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Most tweeted bioRxiv papers, last 24 hours
258 results found. For more information, click each entry to expand.
5 tweets neuroscience
The mammalian neocortex is subdivided into a series of ‘cortical areas’ that are functionally and anatomically distinct, and are often distinguished in brain sections using histochemical stains and other markers of protein expression. We searched the Allen Mouse Brain Atlas, a database of gene expression, for novel markers of cortical areas. We employed a random forest algorithm to screen for genes that change expression at area borders. We found novel genetic markers for 19 of 39 areas and provide code that quickly and efficiently searches the Allen Mouse Brain Atlas.
5 tweets neuroscience
J. Edward van Veen, Laura G. Kammel, Patricia C. Bunda, Michael Shum, Michelle S Reid, Jae W. Park, Zhi Zhang, Megan G. Massa, Douglas Arneson, Haley Hrncir, Marc Liesa, Arthur P. Arnold, Xia Yang, Stephanie M Correa
Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ERα) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.
5 tweets systems biology
Although mRNAs are key molecules for understanding life, there exists no method to determine the full-length sequence of endogenous mRNAs including their poly(A) tails. Moreover, although poly(A) tails can be modified in functionally important ways, there also exists no method to accurately sequence them. Here, we present FLAM-seq, a rapid and simple method for high-quality sequencing of entire mRNAs. We report a cDNA library preparation method coupled to single-molecule sequencing to perform FLAM-seq. Using human cell lines, brain organoids, and C. elegans we show that FLAM-seq delivers high-quality full-length mRNA sequences for thousands of different genes per sample. We find that (a) 3' UTR length is correlated with poly(A) tail length, (b) alternative polyadenylation sites and alternative promoters for the same gene are linked to different tail lengths, (c) tails contain a significant number of cytosines. Thus, we provide a widely useful method and fundamental insights into poly(A) tail regulation.
5 tweets genetics
Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. ARHI is a multifactorial condition caused by both genetic and environmental factors, with estimates of heritability between 35% and 55%. The genetic risk factors and underlying biological pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive. We performed genome-wide association studies (GWAS) for two self-reported hearing phenotypes, hearing difficulty (HDiff) and hearing aid use (HAid), using over 250,000 UK Biobank volunteers aged between 40-69 years. We identified 44 independent genome-wide significant loci (P<5E-08), 33 of which have not previously been associated with any form of hearing loss. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology and cognition. Immunohistochemistry for protein localisation in adult mouse cochlea indicate metabolic, sensory and neuronal functions for NID2, CLRN2 and ARHGEF28 identified in the GWAS. These results provide new insight into the genetic landscape underlying susceptibility to ARHI.
5 tweets cancer biology
The immune system is increasingly being recognized for its untapped potential in being recruited to attack tumors in cancer therapy. The main challenge, however, is that most tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. In order to investigate the ability to use chemotherapy to break immune tolerance, we created a mathematical modeling framework for tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximal tumor reduction and preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right", we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control.
5 tweets genetics
Loss-of-function (LoF) mutations associated with disease don't manifest equally in different individuals, a phenomenon known as incomplete penetrance. The impact of the genetic background on incomplete penetrance remains poorly characterized. Here, we systematically assessed the changes in gene deletion phenotypes for 3,786 gene knockouts in four Saccharomyces cerevisiae strains and 38 conditions. We observed 16% to 42% of deletion phenotypes changing between pairs of strains with a small fraction conserved in all strains. Conditions causing higher WT growth differences and the deletion of pleiotropic genes showed above average changes in phenotypes. We further illustrate how these changes affect the interpretation of the impact of genetic variants across 925 yeast isolates. These results show the high degree of genetic background dependencies for LoF phenotypes.
5 tweets ecology
Despite the great cultural and economic benefits associated with birdwatching and other bird-related cultural ecosystem services (CES), little is known about the bird-related CES perceived by people, and how they differ across stakeholder groups and species. The goal of this study was to explore CES across three stakeholder groups in northwestern Costa Rica. We conducted surveys (n=404 total) in which we presented farmers (n=140), urbanites (n=149), and birdwatchers (n=115) with pictures and songs of bird species and collected participants ratings on items designed to measure multiple CES. We found bird-related CES were perceived as six different constructs: identity, bequest, education, birdwatching, acoustic aesthetic, and disservices. The three stakeholder groups varied across these constructs and across species. Specifically, birdwatchers ranked species higher in terms of their education scores and lower in disservices scores compared to the other two groups. Positive correlations across CES, and negative correlations with disservices, suggest that the affect heuristic (by which generalized positive or negative feelings sway judgements of risks and benefits) might be informing bird-related CES. Our approach represents a novel method for assessing CES that can be adapted and modified for different taxa and multiple geographical contexts.
5 tweets cancer biology
Akimasa Hayashi, Jun Fan, Ruoyao Chen, Alvin P Makohon-Moore, Yi Zhong, Jungeui Hong, Hitomi Sakamoto, Marc A Attiyeh, Zachary A Kohutek, Lance Zhang, Jinlong Huang, Aida Boumiza, Rajya Kappagantula, Priscilla Baez, Laura D. Wood, Ralph H. Hruban, Lisi Marta, Kalyani Chadalavada, Gouri J Nanjangud, Olca Basturk, David S Klimstra, Michael Overholtzer, Christine A. Iacobuzio-Donahue
Recent studies indicate that pancreatic cancer expression profiles are variable and largely reflect a classical or basal-type phenotype. We performed genetic sequencing, RNA-seq, and histologic review of multiregion sampled pancreatic cancers and found that squamous and squamoid features, indicators of poor prognosis, correlate with a "basal -like" expressional type. Cancers with squamous features were more likely to have truncal mutations in chromatin modifier genes and intercellular heterogeneity for MYC amplification that was associated with entosis. In most patients the basal phenotype coexisted with a glandular component, and phylogenetic studies indicated that it arose from a subclonal population in the tumor. These data provide a unifying paradigm for understanding the interrelationship of basal-type features, squamous histology, and somatic mutations in chromatin modifier genes in the context of the clonal evolution of pancreatic cancer.
4 tweets neuroscience
Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (NOS1)-expressing interneurons might influence neurovascular relationships. In mice, specific activation of SST- or NOS1-interneurons was sufficient to evoke haemodynamic changes similar to those evoked by physiological whisker stimulation. In the case of NOS1-interneurons, robust haemodynamic changes occurred with minimal changes in neural activity. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. This often resulted in a central increase in blood volume with corresponding surround decrease, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.
4 tweets evolutionary biology
Understanding the mechanisms by which an introduced species adapt to newly encountered habitats is a major question in ecology. A key method to address this question is to collect data on introduced species that have successfully invaded a broad diversity of novel environments, and analyze how their life-history traits changed with these new constraints. Here, we present and analyze such a unique data set in the European earwig Forficula auricularia L, an insect that invaded North America during the last century. We conducted a common garden experiment, in which we measured 13 life-history traits in 4158 individuals from 19 populations across North America. Our results demonstrate that the successful invasion of this species came with changes in 10 of their life-history traits in response to thermal regimes (winter-summer and autumn-spring temperatures), but with no change in response to the overall mean temperatures of the invaded locations. Importantly, we show that some of these changes are by-products of novel thermal regimes, whereas others reflect adaptive strategies of females to these constraints. Overall, our findings reveal the importance of thermal regimes over mean temperatures in climate adaptation, and emphasize that studying adaptive capabilities is crucial to predict the limits of biological invasions.
4 tweets ecology
Tzemach Aouizerat, Itai Gutman, Yitzhak Paz, Aren M Maeir, Yuval Gadot, Daniel Gelman, Amir Szitenberg, Elyashiv Drori, Ania Pinkus, Miriam Schoemann, Rachel Kaplan, Tziona Ben-Gedalya, Shunit Coppenhagen-Glazer, Eli Reich, Amijai Saragovi Saragovi, Oded Lipschits, Michael Klutstein, Ronen Hazan
Ancient fermented food has been studied based on recipes, residue analysis and ancient-DNA techniques and reconstructed using modern domesticated yeast. Here, we present a novel approach. We hypothesize that enriched yeast populations in fermented beverages could have become the dominant species in storage vessels and the descendants of these yeast could be isolated and studied long after. To this end, using a pipeline of yeast isolation from clay vessels developed here, we screened for yeast cells in beverage-related and non-related ancient vessels and sediments, from several archeological sites. We found that yeast cells could be successfully isolated specifically from clay containers of fermented beverages. Genomic analysis revealed that these yeast are similar to those found in traditional African beverages. Phenotypically, they grow similar to modern-beer producing yeast. Both strongly suggesting that they are descendants of the original fermenting yeast. These findings provide modern microorganisms as a new tool in bio-archeology.
4 tweets neuroscience
Vladimir V Senatorov, Aaron R Friedman, Dan Z Milikovsky, Jonathan Ofer, Rotem Saar-Ashkenazy, Adiel Charbash, Naznin Jahan, Gregory Chin, Eszter Mihaly, Jessica M Lin, Harrison J Ramsay, Ariana Moghbel, Marcela K Preininger, Chelsy R Eddings, Helen V Harrison, Rishi Patel, Yishuo Shen, Hana Ghanim, Huanjie Sheng, Ronel Veksler, Peter Sudmant, Albert Becker, Barry Hart, Michael Rogawski, Andrew Dillin, Alon Friedman, Daniela Kaufer
Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling.
4 tweets genetics
Jeffrey C Barrett, Joseph Buxbaum, David Cutler, Mark Daly, Bernie Devlin, Jacob Gratten, Matthew E Hurles, Jack A. Kosmicki, Eric S Lander, Daniel G. MacArthur, Benjamin M Neale, Kathryn Roeder, Peter M. Visscher, Naomi R. Wray
Based on targeted sequencing of 208 genes in 11,730 neurodevelopmental disorder cases, Stessman et al. report the identification of 91 genes associated (at a False Discovery Rate [FDR] of 0.1) with autism spectrum disorders (ASD), intellectual disability (ID), and developmental delay (DD)-including what they characterize as 38 novel genes, not previously reported as connected with these diseases. If true, this would represent a substantial step forward. Unfortunately, each of the two discovery analyses (1. De novo mutation analysis and, 2. a comparison of private mutations with public control data) contain critical statistical flaws. When one accounts for these problems, fewer than half of the genes-and very few, if any, of the novel findings-survive. These errors have implications for how future analyses should be conducted, for understanding the genetic basis of these disorders, and for genomic medicine. We discuss the two main analyses in turn and provide more detailed treatment of the issues in a supplementary technical note.
4 tweets genomics
Obtaining genome-wide genotype information for millions of SNPs in soybean [Glycine max (L.) Merr.] often involves completely resequencing a line at 5X or greater coverage. Currently, hundreds of soybean lines have been resequenced at high depth levels with their data deposited in the NCBI short read achieve. This publicly available dataset may be leveraged as an imputation reference panel in combination with skim (low coverage) sequencing of new soybean genotypes to economically obtain high-density SNP information. Ninety-nine soybean lines resequenced at an average of 17.1X were used to generate a reference panel, with over 10 million SNPs called using GATK's Haplotype Caller tool. Whole genome resequencing at approximately 1X depth was performed on 114 previously ungenotyped experimental soybean lines. Coverages down to 0.1X were analyzed by randomly subsetting raw reads from the original 1X sequence data. SNPs discovered in the reference panel were genotyped in the experimental lines after aligning to the soybean reference genome, and missing markers imputed using Beagle 4.1. Sequencing depth of the experimental lines could be reduced to 0.3X while still retaining an accuracy of 97.8%. Accuracy was inversely related to minor allele frequency, and highly correlated with marker linkage disequilibrium. The high accuracy of skim sequencing combined with imputation provides a low cost method for obtaining dense genotypic information that can be used for various genomics applications in soybean.
4 tweets neuroscience
One fundamental question is what makes two brain states similar. For example, what makes the activity in visual cortex elicited from viewing a robin similar to a sparrow? One common assumption in fMRI analysis is that neural similarity is described by Pearson correlation. However, there are a host of other possibilities, including Minkowski and Mahalanobis measures, with each differing in its mathematical, theoretical, neural computational assumptions. Moreover, the operable measures may vary across brain regions and tasks. Here, we evaluated which of several competing similarity measures best captured neural similarity. Our technique uses a decoding approach to assess the information present in a brain region and the similarity measures that best correspond to the classifier's confusion matrix are preferred. Across two published fMRI datasets, we found the preferred neural similarity measures were common across brain regions, but differed across tasks. Moreover, Pearson correlation was consistently surpassed by alternatives.
4 tweets genetics
Jiarui Li, Tomas Benjamin Conzalez Zarzar, Julie D White, Karlijne Indencleef, Hanne Hoskens, Alejandra Ortega Castrillon, Nele Nauwelaers, Arslan A Zaidi, Ryan Joseph Eller, Torsten Günther, Emma M. Svensson, Mattias Jakobsson, Susan Walsh, Kristel Van Steen, Mark D Shriver, Peter Claes
Accurate inference of genomic ancestry is critically important in human genetics, epidemiology, and related fields. Geneticists today have access to multiple heterogeneous population-based datasets from studies collected under different protocols. Therefore, joint analyses of these datasets require robust and consistent inference of ancestry, where a common strategy is to yield an ancestry space generated by a reference dataset. However, such a strategy is sensitive to batch artefacts introduced by different protocols. In this work, we propose a novel robust genome-wide ancestry inference method; referred to as SUGIBS, based on an unnormalized genomic (UG) relationship matrix whose spectral (S) decomposition is generalized by an Identity-by-State (IBS) similarity degree matrix. SUGIBS robustly constructs an ancestry space from a single reference dataset, and provides a robust projection of new samples, from different studies. In experiments and simulations, we show that, SUGIBS is robust against individual outliers and batch artifacts introduced by different genotyping protocols. The performance of SUGIBS is equivalent to the widely used principal component analysis (PCA) on normalized genotype data in revealing the underlying structure of an admixed population and in adjusting for false positive findings in a case-control admixed GWAS. We applied SUGIBS on the 1000 Genome project, as a reference, in combination with a large heterogeneous dataset containing auxiliary 3D facial images, to predict population stratified average or ancestry faces. In addition, we projected eight ancient DNA profiles into the 1000 Genome ancestry space and reconstructed their ancestry face. Based on the visually strong and recognizable human facial phenotype, comprehensive facial illustrations of the populations embedded in the 1000 Genome project are provided. Furthermore, ancestry facial imaging has important applications in personalized and precision medicine along with forensic and archeological DNA phenotyping.
4 tweets bioinformatics
Novel genomes are today often annotated by small consortia or individuals whose background is not from bioinformatics. This audience requires tools that are easy to use. This need had been addressed by several genome annotation tools and pipelines. Visualizing resulting annotation is a crucial step of quality control. The UCSC Genome Browser is a powerful and popular genome visualization tool. Assembly Hubs allow browsing genomes that are hosted locally via already available UCSC Genome Browser servers. The steps for creating custom Assembly Hubs are well documented and the required tools are publicly available. However, the number of steps for creating a novel Assembly Hub is large. In some cases the format of input files needs to be adapted which is a difficult task for scientists without programming background. Here, we describe the novel command line tool MakeHub that generates Assembly Hubs for the UCSC Genome Browser in a fully automated fashion. The pipeline also allows extending previously created Hubs by additional tracks. MakeHub is freely available for download from https://github.com/Gaius-Augustus/MakeHub.
4 tweets genomics
Transposable elements are abundant genetic components of eukaryotic genomes with important regulatory features affecting transcription, splicing, and recombination, among others. Here we demonstrate that the Murine Endogenous Retroviral Element (MuERV-L/MERVL) family of transposable elements drives the 3D reorganisation of the genome in the early mouse embryo. By generating Hi-C data in 2-cell-like cells, we show that MERLV elements promote the formation of insulating domain boundaries throughout the genome in vivo and in vitro. The formation of these boundaries is coupled to the upregulation of directional transcription from MERVL, which results in the activation of a subset of the gene expression programme of the 2-cell stage embryo. Domain boundaries in the 2-cell stage embryo are transient and can be remodelled without undergoing cell division. Remarkably, we find extensive inter-strain MERVL variation, suggesting multiple non-overlapping rounds of recent genome invasion and a high regulatory plasticity of genome organisation. Our results demonstrate that MERVL drive chromatin organisation during early embryonic development shedding light into how nuclear organisation emerges during zygotic genome activation in mammals.
4 tweets developmental biology
Tissue morphogenesis emerges from coordinated cell shape changes driven by actomyosin contraction1. Spatial patterns of gene expression regionalize and polarize cell behaviours, such as apical constriction in the ventral mesoderm and cell intercalation in the lateral ectoderm of Drosophila. Thus, tissue dynamics is largely governed genetically. Actomyosin contractile networks drive cell and tissue-level shape changes and can respond to mechanical stimuli. However how genetic information and mechanical control drive tissue-level morphogenesis is not well understood. Here we report two phases and modalities of Rho1 and non-muscle MyosinII (MyoII) activation in the Drosophila posterior endoderm. First, Rho1/MyoII are induced apically in a spatially restricted primordium region via localized transcription of the GPCR ligand Fog. Second, a tissue-scale travelling wave of Rho1/MyoII activation and cell invagination progresses anteriorly across the dorsal epithelium at a constant speed of 1 cell every 3 minutes. Remarkably, the MyoII wave does not require sustained gene transcription, and is also insensitive to perturbations in the level and pattern of Fog expression. Thus, while fog transcription initiates Rho1/MyoII activation in the primordium, Fog delivery does not govern wave dynamics. Instead, perturbing the mechanical environment of the endoderm impaired MyoII wave dynamics. MyoII inhibition blocked acute Rho1 activation and propagation, suggesting that MyoII contractility provides both local feedback amplification and spatial coupling necessary for wave progression. Finally, we identify a cycle of 3D cell deformations that link MyoII activation and invagination in one row of cells to vitelline membrane attachment, apical spreading, MyoII activation and invagination in the next row, to drive anterior progression of the invagination wave. Thus endoderm morphogenesis emerges from local transcriptional initiation and a mechanically driven travelling cycle of cell contraction and deformation.
4 tweets microbiology
Clostridium is a large genus of obligate anaerobes belonging to the Firmicutes phylum of bacteria, most of which have a Gram-positive cell wall structure. The genus includes significant human and animal pathogens, causative of potentially deadly diseases such as tetanus and botulism. Despite their relevance and many studies suggesting that they are not a monophyletic group, the taxonomy of the group has largely been neglected. Currently, species belonging to the genus are placed in the unnatural order defined as Clostridiales, which includes the class Clostridia. Here we used genomic data from 779 strains to study the taxonomy and evolution of the group. This analysis allowed us to; (i) confirm that the group is composed of more than one genus (ii), detect major differences between pathogens classified as a single species within the group of authentic Clostridium spp. (sensu stricto), (iii) identify inconsistencies between taxonomy and toxin evolution that reflect on the pervasive misclassification of strains and, (iv) identify differential traits within central metabolism of members of what has been defined earlier and confirmed by us as cluster I. Our analysis shows that the current taxonomic classification of Clostridium species hinders the prediction of functions and traits, suggests a new classification for this fascinating class of bacteria and highlights the importance of phylogenomics for taxonomic studies.
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