Miracle-dz/UniFAR-FTUs huggingface dataset:
Cumulative Risk on Oxytocin-Pathway Genes Impairs Default Mode Network Connectivity in Trauma-Exposed Youth

Background: Although the default mode network (DMN) is a core network essential for brain functioning, little is known about its developmental trajectory, particularly on factors associated with its coherence into a functional network. In light of adult studies indicating DMN's susceptibility to stress-related conditions, we examined links between variability on oxytocin-pathway genes and DMN connectivity in youth exposed to chronic war-related trauma Methods: Following a cohort of war-exposed children from early childhood, we imaged the brains of 74 preadolescents (age 11–13 years; 39 war-exposed) during rest using magnetoencephalography (MEG). A cumulative risk index on oxytocin-pathway genes was constructed by combining single nucleotide polymorphisms on five genes previously linked with social deficits and psychopathology; OXTR rs1042778, OXTR rs2254298, OXTRrs53576, CD38 rs3796863, and AVPR1A RS3. Avoidant response to trauma reminders in early childhood and anxiety disorders in late childhood were assessed as predictors of disruptions to DMN theta connectivity. Results: Higher vulnerability on oxytocin-pathway genes predicted greater disruptions to DMN theta connectivity. Avoidant symptoms in early childhood and generalized anxiety disorder in later childhood were related to impaired DMN connectivity. In combination, stress exposure, oxytocin-pathway genes, and stress-related symptoms explained 24.6% of the variance in DMN connectivity, highlighting the significant effect of stress on the maturing brain. Conclusions: Findings are the first to link the oxytocin system and maturation of the DMN, a core system sustaining autobiographical memories, alteration of intrinsic and extrinsic attention, mentalization, and sense of self. Results suggest that oxytocin may buffer the effects of chronic early stress on the DMN, particularly theta rhythms that typify the developing brain.
Conjugate graph resolves the complex structures at the virus integration loci with NGS data

Oncovirus integration introduced local genome instability on host genomes, in terms of copy number changes and structural variations. We present an algorithm, which implements double-strand-aware conjugate graph, to construct the rearranged local genomic map at viral integration loci. Diverse simulation data tests prove the availability and credibility of our algorithm. Applications of the algorithm to whole genome sequencing data of cervical carcinomas support reliable biological investigation on human papillomavirus integrations.
An updated global COI barcode reference data set for Fall Armyworm (Spodoptera frugiperda) and first record of this species in Bhutan

We report the first detection of Fall Armyworm (FAW), Spodoptera frugiperda (Smith, 1797), in Bhutan. FAW feeds on more than 300 plant species and is a serious pest of many. It has been spreading through Africa since 2016 and Asia since 2018. In Bhutan, this species was first detected in maize fields in the western part of the country in September 2019 and subsequently found infesting maize crop in southern parts of the country in December 2019 and April 2020. Using morphological and molecular techniques the presence of the first invading populations of S. frugiperda in Bhutan is confirmed through this study. We present an updated reference DNA barcode data set for FAW comprising 374 sequences, which can be used to reliably identify this serious pest species, and discuss some of the reasons why such compiled reference data sets are necessary, despite the publicly availability of the underlying data. We also report on a second armyworm species, the Northern Armyworm, Mythimna separata (Walker, 1865), in rice, maize and other crops in eighteen districts of Bhutan.
Two mutations P/L and Y/C in SARS-CoV-2 helicase domain exist together and influence helicase RNA binding

RNA helicases play pivotal role in RNA replication by catalysing the unwinding of complex RNA duplex structures into single strands in ATP/NTP dependent manner. SARS coronavirus 2 (SARS-CoV-2) is a single stranded positive sense RNA virus belonging to the family Coronaviridae. The viral RNA encodes non structural protein Nsp13 or the viral helicase protein that helps the viral RNA dependent RNA polymerase (RdRp) to execute RNA replication by unwinding the RNA duplexes. In this study we identified a novel mutation at position 541of the helicase where the tyrosine (Y) got substituted with cytosine (C). We found that Y541C is a destabilizing mutation increasing the molecular flexibility and leading to decreased affinity of helicase binding with RNA. Earlier we had reported a mutation P504L in the helicase protein for which had not performed RNA binding study. Here we report that P504L mutation leads to increased affinity of helicase RNA interaction. So, both these mutations have opposite effects on RNA binding. Moreover, we found a significant fraction of isolate population where both P504L and Y541C mutations were co-existing.
NAIP–NLRC4-deficient mice are susceptible to shigellosis

Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Shigellosis develops upon oral ingestion of as few as 100 bacteria, but million-fold higher doses fail to cause disease in mice. The lack of a physiologically relevant mouse model of shigellosis has impeded our understanding of this important human disease, but why mice are resistant is unknown. Here we show that in human cells, but not in mice, Shigella evades detection by the NAIP–NLRC4 inflammasome, an immune sensor present in intestinal epithelial cells (IECs). We find that NAIP–NLRC4-deficient mice are highly susceptible to oral Shigella infection and recapitulate the clinical features of human shigellosis, including bacterial replication in IECs and neutrophilic inflammation of the colon. Confirming a role for bacterial replication in IECs in our new model, a Shigella mutant lacking IcsA, a factor required for cell-to-cell spread among IECs, is attenuated in otherwise susceptible NAIP–NLRC4-deficient mice. Although inflammasome-mediated cell death is widely held to promote Shigella infection and pathogenesis, we instead demonstrate that IEC-specific NAIP–NLRC4-induced cell death is sufficient to protect the host from shigellosis. Thus, NAIP–NLRC4-deficient mice are a physiologically relevant and experimentally tractable model for shigellosis. More broadly, our results suggest that the lack of an inflammasome response in IECs may help explain the extreme susceptibility of humans to shigellosis.
Enhancer RNAs are necessary and sufficient for activity-dependent neuronal gene transcription

Enhancer elements in DNA regulate gene expression programs important for neuronal fate and function, and are increasingly implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs), but the function of eRNAs in neuronal systems remains controversial. Here, we performed genome-wide characterization of transcribed enhancers from rat cortical neurons, revealing elevated sequence conservation, enriched localization near genes involved in neuronal or synaptic function, and correlated activity-dependent regulation of putative eRNA-mRNA pairs. Functional validation using a CRISPR-dCas9 fusion system to drive eRNA synthesis from enhancers produced corresponding increases in mRNA at linked genes. Focusing on eRNAs arising from enhancers at the Fos gene locus, we report that eRNA and mRNA correlate on a single-cell level, that CRISPR-targeted eRNA delivery to an enhancer is sufficient for mRNA induction, and that eRNA knockdown decreases mRNA and alters neuronal physiology. These results suggest that eRNAs regulate gene expression and neuronal function.
Spatiotemporal variation in drivers of parasitism in a wild wood mouse population

Host-parasite interactions in nature are driven by a range of factors across several ecological scales, so observed relationships are often context-dependent. Importantly, if these factors vary across space and time, practical sampling limitations can limit or bias inferences, and the relative importance of different drivers can be hard to discern. We collected a replicated, longitudinal dataset of >1000 individual wood mice (Apodemus sylvaticus) encompassing 6 years of sampling across 5 different woodland sites to investigate how environmental, host and within-host factors determine infection intensity of a highly prevalent gastrointestinal nematode, Heligmosomoides polygyrus. We used a Bayesian modelling approach to further quantify if and how each factor varied in space and time. Finally, we examined the extent to which a lack of spatially or temporally replication (i.e., within single years or single sites) and single (cross-sectional) versus repeated (longitudinal) sampling of individuals would affect which drivers were found to predict H. polygyrus infection. Season, host body condition, and sex were the three most important determinants of infection intensity; however, the strength and even direction of these effects varied in time, but not in space. Additionally, longitudinal datasets, in which we can control for within-individual variation through repeat observations, provided more robust estimates of the drivers of parasite intensity compared to cross-sectional data. These results highlight the importance of accounting for spatiotemporal variation in drivers of disease dynamics and the need to incorporate spatiotemporal replication when designing sampling regimes. Furthermore, they suggest that embracing rather than simply controlling for spatiotemporal variation can reveal important insight into host-parasite relationships in the wild.
Diazotrophic bacteria from maize exhibit multifaceted plant growth promotion traits in multiple hosts

Sierra Mixe maize is a geographically remote landrace variety grown on nitrogen-deficient fields in Oaxaca, Mexico that meets its nutritional requirements without synthetic fertilizer by associating with free-living diazotrophs comprising the microbiota of its aerial root mucilage. We selected nearly 500 diazotrophic bacteria isolated from Sierra Mixe maize mucilage and sequenced their genomes. Comparative genomic analysis demonstrated that isolates represented diverse genera and possessed multiple marker genes for mechanisms of direct plant growth promotion (PGP). In addition to nitrogen fixation, we examined deamination of 1-amino-1-cyclopropanecarboxylic acid, biosynthesis of indole-3-acetic acid, and phosphate solubilization. Implementing in vitro colorimetric assays revealed each isolate’s potential to confer the alternative PGP activities that corroborated genotype and pathway content. We examined the ability of mucilage diazotrophs to confer PGP by direct inoculation of clonally propagated potato plants in planta, which led to the identification of bio-stimulant candidates that were tested for PGP by inoculating a conventional maize variety. The results indicate that, while many diazotrophic isolates from Sierra Mixe maize possessed genotypes and in vitro phenotypes for targeted PGP traits, a subset of these organisms promoted the growth of potato and conventional maize using multiple promotion mechanisms.
Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel

CLC-2 is a voltage-gated chloride channel that is widely expressed in many mammalian tissues. In the central nervous system (CNS), CLC-2 is expressed in neurons and glia. Studies to define how this channel contributes to normal and pathophysiological function in the CNS have been controversial, in part due to the absence of precise pharmacological tools for modulating CLC-2 activity. Herein, we describe the development and optimization of AK-42, a specific small-molecule inhibitor of CLC-2 with nanomolar potency (IC50 = 17 ± 1 nM). AK-42 displays unprecedented selectivity (>1000-fold) over CLC-1, the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 58 common channels, receptors, and transporters expressed in brain tissue. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. In electrophysiological recordings of mouse CA1 hippocampal pyramidal neurons, AK-42 acutely and reversibly inhibits CLC-2 currents; no effect on current is observed on brain slices taken from CLC-2 knockout mice. These results establish AK-42 as a powerful new tool for investigating CLC-2 neurophysiology. Significance Statement The CLC-2 ion channel facilitates selective passage of Cl− ions across cell membranes. In the central nervous system (CNS), CLC-2 is expressed in both neurons and glia and is proposed to regulate electrical excitability and ion homeostasis. CLC-2 has been implicated in various CNS disorders, including certain types of epilepsy and leukodystrophy. Establishing a causative role for CLC-2 in neuropathologies, however, has been limited by the absence of selective reagents that enable acute and specific channel modulation. Our studies have resulted in the identification of a highly potent, small-molecule inhibitor that enables specific block of CLC-2 Cl− currents in hippocampal brain slices. This precise molecular tool should enable future efforts to identify and treat CLC-2-related disease.
A unique and evolutionarily conserved retinal interneuron relays rod and cone input to the inner plexiform layer

Neurons in the CNS are distinguished from each other by their morphology, the types of the neurotransmitter they release, their synaptic connections, and their genetic profiles. While attempting to characterize the retinal bipolar cell (BC) input to retinal ganglion cells (RGCs), we discovered a previously undescribed type of interneuron in mice and primates. This interneuron shares some morphological, physiological, and molecular features with traditional BCs, such as having dendrites that ramify in the outer plexiform layer (OPL) and axons that ramify in the inner plexiform layer (IPL) to relay visual signals from photoreceptors to inner retinal neurons. It also shares some features with amacrine cells, particularly Aii amacrine cells, such as their axonal morphology and possibly the release of the inhibitory neurotransmitter glycine, along with the expression of some amacrine cell specific markers. Thus, we unveil an unrecognized type of interneuron, which may play unique roles in vision. Significance Statement Cell types are the building blocks upon which neural circuitry is based. In the retina, it is widely believed that all neuronal types have been identified. We describe a cell type, which we call the Campana cell, that does not fit into the conventional neuronal retina categories but is evolutionarily conserved. Unlike retinal bipolar cells, the Campana cell receives synaptic input from both rods and cones, has broad axonal ramifications, and may release an inhibitory neurotransmitter. Unlike retinal amacrine cells, the Campana cell receives direct photoreceptor input has bipolar-like ribbon synapses. With this discovery, we open the possibility for new forms of visual processing in the retina.
Shifts from pulled to pushed range expansions caused by reduction of landscape connectedness

Range expansions are key processes shaping the distribution of species; their ecological and evolutionary dynamics have become especially relevant today, as human influence reshapes ecosystems worldwide. Many attempts to explain and predict these phenomena assume, explicitly or implicitly, so-called “pulled” expansion dynamics, in which the low-density edge populations provide most of the “fuel” for the species advance. Some expansions, however, exhibit very different dynamics, with high-density populations behind the front “pushing” the expansion forward. These two types of expansions are predicted to have different effects on factors such as genetic diversity and habitat quality sensitivity. However, studies are lacking due to the challenge of generating reliably pushed vs. pulled expansions in the laboratory, or discriminating them in the field. We here propose that manipulating the degree of structural connectivity (connectedness) among populations may prove a more generalizable way to create pushed expansions. We demonstrate this with both individual-based simulations as well as replicated experimental range expansions (using the parasitoid wasp Trichogramma brassicae as model). By analysing expansion velocities and neutral genetic diversity, we showed that reducing connectedness led to pushed dynamics. Our numerical and experimental results suggest that reducing connectedness can cause density-dependent spread (and thus pushed range expansions) both directly or by amplifying existing density-dependence. In the current context of habitat loss and fragmentation, we need to better account for this relationship between connectedness and expansion regimes to successfully predict the ecological and evolutionary consequences of range expansions.
The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.
Genomic diversity of 39 samples of Pyropia species grown in Japan

Some Pyropia species, such as nori (P. yezoensis), are important marine crops. We conducted a phylogenetic analysis of 39 samples of Pyropia species grown in Japan using organellar genome sequences. A comparison of the chloroplast DNA sequences with those from China showed a clear genetic separation between Japanese and Chinese P. yezoensis. Conversely, comparing the mitochondrial DNA sequences did not separate Japanese and Chinese P. yezoensis. Analysis of organellar genomes showed that the genetic diversity of Japanese P. yezoensis used in this study is lower than that of Chinese wild P. yezoensis. To analyze the genetic relationships between samples of Japanese Pyropia, we used whole-genome resequencing to analyze their nuclear genomes. In the offspring resulting from cross-breeding between P. yezoensis and P. tenera, nearly 90% of the genotypes analyzed by mapping were explained by the presence of different chromosomes originating from two different parental species. Although the genetic diversity of Japanese P. yezoensis is low, analysis of nuclear genomes genetically separated each sample. Samples isolated from the sea were often genetically similar to those being farmed. Study of genetic heterogeneity of samples within a single aquaculture strain of P. yezoensis showed that samples were divided into two groups and the samples with frequent abnormal budding formed a single, genetically similar group. The results of this study will be useful for breeding and the conservation of Pyropia species.
Pair-wise Interactions in Gene Expression Determine a Hierarchical Transcription Profile of the Human Brain

Orchestrated expressions of tens of thousands of genes give rise to the complexity of the brain. However, it is unclear what is the structure governing these myriads of gene-gene interactions. By analyzing the transcription data obtained from more than 3000 sites in human brains, we found that pair-wise interactions between genes are sufficient to accurately predict both the transcription pattern of the whole genome for individual brain areas and the transcription profile of the entire brain, suggesting a surprisingly simple interaction structure of the transcriptome itself. We further revealed that the strength of gene-gene interaction observed empirically allows the nearly maximal number of transcriptionally similar clusters of areas to form, which may account for the functional and structural richness of the brain. One Sentence Summary Pairwise interactions among genes shape the overall structure of human brain transcriptome.
Lipid Droplet Is an Ancient and Inheritable Organelle in Bacteria

Lipid droplet (LD) is a monolayer phospholipid membrane-bound organelle found in all eukaryotes and several prokaryotes which plays key roles in cellular lipid homeostasis and human health. The origin and evolution of the organelle remains unknown. Here, we report that through screening over 660 bacteria using biophysical and biochemical methods, plus LD isolation and proteomic tool, LDs were identified in most of these microbes, affiliated with five main bacterial phyla. Moreover, LDs were also identified in E. coli overexpressing lipid synthesis enzymes, indicating that bacteria without detectable LDs possessed the ability of LD biogenesis. The similarity of isolated LDs from representative strains and evolutionary analysis of LD major protein PspA demonstrate that LDs were conserved in bacteria. Furthermore, time-lapse imaging revealed that LDs were inheritable accompanying with bacterial growth and division. Finally, a common ancestor of LD-containing bacteria was predicted to originate 3.19 billion years ago by a phylogenetic analysis. Our findings suggest that LD is a widespread and inheritable organelle from an ancient common ancestor.
Single-cell regulatory landscape and disease vulnerability map of adult Macaque cortex

Non-human primates (NHP) provide a unique opportunity to study human neurological diseases, yet detailed characterization of the cell types and transcriptional regulatory features in the NHP brain is lacking. We applied a combinatorial indexing assay, sci-ATAC-seq, as well as single-nuclei RNA-seq, to profile chromatin accessibility in 43,793 single cells and transcriptomics in 11,477 cells, respectively, from prefrontal cortex, primary motor cortex and the primary visual cortex of adult cynomolgus monkey Macaca fascularis. Integrative analysis of these two datasets, resolved regulatory elements and transcription factors that specify cell type distinctions, and discovered area-specific diversity in chromatin accessibility and gene expression within excitatory neurons. We also constructed the dynamic landscape of chromatin accessibility and gene expression of oligodendrocyte maturation to characterize adult remyelination. Furthermore, we identified cell type-specific enrichment of differentially spliced gene isoforms and disease-associated single nucleotide polymorphisms. Our datasets permit integrative exploration of complex regulatory dynamics in macaque brain tissue at single-cell resolution.