibly the most prolific mentor of all Santiago Ramon y Cajal’s disciples (Nobel awardee in Physiology or Medicine 1906 and considered as the father of modern Neuroscience). Among Río-Hortega’s mentees, three exceptional women are frequently forgotten, chronologically: Pio’s niece Asunción Amo del Río who worked with Río-Hortega at Madrid, Paris, and Oxford; the distinguished British neuropathologist Dorothy Russell who also worked with Don Pío at Oxford; and Amanda Pellegrino de Iraldi, the last mentee in his career. Our present work analyzes the figures of these three women who were in contact and collaborated with Don Pío del Río-Hortega, describing the influences received and the impact on their careers and the History of Neuroscience. The present work completes the contribution of women neuroscientists who worked with Cajal and his main disciples of the Spanish Neurological School both in Spain (previous work) and in other countries (present work).

in Frontiers in Neuroanatomy on May 10, 2021 12:00 AM.

• #### Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population

Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer’s disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1–42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.

in Frontiers in Ageing Neuroscience on May 10, 2021 12:00 AM.

• #### The cerebellum-driven social basis of mathematics: implications for one-on-one tutoring of children with mathematics learning disabilities

The purpose of this article is to argue that the patterns of sequence control over kinematics (movements) and dynamics (forces) which evolved in phonological processing in inner speech during the evolution of ...

in Cerebellum and Ataxias on May 10, 2021 12:00 AM.

• #### Graph embedding clustering: Graph attention auto-encoder with cluster-specificity distribution

Publication date: Available online 8 May 2021

Source: Neural Networks

Author(s): Huiling Xu, Wei Xia, Quanxue Gao, Jungong Han, Xinbo Gao

in Neural Networks on May 09, 2021 06:00 PM.

• #### Novel criteria for global robust stability of dynamical neural networks with multiple time delays

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Emel Arslan

in Neural Networks on May 08, 2021 06:00 PM.

• #### Arguments for the unsuitability of convolutional neural networks for non-local tasks

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Sebastian Stabinger, David Peer, Antonio Rodríguez-Sánchez

in Neural Networks on May 08, 2021 06:00 PM.

• #### Hippocampal subfield‐specific Homer1a expression is triggered by learning‐facilitated long‐term potentiation and long‐term depression at medial perforant path synapses

Abstract Learning about general aspects, or content details, of space results in differentiated neuronal information encoding within the proximodistal axis of the hippocampus. These processes are tightly linked to long‐term potentiation (LTP) and long‐term depression (LTD). Here, we explored the precise sites of encoding of synaptic plasticity in the hippocampus that are mediated by information throughput from the perforant path. We assessed nuclear Homer1a‐expression that was triggered by electrophysiological induction of short and long forms of hippocampal synaptic plasticity, and compared it to Homer1a‐expression that was triggered by LTP and LTD enabled by different forms of spatial learning. Plasticity responses were induced by patterned stimulation of the perforant path and were recorded in the dentate gyrus (DG) of freely behaving rats. We used fluorescence in situ hybridization to detect experience‐dependent nuclear encoding of Homer1a in proximodistal hippocampal subfields. Induction of neither STP nor STD resulted in immediate early gene (IEG) encoding. Electrophysiological induction of robust LTP, or LTD, resulted in highly significant and widespread induction of nuclear Homer1a in all hippocampal subfields. LTP that was facilitated by novel spatial exploration triggered similar widespread Homer1a‐expression. The coupling of synaptic depression with the exploration of a novel configuration of landmarks resulted in localized IEG expression in the proximal CA3 region and the lower (infrapyramidal) blade of the DG. Our findings support that synaptic plasticity induction via perforant path inputs promotes widespread hippocampal information encoding. Furthermore, novel spatial exploration promotes the selection of a hippocampal neuronal network by means of LTP that is distributed in an experience‐dependent manner across all hippocampus subfields. This network may be modified during spatial content learning by LTD in specific hippocampal subfields. Thus, long‐term plasticity‐inducing events result in IEG expression that supports establishment and/or restructuring of neuronal networks that are necessary for long‐term information storage.

in Hippocampus on May 08, 2021 12:55 PM.

• #### Quantitative Susceptibility Mapping in Woodhouse‐Sakati Syndrome

Annals of Neurology, Accepted Article.

in Annals of Neurology on May 08, 2021 08:14 AM.

• #### Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease

Objective This multilanguage study used simple speech recording and high‐end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α‐synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early‐stage Parkinson disease (PD). Methods We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5–3.4 years), 149 with PD (mean duration of disease across language groups 1.7–2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12‐month follow‐up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. Results No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12‐month follow‐up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. Interpretation Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021

in Annals of Neurology on May 07, 2021 05:24 PM.

• #### Multiplex qPCR discriminates variants of concern to enhance global surveillance of SARS-CoV-2

by Chantal B. F. Vogels, Mallery I. Breban, Isabel M. Ott, Tara Alpert, Mary E. Petrone, Anne E. Watkins, Chaney C. Kalinich, Rebecca Earnest, Jessica E. Rothman, Jaqueline Goes de Jesus, Ingra Morales Claro, Giulia Magalhães Ferreira, Myuki A. E. Crispim, Brazil-UK CADDE Genomic Network , Lavanya Singh, Houriiyah Tegally, Ugochukwu J. Anyaneji, Network for Genomic Surveillance in South Africa , Emma B. Hodcroft, Christopher E. Mason, Gaurav Khullar, Jessica Metti, Joel T. Dudley, Matthew J. MacKay, Megan Nash, Jianhui Wang, Chen Liu, Pei Hui, Steven Murphy, Caleb Neal, Eva Laszlo, Marie L. Landry, Anthony Muyombwe, Randy Downing, Jafar Razeq, Tulio de Oliveira, Nuno R. Faria, Ester C. Sabino, Richard A. Neher, Joseph R. Fauver, Nathan D. Grubaugh

With the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants that may increase transmissibility and/or cause escape from immune responses, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant, first detected in the United Kingdom, could be serendipitously detected by the Thermo Fisher TaqPath Coronavirus Disease 2019 (COVID-19) PCR assay because a key deletion in these viruses, spike Δ69–70, would cause a “spike gene target failure” (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern (VOC) that lack spike Δ69–70, such as B.1.351 (also 501Y.V2), detected in South Africa, and P.1 (also 501Y.V3), recently detected in Brazil. We identified a deletion in the ORF1a gene (ORF1a Δ3675–3677) in all 3 variants, which has not yet been widely detected in other SARS-CoV-2 lineages. Using ORF1a Δ3675–3677 as the primary target and spike Δ69–70 to differentiate, we designed and validated an open-source PCR assay to detect SARS-CoV-2 VOC. Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence and spread of B.1.1.7, B.1.351, and P.1.

in PLoS Biology on May 07, 2021 02:00 PM.

• #### Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes

by Dan Fu, Guangshun Zhang, Yuhui Wang, Zheng Zhang, Hengrui Hu, Shu Shen, Jun Wu, Bo Li, Xin Li, Yaohui Fang, Jia Liu, Qiao Wang, Yunjiao Zhou, Wei Wang, Yufeng Li, Zhonghua Lu, Xiaoxiao Wang, Cui Nie, Yujie Tian, Da Chen, Yuan Wang, Xingdong Zhou, Qisheng Wang, Feng Yu, Chen Zhang, Changjing Deng, Liang Zhou, Guangkuo Guan, Na Shao, Zhiyong Lou, Fei Deng, Hongkai Zhang, Xinwen Chen, Manli Wang, Louis Liu, Zihe Rao, Yu Guo

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.

in PLoS Biology on May 07, 2021 02:00 PM.

• #### Two-timescale neurodynamic approaches to supervised feature selection based on alternative problem formulations

Publication date: Available online 7 May 2021

Source: Neural Networks

Author(s): Yadi Wang, Jun Wang, Hangjun Che

in Neural Networks on May 07, 2021 01:00 PM.

• #### Comparison of the effects of two therapeutic strategies based on olfactory ensheathing cell transplantation and repetitive magnetic stimulation after spinal cord injury in female mice

Summary of the main results of the study. Abstract Spinal cord injury (SCI) is a debilitating condition, which leads to a permanent loss of functions below the injury site. The events which take place after SCI are characterized by cellular death, release of inhibitory factors, and inflammation. Many therapies have been studied to cure SCI, among them magnetic stimulation aims to reduce the secondary damages in particular by decreasing apoptosis, while, cellular transplantation promotes neuroregeneration by enhancing axonal regrowth. In the present study, we compared individually primary olfactory ensheathing cell (OEC) transplantation and repetitive trans‐spinal magnetic stimulation (rTSMS) and then, we combined these two therapeutic approaches on tissue repair and functional recovery after SCI. To do so, SCIs were performed at Th10 level on female C57BL/6 mice, which were randomized into four groups: SCI, SCI + primary bOECs, SCI + STM, SCI + primary bulbar olfactory ensheathing cells (bOECs) + stimulation (STM). On these animals bioluminescence, immunohistological, and behavioral experiments were performed after SCI. Our results show that rTSMS has beneficial effect on the modulation of spinal scar by reducing fibrosis, demyelination, and microglial cell activation and by increasing the astroglial component of the scar, while, primary bOEC transplantation decreases microglial reactivity. At the opposite, locotronic experiments show that both treatments induce functional recovery. We did not observed any additional effect by combining the two therapeutic approaches. Taken together, the present study indicates that primary bOEC transplantation and rTSMS treatment act through different mechanisms after SCI to induce functional recovery. In our experimental paradigm, the combination of the two therapies does not induce any additional benefit.

in Journal of Neuroscience Research on May 07, 2021 10:37 AM.

• #### Evolutionary advantage of a dissociative search mechanism in DNA mismatch repair

Author(s): Kyle Crocker, James London, Andrés Medina, Richard Fishel, and Ralf Bundschuh

Protein complexes involved in DNA mismatch repair diffuse along dsDNA as sliding clamps in order to locate a hemimethylated incision site. They have been observed to use a dissociative mechanism, in which two proteins, while continuously remaining attached to the DNA, sometimes associate into a sing...

[Phys. Rev. E 103, 052404] Published Fri May 07, 2021

in Physical Review E: Biological physics on May 07, 2021 10:00 AM.

• #### NRSF deficiency leads to abnormal postnatal development of dentate gyrus and impairment of progenitors in subgranular zone of hippocampus

Abstract Neuron‐restrictive silencing factor (NRSF) is a zinc‐finger transcription factor that regulates expression of a diverse set of genes. However, NRSF function in brain development still remains elusive. In the present study, we generated NRSF‐conditional knockout (NRSF‐cKO) mice by hGFAP‐Cre/loxp system to study the effect of NRSF deficiency on brain development. Results showed that NRSF conditional knockout caused a smaller hippocampus and a thinner granule cell layer (GCL) in mice. Moreover, the reduction and disarrangement of GFAP+ cells in subgranular zone (SGZ) of NRSF‐cKO mice was accompanied with the decreased number of premature neurons, neural stem cells (NSCs) and neural progenitor cells (NPCs), as well as compromising the majority of mitotically active cells. The analysis of postnatal development of hippocampus indicated the existence of an abnormality at postnatal day (P) 8, rather than at P1, in NRSF‐cKO mice, although the densities of Ki67+ cells with mitotic ability in dentate gyrus were relatively unaffected at P1 and P8. Meanwhile, NRSF deficiency led to abnormal organization of SGZ at P8 during postnatal development. RNA‐Seq analysis revealed 79 deregulated genes in hippocampus of NRSF‐cKO mice at P8, which were involved in p53 signal transduction, neuron migration and negative regulation of cell proliferation, etc. The deregulation of p53 pathway in NRSF‐cKO mice at P1 and P8 was evidenced, of which p21/Cdkn1a was accumulated in a portion of NSCs and NPCs in hippocampus during postnatal development. Together, these results, for the first time, revealed that NRSF could significantly influence the postnatal development of hippocampus, especially the formation of SGZ.

in Hippocampus on May 07, 2021 08:34 AM.

• #### As above, so below: Whole transcriptome profiling demonstrates strong molecular similarities between avian dorsal and ventral pallial subdivisions

In 2013, our group examined the expression profiles of 50 genes to develop the continuum hypothesis of avian brain organization. It states that the subdivisions of the dorsal pallium develop continuously with those of the ventral pallium, resulting in a “partial mirror image” organization around the vestigial ventricle divide. However, these claims were challenged due to the small number of genes profiled. The present study uses RNA sequencing to profile the whole transcriptome (~20,000 genes) of the principal subdivisions of the avian telencephalon and confirms the remarkable molecularly similarities between the dorsal and ventral pallium. We recommend adopting a hierarchal nomenclature to reflect these robust molecular similarities. Abstract Over the last two decades, beginning with the Avian Brain Nomenclature Forum in 2000, major revisions have been made to our understanding of the organization and nomenclature of the avian brain. However, there are still unresolved questions on avian pallial organization, particularly whether the cells above the vestigial ventricle represent distinct populations to those below it or similar populations. To test these two hypotheses, we profiled the transcriptomes of the major avian pallial subdivisions dorsal and ventral to the vestigial ventricle boundary using RNA sequencing and a new zebra finch genome assembly containing about 22,000 annotated, complete genes. We found that the transcriptomes of neural populations above and below the ventricle were remarkably similar. Each subdivision in dorsal pallium (Wulst) had a corresponding molecular counterpart in the ventral pallium (dorsal ventricular ridge). In turn, each corresponding subdivision exhibited shared gene co‐expression modules that contained gene sets enriched in functional specializations, such as anatomical structure development, synaptic transmission, signaling, and neurogenesis. These findings are more in line with the continuum hypothesis of avian brain subdivision organization above and below the vestigial ventricle space, with the pallium as a whole consisting of four major cell populations (intercalated pallium, mesopallium, hyper‐nidopallium, and arcopallium) instead of seven (hyperpallium apicale, interstitial hyperpallium apicale, intercalated hyperpallium, hyperpallium densocellare, mesopallium, nidopallium, and arcopallium). We suggest adopting a more streamlined hierarchical naming system that reflects the robust similarities in gene expression, neural connectivity motifs, and function. These findings have important implications for our understanding of overall vertebrate brain evolution.

in Journal of Comparative Neurology on May 07, 2021 07:00 AM.

• #### Social mice seeking circuits

Nature Neuroscience, Published online: 07 May 2021; doi:10.1038/s41593-021-00861-1

Hu et al. show that the posterodorsal medial amygdala selectively controls social-reward seeking through its intersection with canonical dopaminergic reward circuits. To identify this circuitry, the authors developed an elegant new affiliative social operant procedure that separates social interaction from social-reward seeking.

in Nature Neuroscience on May 07, 2021 12:00 AM.

• #### A celebration of structural biology

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01163-x

The Protein Data Bank (PDB) is the primary data resource for structural biology. On its 50th anniversary, we celebrate the future of this ever-growing field.

in Nature Methods on May 07, 2021 12:00 AM.

• #### Genome-wide analysis of structural variation

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01161-z

Phased genomes from diverse human populations are assembled using multiple sequencing technologies.

in Nature Methods on May 07, 2021 12:00 AM.

• #### iSCAT gets a signal boost

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01160-0

Photonic resonator interferometric scattering microscopy offers label-free imaging of biomolecules in vitro with improved signal-to-noise ratio.

in Nature Methods on May 07, 2021 12:00 AM.

• #### Walking through chromatin modifications

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01159-7

The Cell-TALKING technique probes DNA modifications around a histone modification in fixed cells.

in Nature Methods on May 07, 2021 12:00 AM.

• #### Mario Nicodemi

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01152-0

Polymer physics, comparing ways to assess chromatin structure and taking in tales at the Italian seaside.

in Nature Methods on May 07, 2021 12:00 AM.

• #### From structure to mechanism: skiing the energy landscape

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01140-4

It is time for structural biologists to embrace the challenge of quantitatively describing functional energy landscapes.

in Nature Methods on May 07, 2021 12:00 AM.

• #### 50 years of PDB: a catalyst in structural biology

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01138-y

Integrative structural biology, the culmination of experimental and theoretical methods, will provide a holistic view of molecular processes.

in Nature Methods on May 07, 2021 12:00 AM.

• #### Cryo-electron tomography: observing the cell at the atomic level

Nature Methods, Published online: 07 May 2021; doi:10.1038/s41592-021-01133-3

Interest in cryo-ET is rapidly growing, but many technical challenges still require solutions.

in Nature Methods on May 07, 2021 12:00 AM.

• #### A synaptic mismatch

Nature Reviews Neuroscience, Published online: 07 May 2021; doi:10.1038/s41583-021-00472-6

A mismatch between cell adhesion proteins at the mossy fibre synapse drives female-specific synaptic and cognitive dysfunction in a mouse model of developmental and epileptic encephalopathy 9.

in Nature Reviews on May 07, 2021 12:00 AM.

• #### A window of opportunity

Nature Reviews Neuroscience, Published online: 07 May 2021; doi:10.1038/s41583-021-00470-8

Closure of the critical period of a motor circuit in Drosophila melanogaster larvae is regulated by neuroligin–neurexin signalling between astrocytes and motor neurons.

in Nature Reviews on May 07, 2021 12:00 AM.

• #### MicroRNA-181a Is Involved in Methamphetamine Addiction Through the ERAD Pathway

The regulation of microRNA (miRNA) is closely related to methamphetamine (METH) addiction. Past studies have reported that miR-181a is associated with METH addiction, but the mechanism pathways remain elusive. On the basis of our past studies, which reported the endoplasmic reticulum-associated protein degradation (ERAD) mediated ubiquitin protein degradation of GABAAα1, which was involved in METH addiction. The present study, using qRT-PCR and bioinformatics analysis, further revealed that miR-181a may be indirectly responsible for the METH addiction and downregulation of GABAAα1 through the regulation of ERAD.

in Frontiers in Molecular Neuroscience on May 07, 2021 12:00 AM.

• #### Advanced Analysis of Diffusion Tensor Imaging Along With Machine Learning Provides New Sensitive Measures of Tissue Pathology and Intra-Lesion Activity in Multiple Sclerosis

Tissue pathology in multiple sclerosis (MS) is highly complex, requiring multi-dimensional analysis. In this study, our goal was to test the feasibility of obtaining high angular resolution diffusion imaging (HARDI) metrics through single-shell modeling of diffusion tensor imaging (DTI) data, and investigate how advanced measures from single-shell HARDI and DTI tractography perform relative to classical DTI metrics in assessing MS pathology. We examined 52 relapsing-remitting MS patients who had 3T anatomical brain MRI and DTI. Single-shell HARDI modeling yielded 5 sub-voxel-based metrics, totalling 11 diffusion measures including 4 DTI and 2 tractography metrics. Based on machine learning of 3-dimensional regions of interest, we evaluated the importance of the measures through several tissue classification tasks. These included two within-subject comparisons: lesion versus normal appearing white matter (NAWM); and lesion core versus shell. Further, by stratifying patients as having high (above 75%ile) and low (below 25%ile) number of MS lesions, we also performed 2 classifications between subjects for lesions and NAWM respectively. Results showed that in lesion-NAWM analysis, HARDI orientation distribution function (ODF) energy, DTI fractional anisotropy (FA), and HARDI orientation dispersion index were the top three metrics, which together achieved 65.2% accuracy and 0.71 area under the receiver operating characteristic curve (AUROC). In core-shell analysis, DTI mean diffusivity (MD), radial diffusivity, and FA were the top three metrics, and MD dominated the classification, which achieved 59.3% accuracy and 0.59 AUROC alone. Between patients, FA was the leading feature in lesion comparisons, while ODF energy was the best in NAWM separation. Collectively, single-shell modeling of common diffusion data can provide robust orientation measures of lesion and NAWM pathology, and DTI metrics are most sensitive to intra-lesion abnormality. Combined analysis of both advanced and classical diffusion measures may be critical for improved understanding of MS pathology.

in Frontiers in Neuroscience: Brain Imaging Methods on May 07, 2021 12:00 AM.

• #### Framework for the Classification of Emotions in People With Visual Disabilities Through Brain Signals

Nowadays, the recognition of emotions in people with sensory disabilities still represents a challenge due to the difficulty of generalizing and modeling the set of brain signals. In recent years, the technology that has been used to study a person’s behavior and emotions based on brain signals is the brain–computer interface (BCI). Although previous works have already proposed the classification of emotions in people with sensory disabilities using machine learning techniques, a model of recognition of emotions in people with visual disabilities has not yet been evaluated. Consequently, in this work, the authors present a twofold framework focused on people with visual disabilities. Firstly, auditory stimuli have been used, and a component of acquisition and extraction of brain signals has been defined. Secondly, analysis techniques for the modeling of emotions have been developed, and machine learning models for the classification of emotions have been defined. Based on the results, the algorithm with the best performance in the validation is random forest (RF), with an accuracy of 85 and 88% in the classification for negative and positive emotions, respectively. According to the results, the framework is able to classify positive and negative emotions, but the experimentation performed also shows that the framework performance depends on the number of features in the dataset and the quality of the Electroencephalogram (EEG) signals is a determining factor.

in Frontiers in Neuroinformatics on May 07, 2021 12:00 AM.

• #### Editorial: Understanding the Link Between the Developing Brain and Behavior in Adolescents

in Frontiers in Human Neuroscience on May 07, 2021 12:00 AM.

• #### A New Statistical Approach for fNIRS Hyperscanning to Predict Brain Activity of Preschoolers’ Using Teacher’s

Hyperscanning studies using functional Near-Infrared Spectroscopy (fNIRS) have been performed to understand the neural mechanisms underlying human-human interactions. In this study, we propose a novel methodological approach that is developed for fNIRS multi-brain analysis. Our method uses support vector regression (SVR) to predict one brain activity time series using another as the predictor. We applied the proposed methodology to explore the teacher-student interaction, which plays a critical role in the formal learning process. In an illustrative application, we collected fNIRS data of the teacher and preschoolers’ dyads performing an interaction task. The teacher explained to the child how to add two numbers in the context of a game. The Prefrontal cortex and temporal-parietal junction of both teacher and student were recorded. A multivariate regression model was built for each channel in each dyad, with the student’s signal as the response variable and the teacher’s ones as the predictors. We compared the predictions of SVR with the conventional ordinary least square (OLS) predictor. The results predicted by the SVR model were statistically significantly correlated with the actual test data at least one channel-pair for all dyads. Overall, 29/90 channel-pairs across the five dyads (18 channels 5 dyads = 90 channel-pairs) presented significant signal predictions withthe SVR approach. The conventional OLS resulted in only 4 out of 90 valid predictions. These results demonstrated that the SVR could be used to perform channel-wise predictions across individuals, and the teachers’ cortical activity can be used to predict the student brain hemodynamic response.

in Frontiers in Human Neuroscience on May 07, 2021 12:00 AM.

• #### Editorial: Neuronal Pathways Affecting Glial Function

in Frontiers in Cellular Neuroscience on May 07, 2021 12:00 AM.

• #### Homeostatic Depression Shows Heightened Sensitivity to Synaptic Calcium

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content (QC) during evoked neurotransmission—again, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapse’s ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we found loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R —itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.

in Frontiers in Cellular Neuroscience on May 07, 2021 12:00 AM.

• #### Editorial: Brain Evolution: Clues From Aquatic Organisms

in Frontiers in Neuroanatomy on May 07, 2021 12:00 AM.

• #### Probiotic Supplementation Facilitates Recovery of 6-OHDA-Induced Motor Deficit via Improving Mitochondrial Function and Energy Metabolism

Parkinson’s disease (PD) is a neurodegenerative disease associated with progressive impairment of motor and non-motor functions in aging people. Overwhelming evidence indicate that mitochondrial dysfunction is a central factor in PD pathophysiology, which impairs energy metabolism. While, several other studies have shown probiotic supplementations to improve host energy metabolism, alleviate the disease progression, prevent gut microbiota dysbiosis and alter commensal bacterial metabolites. But, whether probiotic and/or prebiotic supplementation can affect energy metabolism and cause the impediment of PD progression remains poorly characterized. Therefore, we investigated 8-weeks supplementation effects of probiotic [Lactobacillus salivarius subsp. salicinius AP-32 (AP-32)], residual medium (RM) obtained from the AP-32 culture medium, and combination of AP-32 and RM (A-RM) on unilateral 6-hydroxydopamine (6-OHDA)-induced PD rats. We found that AP-32, RM and A-RM supplementation induced neuroprotective effects on dopaminergic neurons along with improved motor functions in PD rats. These effects were accompanied by significant increases in mitochondrial activities in the brain and muscle, antioxidative enzymes level in serum, and altered SCFAs profile in fecal samples. Importantly, the AP-32 supplement restored muscle mass along with improved motor function in PD rats, and produced the best results among the supplements. Our results demonstrate that probiotic AP-32 and A-RM supplementations can recover energy metabolism via increasing SCFAs producing and mitochondria function. This restoring of mitochondrial function in the brain and muscles with improved energy metabolism might additionally be potentiated by ROS suppression by the elevated generation of antioxidants, and which finally leads to facilitated recovery of 6-OHDA-induced motor deficit. Taken together, this work demonstrates that probiotic AP-32 supplementation could be a potential candidate for alternate treatment strategy to avert PD progression.

in Frontiers in Ageing Neuroscience on May 07, 2021 12:00 AM.

• #### Endogenous µ‐opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain

Incision causes neuronal sensitization and acute postoperative pain. After injury resolves, endogenous µ‐opioid receptor (MOR) signaling in the central nucleus of the amygdala (CeA) suppresses latent pain sensitization. Inhibiting MOR signaling, either systemically or within the CeA, unmasks latent sensitization, leading to reinstatement of hypersensitivity. ​ Abstract Tissue injury induces a long‐lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ‐opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β‐funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co‐expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co‐expressed tdTomato+ in Oprm1Cre::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra‐CeA injection of the MOR‐selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.

in Journal of Neuroscience Research on May 06, 2021 05:15 PM.

• #### An update to Hippocampome.org by integrating single-cell phenotypes with circuit function in vivo

by Alberto Sanchez-Aguilera, Diek W. Wheeler, Teresa Jurado-Parras, Manuel Valero, Miriam S. Nokia, Elena Cid, Ivan Fernandez-Lamo, Nate Sutton, Daniel García-Rincón, Liset M. de la Prida, Giorgio A. Ascoli

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal–hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.

in PLoS Biology on May 06, 2021 02:00 PM.

• #### Generalized two-dimensional linear discriminant analysis with regularization

Publication date: October 2021

Source: Neural Networks, Volume 142

Author(s): Chun-Na Li, Yuan-Hai Shao, Wei-Jie Chen, Zhen Wang, Nai-Yang Deng

in Neural Networks on May 06, 2021 01:00 PM.