title: Structural analysis of the C. elegans dauer larval anterior sensilla by Focused Ion Beam-Scanning Electron Microscopy

abstract: At the end of the first larval stage, the nematode Caenorhabditis elegans developing in harsh environmental conditions is able to choose an alternative developmental path called the dauer diapause. Dauer larvae exhibit different physiology and behaviors from non-dauer larvae. Using focused ion beam scanning electron microscopy (FIB-SEM), we volumetrically reconstructed the anterior sensory apparatus of C. elegans dauer larvae with unprecedented precision. We provide a detailed description of some neurons, focusing on structural details that were unknown or unresolved by previously published studies. They include: 1) dauer-specific branches of the IL2 sensory neurons project into the periphery of anterior sensilla and motor or putative sensory neurons at the sub-lateral cords; 2) ciliated endings of URX sensory neurons are supported by both ILso and AMso socket cells near the amphid openings; 3) variability in amphid sensory dendrites among dauers; 4) somatic RIP interneurons maintain their projection into the pharyngeal nervous system. Our results support the notion that dauer larvae structurally expand their sensory system to facilitate searching for more favorable environments.


title: THERAPEUTIC EFFECTS OF HYPOXIC AND PRO-INFLAMMATORY PRIMING OF MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES IN INFLAMMATORY ARTHRITIS

abstract:
Novel biological therapies have revolutionised the management of Rheumatoid Arthritis (RA) but no cure currently exists. Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA).

EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA.

All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Th17:Treg homeostatic balance.

Priming of MSCs in EV production can be applied to alter the therapeutic efficacy however normoxic EVs present the optimal strategy for broad therapeutic benefit. The varied outcomes observed in MSCs priming may promote EVs optimised for therapies targeted for specific therapeutic priorities. EVs present an effective novel technology with potential for cell-free therapeutic translation.

category: immunology


title: Delayed effects of climate on vital rates lead to demographic divergence in Amazonian forest fragments

abstract: Deforestation often results in landscapes where remaining forest habitat is highly fragmented, with remnants of different sizes embedded in an often highly contrasting matrix. Local extinction of species from individual fragments is common, but the demographic mechanisms underlying these extinctions are poorly understood. It is often hypothesized that altered environmental conditions in fragments drive declines in reproduction, recruitment, or survivorship. The Amazon basin, in addition to experiencing continuing fragmentation, is experiencing climate change related increases in the frequency and intensity of droughts and unusually wet periods. Whether plant populations in tropical forest fragments are particularly susceptible to extremes in precipitation remains unclear. Most studies of plants in fragments are relatively short (1-6 years), focus on a single life-history stage, and often do not compare to populations in continuous forest. Even fewer studies consider delayed effects of climate on demographic vital rates despite the importance of delayed effects in studies that consider them. Using a decade of demographic and climate data from an experimentally fragmented landscape in the Central Amazon, we assess the effects of climate on populations of an understory herb (Heliconia acuminata, Heliconiaceae). We used distributed lag non-linear models to understand the delayed effects of climate (measured as standardized precipitation evapotranspiration index, SPEI) on survival, growth, and flowering. We detected delayed effects of climate up to 36 months. Extremes in SPEI in the previous year reduced survival, drought in the wet season 8-11 months prior to the February census increased growth, and drought two dry seasons prior increased flowering probability. Effects of extremes in precipitation on survival and growth were more pronounced in forest fragments compared to continuous forest. The complex delayed effects of climate and habitat fragmentation in our study point to the importance of long-term demography experiments in understanding the effects of anthropogenic change on plant populations.

category: ecology


title: Whole genome sequencing elucidates the species-wide diversity and evolution of fungicide resistance in the early blight pathogen Alternaria solani

abstract:
Early blight of potato is caused by the fungal pathogen Alternaria solani and is an increasing problem worldwide. The primary strategy to control the disease is applying fungicides such as succinate dehydrogenase inhibitors (SDHI). SDHI-resistant strains, showing reduced sensitivity to treatments, appeared in Germany in 2013, five years after the introduction of SDHIs. Two primary mutations in the Sdh complex (SdhB-H278Y and SdhC-H134R) have been frequently found throughout Europe. How these resistances arose and spread, and whether they are linked to other genomic features, remains unknown.

We performed whole-genome sequencing for A. solani isolates from potato fields across Europe (Germany, Sweden, Belgium, and Serbia) to better understand the pathogens genetic diversity in general and understand the development and spread of the genetic mutations that lead to SDHI resistance. We used ancestry analysis and phylogenetics to determine the genetic background of 48 isolates. The isolates can be grouped into 7 genotypes. These genotypes do not show a geographical pattern but appear spread throughout Europe. The Sdh mutations appear in different genetic backgrounds, suggesting they arose independently, and the observed admixtures might indicate a higher adaptive potential in the fungus than previously thought.

Our research gives insights into the genetic diversity of A. solani on a genome level. The mixed occurrence of different genotypes and apparent admixture in the populations indicate higher genomic complexity than anticipated. The conclusion that SDHI tolerance arose multiple times independently has important implications for future fungicide resistance management strategies. These should not solely focus on preventing the spread of isolates between locations but also on limiting population size and the selective pressure posed by fungicides in a given field to avoid the rise of new mutations in other genetic backgrounds.

category: evolutionary biology


title: Pleiotropy is associated with fitness consequences of new mutations in mutation accumulation lines

abstract:
Understanding the mechanisms by which mutations affect fitness and the distribution of mutational effects are central goals in evolutionary biology. Mutation accumulation (MA) lines have long been an important tool for understanding the effect of new mutations on fitness, phenotypic variation, and mutational parameters. However, there is a clear gap in predicting the effect of specific new mutations to their effects on fitness. Here, we complete gene ontology analysis and metabolomics experiments on Arabidopsis thaliana MA lines to determine how spontaneous mutations directly affect global metabolic output in lines that have measured fitness consequences. For these analyses, we compared three lines with relative fitness consistently higher than the unmutated progenitor and three lines with lower relative fitness as measured in four different field trials. In a gene ontology analysis, we find that the high fitness lines were significantly enriched in mutations in or near genes with transcription regulator activity. We also find that although they do not have an average difference in the number of mutations, low fitness lines have significantly more metabolic subpathways disrupted than high fitness lines. Taken together, these results suggest that the effect of a new mutation on fitness depends less on the specific metabolic pathways disrupted and more on the pleiotropic effects of those mutations, and that organisms can explore a considerable amount of physiological space with only a few mutations.

Significance StatementAs the source of all genetic variation, new mutations are crucial for understanding how organisms adapt to their environment. However, the ways in which new mutations affect the range of metabolic reactions that occur in the cell is unknown. With a combination of gene functional analyses and measurement of the small molecules that drive cellular function and physiology, we find that mutations associated with high fitness are disproportionately found in or near proteins-coding genes that regulate the specific timing and location of gene expression and are less disruptive of cellular physiology.


title: Analysis of the leaf metabolome in Arabidopsis thaliana mutation accumulation lines reveals association of pleiotropy and fitness consequences


title: Epigenetic Regulation of Nuclear Lamina-Associated Heterochromatin by HAT1 and the Acetylation of Newly Synthesized Histones

abstract: During S phase, eukaryotic cells must faithfully duplicate both the sequence of the genome and the regulatory information found in the epigenome. A central component of the epigenome is the pattern of histone post-translational modifications that play a critical role in the formation of specific chromatin states. During DNA replication, parental nucleosomes are disrupted and re-deposited on the nascent DNA near their original location to preserve the spatial memory of the epigenetic modifications. Newly synthesized histones must also be incorporated into the nascent chromatin to maintain nucleosome density. Transfer of modification patterns from parental histones to new histones is a fundamental step in epigenetic inheritance. Whether new histones play an active or passive role in epigenetic inheritance is unknown. Here we report that HAT1, which acetylates lysines 5 and 12 of newly synthesized histone H4 during replication-coupled chromatin assembly, regulates the epigenetic inheritance of chromatin states. HAT1 regulates the accessibility of large domains of heterochromatin termed HAT1-dependent Accessibility Domains (HADs). HADs are mega base-scale domains that comprise ~10% of the mouse genome. HAT1 functions as a global negative regulator of H3 K9me2/3 and HADs correspond to the regions of the genome that display HAT1-dependent increases in H3 K9me3 peak density. HADs display a high degree of overlap with a subset of Lamin-Associated Domains (LADs). HAT1 is required to maintain nuclear structure and integrity. These results indicate that HAT1 and the acetylation of newly synthesized histones are critical regulators of the epigenetic inheritance of heterochromatin and suggest a new mechanism for the epigenetic regulation of nuclear lamina-heterochromatin interactions.

category: genomics


title: The myopathic transcription factor DUX4 induces the production of truncated RNA-bindingproteins in human muscle cells

abstract: DUX4 is an embryonic transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4 induces the transcription of thousands of RNAs and dysregulates multiple pathways that could contribute to FSHD pathophysiology. However, lack of temporal data and the knowledge of which RNAs are actively translated following DUX4 expression has hindered our understanding of the cascade of events that lead to muscle cell death. Here, we interrogate the DUX4 transcriptome and translatome over time and find dysregulation of most key pathways as early as 4 hours after DUX4 induction, demonstrating the potent effect of DUX4 in disrupting muscle biology. We also observe extensive transcript downregulation as well as induction, and a high concordance between mRNA abundance and translation status. Significantly, DUX4 triggers widespread production of truncated protein products derived from aberrant RNAs that are degraded in normal muscle cells. One such protein, truncated serine/arginine-rich splicing factor 3 (SRSF3-TR), is present in FSHD muscle cells and disrupts splicing autoregulation when ectopically expressed in myoblasts. Taken together, the temporal dynamics of DUX4 induction show how the pathologic presence of an embryonic transcription factor in muscle cells alters gene expression to ultimately perturb RNA homeostasis.


title: The ACF Chromatin Remodeling Complex is Essential for Polycomb Repression

abstract: Establishing and maintaining appropriate gene repression is critical for the health and development of multicellular organisms. Histone H3 lysine 27 (H3K27) methylation is a chromatin modification associated with repressed facultative heterochromatin, but the mechanism of this repression remains unclear. We used a forward genetic approach to identify genes involved in transcriptional silencing of H3K27-methylated chromatin in the filamentous fungus Neurospora crassa. We found that the N. crassa homologs of ISWI (NCU03875) and ACF (NCU00164) are required for repression of a subset of H3K27-methylated genes and that they form an ACF chromatin remodeling complex. This N. crassa ACF complex interacts with chromatin throughout the genome, yet association with facultative heterochromatin is specifically promoted by the H3K27 methyltransferase, SET-7. H3K27-methylated genes that are upregulated when iswi or acf1 are deleted show a downstream shift of the +1 nucleosome, suggesting that proper nucleosome positioning is critical for repression of facultative heterochromatin. Our findings support a direct role for the ACF complex in Polycomb repression.

category: genetics


title: Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR

abstract: Large oligomeric enzymes control a myriad of cellular processes, from protein synthesis and degradation to metabolism. The 0.5 MDa large TET2 aminopeptidase, a prototypical protease important for cellular homeostasis, degrades peptides within a ca. 60 [A] wide tetrahedral chamber with four lateral openings. The mechanisms of substrate trafficking and processing remain debated. Here, we integrate magic-angle spinning (MAS) NMR, mutagenesis, co-evolution analysis and molecular dynamics simulations and reveal that a loop in the catalytic chamber is a key element for enzymatic function. The loop is able to stabilize ligands in the active site and may additionally have a direct role in activating the catalytic water molecule whereby a conserved histidine plays a key role. Our data provide a strong case for the functional importance of highly dynamic - and often overlooked - parts of an enzyme, and the potential of MAS NMR to investigate their dynamics at atomic resolution.

category: biophysics


title: Modeling adsorption, conformation, and orientation of the Fis1 tail anchor at the mitochondrial outer membrane

abstract: Proteins can be targeted to organellar membranes using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained simulations to analyze the adsorption, conformation and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.


title: Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane


title: Cystinosin deficient rats recapitulate the phenotype of nephropathic cystinosis

abstract:
BackgroundThe lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding a cystine transporter, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease and a kidney transplant is inevitable. Pre-clinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are sub-optimal. To solve this problem we generated a new cystinotic rat model.

MethodsWe utilized CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-month time-course including blood and tissue cystine levels, urine and serum electrolytes, and analysed the histopathology and immunohistochemistry of the kidney.

ResultsCtns-/- rats display hallmarks of cystinosis by 3-6 months of age as seen by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, a loss of Lrp2 in proximal tubules and immune cell infiltration. High levels of glucose, calcium, albumin and protein are excreted at 6-months of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9-months of age, indicative of chronic kidney disease. The kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic  swan neck lesions. Overall, Ctns-/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models.

ConclusionsThe Ctns-/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting pre-clinical drug testing and a powerful tool to advance cystinosis research.

Translational StatementGood animal models of disease are essential to perform pre-clinical testing of potential new drugs and therapies before they can progress to human clinical trials. Unfortunately, the cystinosis field has been hampered by a lack of suitable animal models that fully recapitulate the disease. We have overcome this by generating a new rat model of cystinosis by CRISPR-Cas9 gene editing. These rodents closely model the human condition in a time-frame that makes them an excellent model ideally suited for pre-clinical drug testing as well as being a powerful tool to advance cystinosis research.

category: physiology


title: Deep learning model for the prediction and classification of protein toxins across all domains of life

abstract: Toxins are widely produced by different organisms to disrupt the physiology of other organisms, and support their own existence. Their study is useful to understand protein evolution, environmental adaptation and survival competition. In-silico predictions of toxic proteins can support empirical frameworks, and help in the safety measurements needed for various industrial related processes. Some in-silico methods are slow, hard to implement or lack taxa representation in their training datasets. Here we present a deep learning model to classify protein toxins, through the use of Convolutional Neural Networks (ConvTOX). ConvTOX is able to accurately identify toxic proteins across the domains of life, with accuracies over 80% for animal and plant toxins, and over 50% for bacterial toxins. Moreover, ConvTOX is able to generalize the identification of differences among toxin types, such as neurotoxins and myotoxins, and to accurately identify structural similarities between different protein toxins. ConvTOX overcomes limitations from previous models by being able to predict toxin proteins from across all domains of life, and by not being limited to only short toxin peptides. Limitations are still clear in terms of lower accuracies for specific phylogenetic groups (such as bacterial toxins), but still this works presents itself as a one step forward for the universal use, classification and study of toxic proteins.

category: synthetic biology


title: Analyzing Nested Experimental Designs - A User-Friendly Resampling Method to Determine Experimental Significance

abstract: We report Hierarch, a Python package to perform hypothesis tests and compute confidence intervals on hierarchical experimental designs. Using a combination of permutation resampling and bootstrap aggregation, Hierarch can be used to perform hypothesis tests that maintain nominal Type I error rates and generate confidence intervals that maintain the nominal coverage probability without making distributional assumptions about the dataset of interest. Hierarch makes use of the Numba JIT compiler to reduce p-value computation times to under one second for typical datasets in biomedical research. Hierarch also enables researchers to construct user-defined resampling plans that take advantage of Hierarchs Numba-accelerated functions. Hierarch is freely available as a Python package at https://github.com/rishi-kulkarni/hierarch.

category: neuroscience


title: Deciphering the landscape of phosphorylated HLA-II ligands

abstract: CD4+ T-cell activation in infectious diseases and cancer is governed by the recognition of peptides presented on class II human leukocyte antigen (HLA-II) molecules. Therefore, HLA-II ligands represent promising targets for vaccine design and personalized cancer immunotherapy. Much work has been done to identify and predict unmodified peptides presented on HLA-II molecules. However, little is known about the presentation of phosphorylated HLA-II ligands. Here, we analyzed Mass Spectrometry HLA-II peptidomics data and identified 1,113 unique phosphorylated HLA-II ligands. This enabled us to precisely define phosphorylated binding motifs for more than 30 common HLA-II alleles and to explore various molecular properties of phosphorylated peptides. Our data were further used to develop the first predictor of phosphorylated peptide presentation on HLA-II molecules.


title: Glycomic profiling of the gut microbiota by Glycan-seq

abstract:
BackgroundThere has been immense interest in studying the relationship between the gut microbiota and human health. Bacterial glycans modulate the cross talk between the gut microbiota and its host. However, little is known about these glycans because of the lack of appropriate technology to study them.

MethodsWe previously developed a sequencing-based glycan profiling method called Glycan-seq, which is based on the use of 39 DNA-barcoded lectins. In this study, we applied this technology to analyze the glycome of the intact gut microbiota of mice. Fecal microbiota was incubated with 39 DNA-barcoded lectins exposed to UV, and the number of released DNA barcodes were counted by next-generation sequencing to obtain a signal for each lectin bound to the microbiota. In parallel, the bacterial composition of the gut microbiota was analyzed by 16S rRNA gene sequencing. Finally, we performed a lectin pull-down experiment followed by 16S rRNA gene sequencing to identify lectin-reactive bacteria.

ResultsThe evaluation of cultured gram-positive (Deinococcus radiodurans) and gram-negative (Escherichia coli) bacteria showed significantly distinct glycan profiles between these bacteria, which were selected and further analyzed by flow cytometry. The results of flow cytometry agreed well with those obtained by Glycan-seq, indicating that Glycan-seq can be used for bacterial glycomic analysis. We thus applied Glycan-seq to comparatively analyze the glycomes of young and old mice gut microbiotas. The glycomes of the young and old microbiotas had significantly distinct glycan profiles, which reflect the different bacterial compositions of young and old gut microbiotas based on 16S rRNA gene sequencing. Therefore, the difference in the glycomic profiles between young and old microbiotas may be due to their differing bacterial compositions. 2-6Sia-binders bound specifically to the young microbiota. Lectin pull-down followed by 16S rRNA gene sequencing of the young microbiota identified Lactobacillaceae as the most abundant bacterial family with glycans reacting with 2-6Sia-binders.

ConclusionThe Glycan-seq system can, without any prior culturing and fluorescence labeling, reveal the glycomic profile of the intact bacterial gut microbiota. A combination of lectin pull-down and 16S rRNA gene sequencing can identify lectin-reactive bacteria.

category: microbiology


title: The P-selectin ligand PSGL-1 (CD162) is efficiently incorporated by primary HIV-1 isolates and can facilitate trans-infection

abstract:
While P-selectin glycoprotein ligand-1 (PSGL-1/CD162) has been studied extensively for its role in mediating leukocyte rolling through interactions with its receptor, P-selectin, recently, it was identified as a novel HIV-1 host restriction factor. One key mechanism of HIV-1 restriction is the ability of PSGL-1 to be physically incorporated into the external viral envelope, which effectively reduces infectivity by blocking virus attachment through the steric hindrance caused by its large ectodomain. Importantly, a large portion of the literature demonstrating the antiviral activity of PSGL-1 has utilized viruses produced in transfected cells which express high levels of PSGL-1. However, herein we show that virion-incorporated PSGL-1 is far less abundant on the surface of viruses produced via infection of physiologically relevant models (T cell lines and primary cells) compared to transfection (overexpression) models. Unique to this study, we show that PSGL-1 is incorporated in a broad range of HIV-1 and SIV isolates, supporting the physiological relevance of this incorporation. We also report that high levels of virion-incorporated PSGL-1 are detectable in plasma from viremic HIV-1 infected individuals, further corroborating the clinical relevance of PSGL-1 in natural infection. Additionally, we show that PSGL-1 on viruses is functionally active and can bind its cognate receptor, P-selectin, and that virions captured via P-selectin can subsequently be transferred to HIV-permissive bystander cells in a model of trans-infection. Taken together, our data suggest that PSGL-1 may have diverse roles in the physiology of HIV-1 infection, not restricted to the current antiviral paradigm.

IMPORTANCEPSGL-1 is an HIV-1 host restriction factor which reduces viral infectivity by physically incorporating into the envelope of virions. While the antiviral effects of PSGL-1 in viruses produced by transfection models is profound, HIV-1 continues to remain infectious when produced through natural infection, even when PSGL-1 is incorporated. To study this discordance, we compared the differences in infectivity and PSGL-1 abundance in viruses produced by transfection or infection. Viruses produced via transfection contained unnaturally high levels of incorporated PSGL-1 compared to viruses from primary cells, and were much less infectious. We also found PSGL-1 to be present on a broad range of HIV-1 isolates, including those found in plasma from HIV-infected patients. Remarkably, we show that virion-incorporated PSGL-1 facilitates virus capture and transfer to HIV-permissive host cells via binding to P-selectin. These findings suggest that PSGL-1 may also work to enhance infection in vivo.


title: Direct detection of the myosin super-relaxed state and interacting heads motif in solution

abstract: We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to detect the interacting-heads motif (IHM) of {beta}-cardiac myosin in solution. Evidence for the IHM has been observed by several structural techniques, and it has been proposed to be the structural basis for the super-relaxed state (SRX), a low-ATPase state of myosin that has been observed biochemically in skinned muscle fibers using fluorescent ATP. It has been proposed that the disruption of this state, by mutation or chemical modification, is a major cause of heart disease, so drugs are being developed to stabilize it. The goal of the present study is to determine directly and quantitatively the correlation between the measured fractions of myosin in the IHM state and the SRX state under the same conditions in solution. We used TR-FRET to measure the distance between the two heads of bovine cardiac myosin, and found that there are two distinct populations, one of which is observable by FRET at a center distance of 2.0 nm, and the other is not detected, implying a distance greater than 4 nm. Under the same conditions, we also measured the fraction of heads in the SRX state using fluorescent nucleotide and stopped-flow kinetics. We found that, in the absence of crosslinking, the population of SRX exceeded that of IHM. In particular, the stabilizing effect of mavacamten was much greater on SRX (55% increase) than on IHM (4% increase). We conclude that the SRX and IHM states are related, but they are not identical.

category: molecular biology


title: Synthesis and characterization of 5-(2-fluoro-4-pyridine-7-carboxamide as a PET imaging ligand for metabotropic glutamate receptor 2

abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for the treatment of several neuropsychiatric disorders and conditions. The role of mGluR2 function in etiology could be unveiled by in vivo imaging using positron emission tomography (PET). In this regard, 5-(2- fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7- carboxamide ([11C]13), a potent negative allosteric modulator (NAM), was developed to support this endeavor. Radioligand [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 {+/-} 76 GBq/{micro}mol (n = 5) and excellent radiochemical purity (> 99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity, particularly in the regions of striatum, thalamus, hippocampus, and cortex. Accumulation of [11C]13 in these regions of interest (ROIs) was reduced with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions, especially in different cortical areas, putamen, thalamus, and hippocampus, and resulted in high-contrast brain images. The regional total volume of distribution (VT) estimates of [11C]13 decreased by 14% after the pretreatment with 9. Therefore, [11C]13 is a potential candidate for translational PET imaging studies of mGluR2 function.


title: The MuvB Complex Binds and Stabilizes Nucleosomes Downstream of the Transcription Start Site of Cell-Cycle Dependent Genes

abstract: The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene-expression.


title: Neural Correlates of Value-Driven Spatial Attention

abstract: Reward learning has been shown to habitually guide spatial attention to regions of a scene. However, the neural mechanisms that support this bias in spatial orienting are unknown. In the present study, participants learned to orient to a particular quadrant of a scene (high-value quadrant) to maximize monetary gains. This learning was scene-specific, with the high-value quadrant varying across different scenes. During a subsequent test phase, participants were faster at identifying a target if it appeared in the high-value quadrant (valid), and initial saccades were more likely to be made to the high-value quadrant. fMRI analyses during the test phase revealed learning-dependent priority signals in the bilateral caudate tail and superior colliculus, frontal eye field, substantia nigra, and insula, paralleling findings concerning feature-based value-driven attention. In addition, ventral regions typically associated with scene selective and spatial information processing, including the hippocampus, parahippocampal gyrus, and temporo-occipital cortex, were also implicated. Taken together, our findings offer new insights into the neural architecture subserving value-driven attention, both extending our understanding of nodes in the attention network previously implicated in feature-based value-driven attention and identifying a ventral network of brain regions implicated in rewards influence on scene-dependent spatial orienting.


title: Lack of Host Reproductive Trade-offs Associated with Fecundity Compensation Response to Parasitic Castration

abstract: Host-parasite coevolution may result in life-history changes in hosts that can limit the detrimental effects of parasitism. Fecundity compensation is one such life-history response, occurring when hosts increase their current reproductive output to make up for expected losses in future reproduction due to parasitic infection. However, the potential trade-offs between quantity and quality of offspring produced during fecundity compensation are relatively unexplored. This study uses the trematode, Schistosoma mansoni, and its snail intermediate host, Biomphalaria glabrata, to better understand the impacts of this host life-history response. Measures of host reproductive output as well as offspring hatching success and survival were collected to assess the reproductive consequences of infection. Infected snails exhibited fecundity compensation (increase in the number of eggs laid compared to controls) and had a higher probability of laying any eggs at all. Infection status did not play a significant role in hatching or offspring survival to maturity. However, the age of the parental snail had a significant impact on hatching success, as offspring from older parents demonstrated a higher hatching success rate. Overall, the lack of an apparent trade-off between quantity and quality of offspring suggests that infected parental snails invest more resources towards reproduction in order to maintain the fitness of their offspring, possibly at the expense of their own longevity.


title: Emergent Color Categorization in a Neural Network trained for Object Recognition

abstract: Color is a prime example of categorical perception, yet it is unclear why and how color categories emerge. While prelinguistic infants and animals treat color categorically, several recent modeling endeavors have successfully utilized communicative concepts to predict color categories. Rather than modeling categories directly, we investigate the potential emergence of color categories as a result of acquiring visual skills. Specifically, whether color is represented categorically in a convolutional neural network (CNN) trained to recognize objects in natural images. Systematically training new output layers to the CNN for a color classification task, we find clear borders between new (non-training) colors that are largely invariant to the training colors. Using an evolutionary algorithm that relies on the principle of categorical perception we verify these border locations. These results provide strong evidence that color categorization emerges as a function of basic visual skills and provide a new basis for uncovering how they emerge.

category: animal behavior and cognition


title: An efficient coalescent epoch model for Bayesian phylogenetic inference

abstract:
We present a two headed approach called Bayesian Integrated Coalescent Epoch PlotS (BICEPS) for efficient inference of coalescent epoch models. Firstly, we integrate out population size parameters and secondly we introduce a set of more powerful Markov chain Monte Carlo (MCMC) proposals for flexing and stretching trees. Even though population sizes are integrated out and not explicitly sampled through MCMC, we are still able to generate samples from the population size posteriors. This allows demographic reconstruction through time and estimating the timing and magnitude of population bottlenecks and full population histories. Altogether, BICEPS can be considered a more muscular version of the popular Bayesian skyline model.

We demonstrate its power and correctness by a well calibrated simulation study. Furthermore, we demonstrate with an application to SARS-CoV-2 genomic data that some analyses that have trouble converging with the traditional Bayesian skyline prior and standard MCMC proposals can do well with the BICEPS approach.

BICEPS is available as open source package for BEAST 2 under GPL license and has a user friendly graphical user interface. Bayesian phylogenetics, coalescent model, BEAST 2, BICEPS

category: bioinformatics


title: Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome

abstract:
Backgroundparent-of-origin effects (POE) play important roles in development and complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies have mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing these modifiable POE exist.

Methodsin order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as "predicted mRNA expression levels" of DNA methylation/imprinting machinery genes and early/late lifestyle/environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315).

Resultsa set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, "lifetime smoking status" and "predicted mRNA expression levels" of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. Importantly, the POE on one of the CpGs were modified by both genetic and environmental factors. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs.

Conclusionsthe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases.

Key MessagesO_LIPrevious population studies showed that parent-origin-effects(POE) on human methylome can be widespread and affect health-related traits and diseases.
C_LIO_LIWhether the POE remained stable throughout the life or can be modified by genetic or environmental factors were largely unknown.
C_LIO_LIBy systematically screening 101 genetic and environmental factors in a large cohort(GS:SFHS) we provided the first population-level replicated evidence that those measuring lifestyle (smoking) and predicted expression of DNA methylation- or imprinting-machinery genes are amongst the factors that can modulate the POE of mQTLs for a set of CpG sites.
C_LIO_LIWe found those modifiable-POE-regulated CpGs are also phenotypically relevant - one is associated with the plasma levels of CLEC4C and health-related phenotypes such as HDL levels.
C_LIO_LIThe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation and their potential phenotypic consequences. This also provided a paradigm for further studies to explore how environmental and genetic effects can be integrated at methylation level.
C_LI


title: Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

abstract: A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We developed a QSM processing pipeline to estimate magnetic susceptibility of multiple brain structures in 35,885 subjects from the UK Biobank prospective epidemiological study. We identified phenotypic associations of magnetic susceptibility that include body iron, disease, diet, and alcohol consumption. Genome-wide associations related magnetic susceptibility to genetic variants with biological functions involving iron, calcium, myelin, and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers world-wide, creating potential to discover novel, non-invasive markers of brain health.


title: De novo brain-computer interfacing deforms manifold of populational neural activity patterns in human cerebral cortex

abstract:
Human brains are capable of modulating innate activities to adapt to novel environmental stimuli; for sensorimotor cortices (SM1) this means acquisition of a rich repertoire of motor behaviors. We investigated the adaptability of human SM1 motor control by analyzing net neural population activity during the learning of brain-computer interface (BCI) operations. We found systematic interactions between the neural manifold of cortical population activities and BCI classifiers; the neural manifold was stretched by rescaling motor-related features of electroencephalograms with model-based fixed classifiers, but not with adaptive classifiers that were constantly recalibrated to user activity. Moreover, operation of a BCI based on a de novo classifier with a fixed decision boundary based on biologically unnatural features, deformed the neural manifold to be orthogonal to the boundary. These principles of neural adaptation at a macroscopic level may underlie the ability of humans to learn wide-ranging behavioral repertoires and adapt to novel environments.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/450263v1_ufig1.gif" ALT="Figure 1">
View larger version (16K):
org.highwire.dtl.DTLVardef@12a66c3org.highwire.dtl.DTLVardef@c090e8org.highwire.dtl.DTLVardef@698f87org.highwire.dtl.DTLVardef@4e135c_HPS_FORMAT_FIGEXP  M_FIG C_FIG


title: Why are flowers ephemeral? Effects of old flower microbes on fruit set in a wild ginger with one-day flowers, Alpinia japonica (Zingiberaceae)

abstract: Flowers are colonized and inhabited by diverse microbes. Plants rapidly replace flowers with short lifespan, and old flowers senesce. This may contribute to avoiding adverse effects of the microbes. In this study, we investigate if the flower microbial community on old flowers impedes fruit and seed production in a wild ginger with one-day flowers. We inoculated newly opened flowers with old flower microbes, and monitored the effects on fruit and seed set. We also assessed prokaryotic communities on the flowers using amplicon sequencing. We found six bacterial amplicon sequence variants (ASVs) whose proportions were increased on the inoculated flowers. These ASVs were also found on flower buds and flowers that were bagged by net or paper during anthesis, suggesting that they had been present in small numbers prior to flowering. Fruit set was negatively associated with the proportions of these ASVs, while seed set was not. The results suggest that old flowers harbor microbial communities different from those at anthesis, and that the microbes abundant on old flowers negatively affect plant reproduction. Though the short lifespan of flowers has gotten little attention, it might be an essential defense mechanism to cope with antagonistic microbes that rapidly proliferate on the flowers.


title: Are microbes growing on flowers evil? Effects of old flower microbes on fruit set in a wild ginger with one-day flowers, Alpinia japonica (Zingiberaceae)


title: Complex basis of hybrid female sterility and Haldane's rule in Heliconius butterflies: Z-linkage and epistasis

abstract: Hybrids between diverging populations are often sterile or inviable. Hybrid unfitness usually evolves first in the heterogametic sex - a pattern known as Haldanes rule. The genetics of Haldanes Rule have been extensively studied in species where the male is the heterogametic (XX/XY) sex, but its basis in taxa where the female is heterogametic (ZW/ZZ), such as Lepidoptera and birds, is largely unknown. Here, we analyse a new case of female hybrid sterility between geographic subspecies of Heliconius pardalinus. The two subspecies mate freely in captivity, but female F1 hybrids in both directions of cross are sterile. Sterility is due to arrested development of oocytes after they become differentiated from nurse cells, but before yolk deposition. We backcrossed fertile male F1 hybrids to parental females, and mapped quantitative trait loci (QTLs) for female sterility. We also identified genes differentially expressed in the ovary, and as a function of oocyte development. The Z chromosome has a major effect, similar to the "large X effect" in Drosophila, with strong epistatic interactions between loci at either end of the Z chromosome, and between the Z chromosome and autosomal loci on chromosomes 8 and 20. Among loci differentially expressed between females with arrested vs. non-arrested ovary development, we identified six candidate genes known also from Drosophila melanogaster and Parage aegeria oogenesis. This study is the first to characterize hybrid sterility using genome mapping in the Lepidoptera. We demonstrate that sterility is produced by multiple complex epistastic interactions often involving the sex chromosome, as predicted by the dominance theory of Haldanes Rule.


title: Population genetics of polymorphism and divergence in rapidly evolving populations

abstract: In rapidly evolving populations, numerous beneficial and deleterious mutations can arise and segregate within a population at the same time. In this regime, evolutionary dynamics cannot be analyzed using traditional population genetic approaches that assume that sites evolve independently. Instead, the dynamics of many loci must be analyzed simultaneously. Recent work has made progress by first analyzing the fitness variation within a population, and then studying how individual lineages interact with this traveling fitness wave. However, these "traveling wave" models have previously been restricted to extreme cases where selection on individual mutations is either much faster or much slower than the typical coalescent timescale Tc. In this work, we show how the traveling wave framework can be extended to intermediate regimes in which the scaled fitness effects of mutations (Tcs) are neither large nor small compared to one. This enables us to describe the dynamics of populations subject to a wide range of fitness effects, and in particular, in cases where it is not immediately clear which mutations are most important in shaping the dynamics and statistics of genetic diversity. We use this approach to derive new expressions for the fixation probabilities and site frequency spectra of mutations as a function of their scaled fitness effects, along with related results for the coalescent timescale Tc and the rate of adaptation or Mullers ratchet. We find that competition between linked mutations can have a dramatic impact on the proportions of neutral and selected polymorphisms, which is not simply summarized by the scaled selection coefficient Tcs. We conclude by discussing the implications of these results for population genetic inferences.


title: Improving long-read consensus sequencing accuracy with deep learning

abstract: The PacBio HiFi sequencing technology combines less accurate, multi-read passes from the same molecule (subreads) to yield consensus sequencing reads that are both long (averaging 10-25 kb) and highly accurate. However, these reads can retain residual sequencing error, predominantly insertions or deletions at homopolymeric regions. Here, we train deep learning models to polish HiFi reads by recognizing and correcting sequencing errors. We show that our models are effective at reducing these errors by 25-40% in HiFi reads from human as well as E. coli genomes.


title: Comprehensive analysis of full-length transcripts reveal aberrations of splicing variants in liver cancer

abstract: Genes generate various transcripts by alternative splicing, and these transcripts can have diverse functions. However, in most transcriptome studies, short-reads sequencing technologies (next-generation sequencers) have been used and full-length transcripts have not been observed directly. Although long-reads sequencing technologies would enable us to sequence full-length transcripts, analysis of the data is a difficult task. In the present study, we developed an analysis pipeline named SPLICE to analyze full-length cDNA sequences. Using this method, we analyzed cDNA sequences from 42 pairs of hepatocellular carcinoma (HCC) and matched non-cancerous liver with Oxford Nanopore technology. Our analysis detected 46,663 transcripts from the protein-coding genes in the HCCs and the matched non-cancerous livers, of which 5,366 (11.5 %) were novel. Comparison of expression levels identified 9,933 differentially expressed transcripts (DETs) in 4,744 genes. Importantly, 746 genes with DET were not found by the gene-level analysis. We also identified novel exons derived from transposable elements (TEs). In the analysis of transcripts from hepatitis B virus (HBV), HBx-human TE fusions were found to be overexpressed in the HCCs. Furthermore, fusion gene detection showed novel recurrent fusion events. These results suggest that long-reads sequencing technologies allow us to analyze full-length transcripts, and show the importance of splicing variants in carcinogenesis.

category: cancer biology


title: The recent range expansion of Great Cormorants (Phalacrocorax carbo hanedae) in Hokkaido, Japan.

abstract: Though the Japanese subspecies of Great Cormorant (Phalacrocorax carbo hanedae) has increased its population in recent decades, information on its spread to the northern island of Hokkaido has not been reported outside of Japan. The purpose of this paper is to update the scientific community about the breeding and range ecology of P. carbo, and to provide comparative information on the abundant and similar looking resident Japanese Cormorant (P. capillatus). Several ornithological groups and researchers were contacted in order to gather information about the current distribution and breeding activities of P. carbo in the region. Here the findings of Japanese research groups, translated publications, and direct observations are made available.

category: zoology


title: Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

abstract:
Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this problem, we slightly modified previous methods and show robust seizures are common and frequent in both male and female mice. We employed continuous wideband video-EEG monitoring from 4 recording sites to best demonstrate the seizures. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 sec) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE.

SIGNIFICANCE STATEMENTAlthough the IHKA model has been widely used in mice for epilepsy research, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent convulsive seizures that are robust, meaning they are >10 sec and associated with complex high frequency rhythmic activity recorded from 2 hippocampal and 2 cortical sites. Seizure onset patterns usually matched the low-voltage fast and hypersynchronous seizures in TLE. Importantly, there is low mortality, and both sexes can be used. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression, and other topics of broad interest to the epilepsy research community. Finally, the results have implications for preclinical drug screening because seizure frequency increased in approximately half of the mice after a 6 wk interval, suggesting that the typical 2 wk period for monitoring seizure frequency is insufficient.

HIGHLIGHTS* Our implementation of the IHKA model led to robust chronic spontaneous convulsive seizures in mice
* Convulsive seizures were synchronized in both hippocampi and two cortical sites
* Seizure duration increased between 2-4 wks and 10-12 wks after IHKA
* Convulsive seizures fit LVF and HYP types found in human temporal lobe epilepsy
* HFOs (>250 Hz) were common, at >1 location, and were both ictal and interictal


title: Optogenetic suppression of corticogeniculate feedback in anesthetized ferrets is overridden by visual stimulation

abstract:
The feedforward projection from the retina shapes the spatial receptive field properties of neurons in the dorsal lateral geniculate nucleus of the thalamus (LGN). Corticogeniculate feedback from the visual cortex appears to exert a more subtle, modulatory influence on LGN responses. Studies involving manipulations of corticogeniculate feedback have yielded inconsistent findings, but the reasons for these inconsistencies are not known. To examine the functional contributions of corticogeniculate feedback, and to resolve past inconsistencies, we examined the effects of selective optogenetic suppression of corticogeniculate neurons in anesthetized ferrets. In particular, we examined the responses of LGN and V1 neurons during optogenetic suppression of corticogeniculate feedback in the presence and absence of visual stimulation and across conditions in which the frequency of LED illumination varied. Optogenetic suppression of corticogeniculate feedback decreased activity among LGN neurons in the absence of visual stimulation, dispelling the notion that anesthesia causes a floor effect. In contrast, suppressing corticogeniculate feedback did not affect the visual responses of LGN neurons, suggesting that feedforward visual stimulus drive overrides weak corticogeniculate influence. Optogenetic effects on LGN and V1 neuronal responses depended on the frequency of LED illumination, with higher frequency illumination inducing slow oscillations in V1, dis-inhibiting V1 neurons locally, and producing more suppression among LGN neurons. These results demonstrate that corticogeniculate influence depends on stimulation parameters including visual stimulus conditions and frequency of inactivation. Furthermore, weak corticogeniculate influence is overridden by strong feedforward visual stimulus drive - this attribute is the most likely source of inconsistencies in past studies.

Significance StatementAlthough corticogeniculate synapses onto thalamic neurons far outnumber those coming from the retina, the function of corticogeniculate feedback in vision has remained a stubborn puzzle. Prior studies of corticogeniculate feedback have yielded inconsistent findings, but the source for these inconsistencies is unknown. We utilized selective optogenetic suppression of corticogeniculate feedback to examine its effects on thalamic neuronal responses and to resolve sources of prior inconsistencies. We found that suppression of corticogeniculate feedback reduced thalamic responses, but only in the absence of visual input. This suggests that the major source of inconsistencies across prior studies is the fact that weak corticogeniculate influence is overcome by strong feedforward visual stimulus drive.


title: Using diffusion MRI data acquired with ultra-high gradients to improve tractography in routine-quality data

abstract: The development of scanners with ultra-high gradients, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from todays state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.


title: Comparative computational modeling of the bat and human immune response to viral infection with the Comparative Biology Immune Agent Based Model

abstract: Given the impact of pandemics due to viruses of bat origin there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent-based model that encompasses and bridges the differences between bat and human responses to viral infection: the Comparative Biology Immune Agent-based Model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and Type 1 Interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in the preparation for future viral pandemics of zoonotic origin.


title: Strategies of Mycoplasma ovipneumoniae to evade immune clearance by alveolar macrophages

abstract: Chronic nonprogressive pneumonia is a prevalent disease that infects many young sheep. Mycoplasma ovipneumoniae was isolated from the lungs of sheep with chronic nonprogressive pneumonia. Evidences showed that it might associate with the development and duration of chronic pneumonia, moreover, sheep infected with M. ovipneumoniae are easily infected by other organisms, suggesting that M. ovipneumoniae may play an immunosuppressive role during infection. However, the mechanism is still poorly understood. The infection occurs in the airway, where resident alveolar macrophages first encounter M. ovipneumoniae. Therefore, primary alveolar macrophages (AMs) were collected from the lungs of healthy adult sheep, and the (iTRAQ) protein assay was used to investigate the immunosuppressive effects of M. ovipneumoniae on sheep AMs. The RAW264.7 cells were used to confirm the findings. The results showed that M. ovipneumoniae promoted higher expression of anti-apoptotic proteins and lower expression of apoptosis-related proteins in the infected AMs. Moreover, the number of infected AMs increased. However, M. ovipneumoniae reduced ATP levels in AMs and impaired late endosome maturation and phagolysosome fusion. Furthermore, M. ovipneumoniae inhibited the autophagy pathway via the Akt-mTOR axis in AMs. These findings indicated that M. ovipneumoniae had distinctive strategies to evade elimination caused by the AMs. The findings might explain the chronic infection and co-infection in sheep infected by M. ovipneumoniae.


title: Highly-Neutralizing COVID-19-Convalescent-Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters.

abstract:
Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19.

ImportanceConvalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.


title: Early detection of SARS-CoV-2 in circulating immune cells in a mouse model

abstract: SARS-CoV-2 infects the respiratory tract, lung and then other organs. However, its pathogenesis remains largely unknown. We used RareScope Fluorescence Light Sheet Microscopy (FLSM) and fluorescent in situ hybridization of RNA (RNA-FISH) to detect SARS-CoV-2 RNA and dissemination kinetics in mouse blood circulation. By RNA-FISH, we found that SARS-CoV-2 RNA-positive leukocytes, including CD11c cells, appeared as early as one day after infection and continued through day 10 post infection. Our data suggest that SARS-CoV-2-permissive leukocytes contribute to systemic viral dissemination, and RNA-FISH combined with FLSM can be utilized as a sensitive tool for SARS-CoV-2 detection in blood specimens.


title: Meta-analysis shows both congruence and complementarity of DNA metabarcoding to traditional methods for biological community assessment

abstract: Assessment of the diversity and composition of biological communities is central to studies in ecology as well as for ecological monitoring. Historically, individual taxonomic groups have been assessed separately, while for an understanding of the state and change of biodiversity under ongoing global change an integrated assessment would be necessary. DNA metabarcoding has been proposed to be a highly promising approach especially for the assessment of aquatic communities, and numerous studies have investigated the consistency of this new technique with traditional morpho-taxonomic approaches. These individual studies have used DNA metabarcoding to assess diversity and community structure of aquatic organisms both in marine and freshwater systems globally over the last decade. However, a systematic analysis of the comparability and effectiveness of DNA-based community assessment across all of these studies has hitherto been lacking. Here we performed the first meta-analysis of all available studies comparing traditional methods and DNA metabarcoding to measure and assess biological diversity of key aquatic groups, including microorganisms, macroinvertebrates, and fish. Across 215 datasets, we found that DNA metabarcoding provides diversity estimates (richness) that are globally consistent to those obtained using traditional methods. DNA metabarcoding also generates species inventories that are highly congruent with traditional methods for fish. Contrastingly, however, species inventories of microorganisms and macroinvertebrates obtained by DNA metabarcoding showed pronounced differences to traditional methods, missing some taxa but at the same time detecting otherwise overseen diversity. Our results indicate that DNA metabarcoding is efficient to estimate local and regional richness. The method is generally sufficiently advanced to study the composition of fish communities and replace more invasive traditional methods. For smaller organisms, like macroinvertebrates and microorganisms, DNA metabarcoding may continue to give complementary rather than identical estimates compared to traditional approaches. Systematic and comparable data collection will increase the understanding of different aspects of this complementarity, and increase the effectiveness of the method and adequate interpretation of the results.


title: A joint distribution framework to improve presence-only species distribution models by exploiting opportunistic surveys

abstract:
{whitebullet} AimWe propose a Bayesian framework for modelling species distributions using presence-only biodiversity occurrences obtained from historical opportunistic surveys.

 {whitebullet}LocationGlobal applicability with two case studies in south-east Mexico.

 {whitebullet}MethodsThe framework defines a bivariate spatial process separable into ecological and sampling effort processes that jointly generate occurrence observations of biodiversity records. Presence-only data are conceived as incomplete observations where some presences have been filtered out. A choosing principle is used to separate out presences, missing data and absences relative to the species of interest and the sampling observations. The framework provides three modelling alternatives for accounting the spatial autocorrelation structure: independent latent variables (model I); common latent spatial random effect (model II); and correlated latent spatial random effects (model III).

The framework was compared against the Maximum Entropy (MaxEnt) algorithm in two case studies: one for the prediction of pines (Class: Pinopsida), using botanical records as sampling observations and another for the prediction of Flycatchers (Family: Tyranidae), using bird sightings as sampling records.

 {whitebullet} [a]ResultsIn both case studies, at least one of the proposed models achieved higher predictive accuracy than MaxEnt. The model with correlated spatial effects fit best when the sampling effort was informative, while the one with a shared spatial effect was more suitable in cases with high proportion of non sampled sites.

 {whitebullet}Main ConclusionsOur approach provides a flexible framework for presence-only SDMs aided by a sampling effort process informed by the accumulated observations of independent and heterogeneous surveys. For the two case studies, the framework provided a model with a higher predictive accuracy than an optimised version MaxEnt.


title: Epitope order Matters in multi-epitope-based peptide (MEBP) vaccine design: An in silico study

abstract: With different countries facing multiple waves, with some SARS-CoV-2 variants more deadly and virulent, the COVID-19 pandemic is becoming more dangerous by the day and the world is facing an even more dreadful extended pandemic with exponential positive cases and increasing death rates. There is an urgent need for more efficient and faster methods of vaccine development against SARS-CoV-2. Compared to experimental protocols, the opportunities to innovate are very high in immunoinformatics/in silico approaches especially with the recent adoption of structural bioinformatics in peptide vaccine design. In recent times, multi-epitope-based peptide vaccine candidates (MEBPVCs) have shown extraordinarily high humoral and cellular responses to immunization. Most of the publications claim that respective reported MEBPVC(s) assembled using a set of in silico predicted epitopes, to be the computationally validated potent vaccine candidate(s) ready for experimental validation. However, in this article, for a given set of predicted epitopes, it is shown that the published MEBPVC is one among the many possible variants and there is high likelihood of finding more potent MEBPVCs than the published candidate. To test the same, a methodology is developed where novel MEBP variants are derived by changing the epitope order of the published MEBPVC. Further, to overcome the limitations of current qualitative methods of assessment of MEBPVC, to enable quantitative comparison, ranking, and the discovery of more potent MEBPVCs, novel predictors, Percent Epitope Accessibility (PEA), Receptor specific MEBP vaccine potency(RMVP), MEBP vaccine potency(MVP) are introduced. The MEBP variants indeed showed varied MVP scores indicating varied immunogenicity. When the MEBP variants were ranked in descending order of their MVP scores, the published MEBPVC had the least MVP score. Further, the MEBP variants with IDs, SPVC_387 and SPVC_206, had the highest MVP scores indicating these variants to be more potent MEBPVCs than the published MEBPVC and hence should be prioritized for experimental testing and validation. Through this method, more vaccine candidates will be available for experimental validation and testing. This study also opens the opportunity to develop new software tools for designing more potent MEBPVCs in less time. The computationally validated top-ranked MEBPVCs must be experimentally tested, validated, and verified. The differences and deviations between experimental results and computational predictions provide an opportunity for improving and developing more efficient algorithms and reliable scoring schemes and software.

category: biochemistry


title: Validation of Data Acquisition and Phase Estimation for Quantitative Susceptibility Mapping with a Rotating-Tube Phantom

abstract:
PurposeQuantitative Susceptibility Mapping (QSM) is an MRI tool with the potential to reveal pathological changes from magnetic susceptibility measurements. Before phase data can be used to recover susceptibility ({Delta}{chi}), the QSM process begins with two steps: data acquisition and phase estimation. We assess the performance of these steps, when applied without user intervention, on several variations of a phantom imaging task.

ApproachWe used a rotating-tube phantom with five tubes ranging from {Delta}{chi}=0.05 ppm to {Delta}{chi}=0.336 ppm. MRI data was acquired at nine angles of rotation for four different pulse sequences. The images were processed by 10 phase estimation algorithms including Laplacian, region-growing, branch-cut, temporal unwrapping and maximum-likelihood methods. We analyzed errors between measured and expected phase using the probability mass function and Cumulative Distribution Function.

ResultsRepeatable acquisition and estimation methods were identified based on the probability of relative phase errors. For single-echo GRE and segmented EPI sequences, a region-growing method was most reliable with Pr(relative error<0.1)=0.95 and 0.90 respectively. For multi-echo sequences, a Maximum-Likelihood method was most reliable with Pr(relative error<0.1)=0.97. The most repeatable multi-echo methods outperformed the most repeatable single-echo methods.

ConclusionsWe found a wide range of repeatability and reproducibility for off-the-shelf MRI acquisition and phase estimation approaches. The error was dominated in many cases by spatially discontinuous phase unwrapping errors. Any post-processing applied on erroneous phase estimates, such as QSMs background field removal and dipole inversion, would suffer from error propagation. Our paradigm identifies methods that yield consistent and accurate phase estimates that would ultimately yield consistent and accurate {Delta}{chi} estimates.

category: bioengineering


title: HMMploidy: inference of ploidy levels from short-read sequencing data

abstract: The inference of ploidy levels from genomic data is important to understand molecular mechanisms underpinning genome evolution. However, current methods based on allele frequency and sequencing depth variation do not have power to infer ploidy levels at low- and mid-depth sequencing data, as they do not account for data uncertainty. Here we introduce HMMploidy, a novel tool that leverages the information from multiple samples and combines the information from sequencing depth and genotype likelihoods. We demonstrate that HMMploidy outperforms existing methods in most tested scenarios, especially at low-depth with large sample size. We apply HMMploidy to sequencing data from the pathogenic fungus Cryptococcus neoformans and retrieve pervasive patterns of aneuploidy, even when artificially downsampling the sequencing data. We envisage that HMMploidy will have wide applicability to low-depth sequencing data from polyploid and aneuploid species.


title: The convergent CTCF loop formed by DNA extrusion is the basis of promoter enhancer interactions

abstract: 1Aggregate Hi-C maps centered on several genetic elements show significant DNA extrusion features. However, these features are missing from the component Hi-C images. To resolve this discrepancy, we present a new computational framework that reconstructs DNA extrusion scenarios (DESs) and explains the enhancement of DNA extrusion features by aggregation. We showed that the reconstructed DES is essential to understand the site interactions of the relevant genetic elements. For example, CCCTC-binding factor (CTCF) binding elements (CBE) with a specific motif direction are only affected by DNA extrusion activities initiated from one side, manifested as a directional bias. About half of promoters search for enhancers in a specific direction, as indicated by the corresponding DES. Moreover, since DNA extrusion does not pause at promoter or enhancer elements, direct promoter-enhancer contacts are not long-lasting; rather, promoters and enhancers are brought in proximity by continuous, dynamic DNA extrusion.


title: Characterization of DNA extrusion scenarios underlying aggregate Hi-C patterns by a new computational framework


title: Classifying COVID-19 variants based on genetic sequences using deep learning models

abstract: The COrona VIrus Disease (COVID-19) pandemic led to the occurrence of several variants with time. This has led to an increased importance of understanding sequence data related to COVID-19. In this chapter, we propose an alignment-free k-mer based LSTM (Long Short-Term Memory) deep learning model that can classify 20 different variants of COVID-19. We handle the class imbalance problem by sampling a fixed number of sequences for each class label. We handle the vanishing gradient problem in LSTMs arising from long sequences by dividing the sequence into fixed lengths and obtaining results on individual runs. Our results show that one-vs-all classifiers have test accuracies as high as 92.5% with tuned hyperparameters compared to the multi-class classifier model. Our experiments show higher overall accuracies for B.1.1.214, B.1.177.21, B.1.1.7, B.1.526, and P.1 on the one-vs-all classifiers, suggesting the presence of distinct mutations in these variants. Our results show that embedding vector size and batch sizes have insignificant improvement in accuracies, but changing from 2-mers to 3-mers mostly improves accuracies. We also studied individual runs which show that most accuracies improved after the 20th run, indicating that these sequence positions may have more contributions to distinguishing among different COVID-19 variants.


title: Atrazine induced In vivo immunotoxic studies in Bivalves

abstract: Atrazine is ubiquitously used broad-spectrum herbicide to control the weeds in agriculture. The present study aimed to evaluate the acute toxicity and immunotoxicity of Atrazine in two ecologically and economically important bivalves. Acute toxicity of atrazine evaluated in triplicates by taking control and six experimental groups each comprising of 30 animals and treated with a range of atrazine from 2 PPM to 12 PPM for 96 hours. Mortalities were recorded for every 24 hours until 96 hours and data analyzed by one-way ANOVA and Dunnett T-test. The results indicated a significant increase in mortalities with increase in dose and time of exposure in both species. The values of LC50 were determined as 6.10 PPM and 4.90 PPM respectively for Perna viridis and Paphia malabarica. Furthermore, the immunotoxic potential of atrazine assessed by treating mussels and clams with the five sub-lethal doses of atrazine for 14 days and quantifying the viability of hemocytes by using simple yet reliable Tryphan blue exclusion assay. The results of the present study suggest atrazine-induced immunotoxicity by decreasing the number of viable hemocytes in bivalves. Hemocytes with phagocytic function are indispensable to confer innate immunity in bivalves, decreased viability of these cells leads to compromised immunity. This study is first of its kind to implicate atrazine with the immunotoxicity in bivalves.

category: pharmacology and toxicology


title: Atrazine induced In vivo immunotoxicity in Bivalves


title: Unrevealing water and carbon relations during and after heat and hot drought stress in Pinus sylvestris

abstract:
Forests are increasingly affected by heatwaves, often co-occurring with drought, with consequences for water and carbon (C) cycling. However, our ability to project the resilience of trees to an intensification of hot droughts remains limited. Here, we used single tree cuvettes (n=18) allowing us to investigate transpiration (E), net assimilation (Anet), root respiration (Rroot) and stem diameter change in Scots pine seedlings during gradually intensifying heat or drought-heat stress (max. 42{degrees}C), and post-stress. Further, we assessed indicators of stress impacts and recovery capacities.

Under heat stress, well-watered seedlings prevented overheating of leaves effectively via increased E, while under drought-heat leaf temperatures increased to 46{degrees}C. However, leaf electrolyte leakage was negligible, but Fv/Fm declined alongside Anet moderately in heat but strongly in drought-heat seedlings, in which respiration exceeded C uptake. Further, the decrease of needle water potential ({psi}Needle) to -2.7 MPa and relative needle water content (RWCNeedle) under drought-heat reflected a decline of leaf hydraulic conductance (KLeaf) by 90% and stem hydraulic conductivity (KS) by 25%. Alongside, we observed pronounced stem diameter shrinkage.

Heat stress alone resulted in low functional impairment and all measured parameters recovered fast. In contrast, larger impacts following combined heat and drought led to the incomplete recovery of KLeaf and KS. Despite Anet tended to be reduced albeit Fv/Fm had recovered, the seedlings net C balance reached control values 2 d after stress release and stem growth rates exceeded control rates in the 2nd week post-stress. This indicates that a new equilibrium of C uptake and release was maintained at the tree level, slowly supporting regaining of stress-induced losses.

In summary, we highlight that under moderate heatwaves with low functional impairment, recovery is fast in Scots pine, while in combination with drought hydraulic and thermal stress are intensified, resulting in functional damage and delayed recovery processes. The incomplete recovery of hydraulic conductance indicates limited water transport capacities that could become critical under repeated heat events.


title: First report of Lactoria cornuta from the west coast of India, Evidence of the role of tropical cyclone Ockhi

abstract: India is known for its rich biodiversity and is fortunate to have several endemic species from different classes of vertebrates. India is home to 7.5% of the global fish diversity, with 91 endemic species of ray finned fishes, the actinopterygians. Some fish species have never been reported until recently, one such example is the long-horned Cowfish (Ostracidae), best known for inhabiting only certain areas of the Indo-Pacific oceans. However, this fish has been reported from Bay of Bengal, Costs of Goa and Lakshadweep. This is the first time this fish has been found on the Coasts of Karnataka, west coast of India. Given its morphology, the migration seems highly improbable since it can only endure lethargic swimming. In this article, we have explored the role of other external forces that could have contributed to its range extension in the east and west coast of India. In this paper we are exploring the role of Super Cyclones as a vital force in determining the expansion of its range. The fact of collection longhorn cowfish for the first time from the coast of Karwar coincides with the passage of Cyclone Ockhi on the west coast of India this suggests the possible role of super cyclone in its range extension. A year later, another specimen was recovered from a location very close to the first, which indicates the successful establishment of Lacturia cornuta in its new environment. Related morphometric and meristic studies of our specimens are consistent with previous studies reported in the Bay of Bengal.


title: First Report of Lactoria cornuta from Karnataka, West coast of India, Role of tropical cyclones in Range Extension


title: Increasing neural network robustness improves match to macaque V1 eigenspectrum, spatial frequency preference and predictivity

abstract:
Task-optimized convolutional neural networks (CNNs) show striking similarities to the ventral visual stream. However, human-imperceptible image perturbations can cause a CNN to make incorrect predictions. Here we provide insight into this brittleness by investigating the representations of models that are either robust or not robust to image perturbations. Theory suggests that the robustness of a system to these perturbations could be related to the power law exponent of the eigenspectrum of its set of neural responses, where power law exponents closer to and larger than one would indicate a system that is less susceptible to input perturbations. We show that neural responses in mouse and macaque primary visual cortex (V1) obey the predictions of this theory, where their eigenspectra have power law exponents of at least one. We also find that the eigenspectra of model representations decay slowly relative to those observed in neurophysiology and that robust models have eigenspectra that decay slightly faster and have higher power law exponents than those of non-robust models. The slow decay of the eigenspectra suggests that substantial variance in the model responses is related to the encoding of fine stimulus features. We therefore investigated the spatial frequency tuning of artificial neurons and found that a large proportion of them preferred high spatial frequencies and that robust models had preferred spatial frequency distributions more aligned with the measured spatial frequency distribution of macaque V1 cells. Furthermore, robust models were quantitatively better models of V1 than non-robust models. Our results are consistent with other findings that there is a misalignment between human and machine perception. They also suggest that it may be useful to penalize slow-decaying eigenspectra or to bias models to extract features of lower spatial frequencies during task-optimization in order to improve robustness and V1 neural response predictivity.

Author summaryConvolutional neural networks (CNNs) are the most quantitatively accurate models of multiple visual areas. In contrast to humans, however, their image classification behaviour can be modified drastically by human-imperceptible image perturbations. To provide insight as to why CNNs are so brittle, we investigated the image features extracted by models that are robust and not robust to these image perturbations. We found that CNNs had a preference for high spatial frequency image features, unlike primary visual cortex (V1) cells. Models that were more robust to image perturbations had a preference for image features more aligned with those extracted by V1 and also improved predictions of neural responses in V1. This suggests that the dependence on high-frequency image features for image classification may be related to the image perturbations affecting models but not humans. Our work is consistent with other findings that CNNs may be relying on image features not aligned with those used by humans for image classification and suggests possible optimization targets to improve the robustness of and the V1 correspondence of CNNs.


title: Cherry-picking information: humans actively sample evidence to support prior beliefs

abstract: No one likes to be wrong. Previous research has shown that participants may underweight information incompatible with previous choices, a phenomenon called confirmation bias. In this paper we argue that a similar bias exists in the way information is actively sought. We investigate how choice influences information gathering using a perceptual choice task and find that participants sample more information from a previously chosen alternative. Furthermore, the higher the confidence in the initial choice, the more biased information sampling becomes. As a consequence, when faced with the possibility of revising an earlier decision, participants are more likely to stick with their original choice, even when incorrect. Critically, we show that agency controls this phenomenon. The effect disappears in a fixed sampling condition where presentation of evidence is controlled by the experimenter, suggesting that the way in which confirmatory evidence is acquired critically impacts the decision process. These results suggest active information acquisition plays a critical role in the propagation of strongly held beliefs over time.


title: The expectant brain: Being pregnant causes changes in brain morphology in the early postpartum period

abstract:
There is growing evidence that pregnancy may have a significant impact on the maternal brain, causing changes in its structure. However, the patterns of these changes have not yet been systematically investigated. Using voxel-based (VBM) and surface-based morphometry (SBM), we compared a group of healthy primiparous women (n = 40) with healthy multiparous mothers (n = 37) as well as nulliparous women (n = 40). Compared to the nulliparous women, the young mothers showed decreases in gray matter volume in the bilateral hippocampus/amygdala, the orbitofrontal cortex/subgenual prefrontal area, the right superior temporal gyrus, the right insula, and the cerebellum. However, these pregnancy-related changes in brain structure did not predict the quality of mother-infant attachment at either 3 or 12 weeks postpartum, nor were they more pronounced among the multiparous women. SBM analyses showed significant cortical thinning especially in the frontal and parietal cortices, with the parietal cortical thinning likely potentiated by multiple pregnancies. We conclude, therefore, that the widespread morphological changes seen in the brain shortly after childbirth reflect substantial neuroplasticity. Also, the experience of pregnancy alone may not be the underlying cause of the adaptations for mothering and caregiving. As regards the exact biological function of the changes in brain morphology as well as the long-term effect of pregnancy on the maternal brain, further longitudinal research with larger cohorts will be needed to draw any definitive conclusions.

Significance StatementBiological adaptations during pregnancy affect the maternal brain. Here, we evaluated morphological changes in the brain of mentally healthy young mothers within the first four days of childbirth. Compared to the nulliparous women, the young primiparous and multiparous mothers demonstrated a substantial reduction in gray matter volume in brain areas related to socio-cognitive and emotional processes. Cortical alterations due to pregnancy-related adaptations are not the underlying cause of mother-infant attachment.


title: A neuromorphic model of olfactory processing and sparse coding in the Drosophila larva brain

abstract: Animal nervous systems are highly efficient in processing sensory input. The neuromorphic computing paradigm aims at the hardware implementation of neural network computations to support novel solutions for building brain-inspired computing systems. Here, we take inspiration from sensory processing in the nervous system of the fruit fly larva. With its strongly limited computational resources of <200 neurons and <1.000 synapses the larval olfactory pathway employs fundamental computations to transform broadly tuned receptor input at the periphery into an energy efficient sparse code in the central brain. We show how this approach allows us to achieve sparse coding and increased separability of stimulus patterns in a spiking neural network, validated with both software simulation and hardware emulation on mixed-signal real-time neuromorphic hardware. We verify that feedback inhibition is the central motif to support sparseness in the spatial domain, across the neuron population, while the combination of spike frequency adaptation and feedback inhibition determines sparseness in the temporal domain. Our experiments demonstrate that such small-sized, biologically realistic neural networks, efficiently implemented on neuromorphic hardware, can achieve parallel processing and efficient encoding of sensory input at full temporal resolution.


title: Adaptation in cone photoreceptors contributes to an unexpected insensitivity of On parasol retinal ganglion cells to spatial structure in natural images

abstract: Neural circuits are constructed from nonlinear building blocks, and not surprisingly overall circuit behavior is often strongly nonlinear. But neural circuits can also behave near linearly, and some circuits shift from linear to nonlinear behavior depending on stimulus conditions. Such control of the linearity or nonlinearity of circuit behavior is fundamental to neural computation. Here we study a surprising stimulus dependence of the responses of On (but not Off) parasol retinal ganglion cells: these cells respond nonlinearly to spatial structure in temporally-modulated grating stimuli but linearly to spatial structure in flashed gratings and natural visual inputs. We show that this unexpected response linearity can be explained by a shift in the balance of excitatory and inhibitory synaptic inputs that originates at least in part from adaptation in the cone photoreceptors. More generally, this highlights how subtle asymmetries in signaling - here in the cone signals - can qualitatively alter circuit computation.


title: Quercetin ameliorates mitochondrial dysfunction and mitigates methamphetamine-induced anxiety-like behavior

abstract: Methamphetamine (MA) abuse results in neurotoxic outcomes, including increased anxiety and depression, during both MA use and withdrawal. Although numerous studies have reported an association between MA exposure and anxiety, the underlying mechanism remains elusive. In this study, escalating dose of MA was used to establish an MA-treated mouse model presenting anxiety behavior. RNA seq was then performed to profile the gene expression patterns in the hippocampus (HIPP). Differentially expressed genes (DEGs) were identified and function enrichment analysis was conducted to explore the underlying mechanisms. Quercetin as an mitochondria protector was used in vivo and in vitro. The C57BL/6J mice were co-treated with 50 mg/kg Quercetin and escalating MA. Anxiety behavior was evaluated by utilizing the elevated plus maze and the open field test. Transmission electron microscopy and immunohistochemistry were conducted to study the pathology of MA-inducced anxiety. The effects of MA and Quercetin on astrocytes were investigated by fluorescence staining, transmission electron microscopy, flow cytometry, and oxygen consumption rate. Western blot and qPCR were performed to analyze altered protein and gene levels of HIPP in mice and astrtocytes. The results demonstrated that forteen upregulated differentially expressed genes were identified and significantly enriched in signaling pathways related to psychiatric disorders and mitochondrial function. Interestingly, we found that quercetin was able to alleviate MA-induced anxiety-like behavior by improving neuron number and mitochondria injury. Mechanistically, quercetin can mitigate aberrant mitochondrial morphology and mitochondrial dysfunction not only by decreasing the levels of total cytoplasmic reactive oxygen species (ROS), mitochondria-derived ROS (mtROS), and mitochondrial membrane potential (MMP), but also increasing the oxygen consumption rate (OCR) and mitochondrial ATP production in vitro, indicating Quercetin ameliorated MA-induced anxiety-like behavior by modifying mitochondrial morphology and function. Furthermore, quercetin reversed OPA1 and DRP1 expression in astrocytes, and mitigated astrocyte activation and the release of inflammatory factors, which can trigger neuronal apoptosis and synaptic loss. Taken together, we provided evidence showing that MA can induce anxiety-like behavior via the induction of oxidative stress and mitochondrial dysfunction. Quercetin exerted antipsychotic activity through mitochondrial modulation, suggesting its potential for further therapeutic development in MA-induced anxiety.