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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 66,973 bioRxiv papers from 294,811 authors.

Most tweeted bioRxiv papers, last 24 hours

174 results found. For more information, click each entry to expand.

61: Experience dependent contextual codes in the hippocampus
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Posted to bioRxiv 03 Dec 2019

Experience dependent contextual codes in the hippocampus
2 tweets neuroscience

Mark H Plitt, Lisa M Giocomo

The hippocampus is a medial temporal lobe brain structure that contains circuitry and neural representations capable of supporting declarative memory. Hippocampal place cells fire in one or few restricted spatial locations in a given environment. Between environmental contexts, place cell firing fields remap (turning on/off or moving to a new spatial location), providing a unique population-wide neural code for context specificity. However, the manner by which features associated with a given context combine to drive place cell remapping remains a matter of debate. Here we show that remapping of neural representations in region CA1 of the hippocampus is strongly driven by prior beliefs about the frequency of certain contexts, and that remapping is equivalent to an optimal estimate of the identity of the current context under that prior. This prior-driven remapping is learned early in training and remains robust to changes in behavioral task-demands. Furthermore, a simple associative learning mechanism is sufficient to reproduce these results. Our findings demonstrate that place cell remapping is a generalization of representing an animal's location. Rather than simply representing location in physical space, the hippocampus represents an optimal estimate of location in a multi-dimensional stimulus space.

62: Highly diverse Asgard archaea participate in organic matter degradation in coastal sediments
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Posted to bioRxiv 29 Nov 2019

Highly diverse Asgard archaea participate in organic matter degradation in coastal sediments
2 tweets microbiology

Mingwei Cai, Yang Liu, Xiuran Yin, Zhichao Zhou, Michael W. Friedrich, Tim Richter-Heitmann, Rolf Nimzyk, Ajinkya Kulkarni, Xiaowen Wang, Wenjin Li, Jie Pan, Yuchun Yang, Ji-Dong Gu, Meng Li

Asgard is an archaeal superphylum that might hold the key to understand the origin of eukaryotes, but its diversity and ecological roles remain poorly understood. Here, we reconstructed 15 metagenomic-assembled genomes (MAGs) from coastal sediments covering most known Asgard archaea and a novel group, which is proposed as a new Asgard phylum named as the 'Gerdarchaeota'. Genomic analyses predict that Gerdarchaeota are facultative anaerobes in utilizing both organic and inorganic carbon. Unlike their closest relatives Heimdallarchaeota, Gerdarchaeota have genes encoding for cellulase and enzymes involving in the tetrahydromethanopterin-based Wood-Ljungdahl pathway. Transcriptomic evidence showed that all known Asgard archaea are capable of degrading organic matter, including peptides, amino acids and fatty acids, in different ecological niches in sediments. Overall, this study broadens the diversity of the mysterious Asgard archaea and provides evidence for their ecological roles in coastal sediments.

63: The effect of bioRxiv preprints on citations and altmetrics
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Posted to bioRxiv 22 Jun 2019

The effect of bioRxiv preprints on citations and altmetrics
2 tweets scientific communication and education

Nicholas Fraser, Fakhri Momeni, Philipp Mayr, Isabella Peters

A potential motivation for scientists to deposit their scientific work as preprints is to enhance its citation or social impact, an effect which has been empirically observed for preprints in physics, astronomy and mathematics deposited to arXiv. In this study we assessed the citation and altmetric advantage of bioRxiv, a preprint server for the biological sciences. We retrieved metadata of all bioRxiv preprints deposited between November 2013 and December 2017, and matched them to articles that were subsequently published in peer-reviewed journals. Citation data from Scopus and altmetric data from Altmetric.com were used to compare citation and online sharing behaviour of bioRxiv preprints, their related journal articles, and non-deposited articles published in the same journals. We found that bioRxiv-deposited journal articles received a sizeable citation and altmetric advantage over non-deposited articles. Regression analysis reveals that this advantage is not explained by multiple explanatory variables related to the article and its authorship. bioRxiv preprints themselves are being directly cited in journal articles, regardless of whether the preprint has been subsequently published in a journal. bioRxiv preprints are also shared widely on Twitter and in blogs, but remain relatively scarce in mainstream media and Wikipedia articles, in comparison to peer-reviewed journal articles.

64: Characterization of the impact of daclizumab beta on circulating natural killer cells by mass cytometry
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Posted to bioRxiv 05 Dec 2019

Characterization of the impact of daclizumab beta on circulating natural killer cells by mass cytometry
2 tweets immunology

Thanmayi Ranganath, Laura Jane Simpson, Christof Seiler, Anne-Maud Ferreira, Elena Vendrame, Nancy Q Zhao, Jason D. Fontenot, Susan P Holmes, Catherine A Blish

Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56bright subpopulation of NK cells that is correlated with the drugs therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of one year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56bright NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. While the changes were less dramatic, CD56dim NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.

65: A synthetic Calvin cycle enables autotrophic growth in yeast
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Posted to bioRxiv 03 Dec 2019

A synthetic Calvin cycle enables autotrophic growth in yeast
2 tweets synthetic biology

Thomas Gassler, Michael Sauer, Brigitte Gasser, Diethard Mattanovich, Matthias G Steiger

The methylotrophic yeast Pichia pastoris is frequently used for heterologous protein production and it assimilates methanol efficiently via the xylulose-5-phosphate pathway. This pathway is entirely localized in the peroxisomes and has striking similarities to the Calvin-Benson-Bassham (CBB) cycle, which is used by a plethora of organisms like plants to assimilate CO2 and is likewise compartmentalized in chloroplasts. By metabolic engineering the methanol assimilation pathway of P. pastoris was re-wired to a CO2 fixation pathway resembling the CBB cycle. This new yeast strain efficiently assimilates CO2 into biomass and utilizes it as its sole carbon source, which changes the lifestyle from heterotrophic to autotrophic. In total eight genes, including genes encoding for RuBisCO and phosphoribulokinase, were integrated into the genome of P. pastoris , while three endogenous genes were deleted to block methanol assimilation. The enzymes necessary for the synthetic CBB cycle were targeted to the peroxisome. Methanol oxidation, which yields NADH, is employed for energy generation defining the lifestyle as chemoorganoautotrophic. This work demonstrates that the lifestyle of an organism can be changed from chemoorganoheterotrophic to chemoorganoautotrophic by metabolic engineering. The resulting strain can grow exponentially and perform multiple cell doublings on CO2 as sole carbon source with a μmax of 0.008 h-1.

66: Genetic Underpinnings of Risky Behavior Relate to Altered Neuroanatomy
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Posted to bioRxiv 02 Dec 2019

Genetic Underpinnings of Risky Behavior Relate to Altered Neuroanatomy
2 tweets neuroscience

Goekhan Aydogan, Remi Daviet, Richard Karlsson Linner, Todd A Hare, Joseph W Kable, Henry R. Kranzler, Reagan R Wetherill, Christian C Ruff, Philipp D Koellinger, Gideon Nave

Previous research points to the heritability of risk-taking behavior. However, evidence on how genetic dispositions are translated into risky behavior is scarce. Here, we report a genetically-informed neuroimaging study of real-world risky behavior in a large European sample (N=12,675). We found negative associations between risky behavior and grey matter volume (GMV) in distinct brain regions, including amygdala, ventral striatum, hypothalamus and dorsolateral prefrontal cortex (dlPFC). Polygenic risk scores for risky behaviors, derived from a genome-wide association study in an independent sample (N=297,025), were inversely associated with GMV in dlPFC, putamen, and hypothalamus. This relation mediated ~2.2% of the association between genes and behavior. Our results highlight distinct heritable neuroanatomical features as manifestations of the genetic propensity for risk taking.

67: Corollary Discharge Promotes a Sustained Motor State in a Neural Circuit for Navigation
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Posted to bioRxiv 03 Dec 2019

Corollary Discharge Promotes a Sustained Motor State in a Neural Circuit for Navigation
2 tweets neuroscience

Ni Ji, Vivek Venkatachalam, Hillary Rodgers, Wesley Hung, Taizo Kawano, Christopher Clark, Maria Lim, Mark J. Alkema, Mei J Zhen, Aravinthan Samuel

Animals exhibit behavioral and neural responses that persist on longer time scales than transient or fluctuating stimulus inputs. Here, we report that C. elegans uses corollary discharge to sustain motor responses during thermotactic navigation. By imaging circuit activity in behaving animals, we show that a principal postsynaptic partner of the AFD thermosensory neuron, the AIY interneuron, encodes both temperature and motor state information. By optogenetic and genetic manipulation of this circuit, we demonstrate that the motor state representation in AIY is a corollary discharge signal. RIM, an interneuron that is connected with premotor interneurons, is required for corollary discharge. Ablation of RIM eliminates the motor representation in AIY, allows thermosensory representations to reach downstream premotor interneurons, and reduces the animal's ability to sustain forward movements during thermotaxis. We propose that corollary discharge underlies a positive feedback mechanism to generate persistent neural activity and sustained behavioral patterns in a sensorimotor transformation.

68: Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia
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Posted to bioRxiv 29 Nov 2019

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia
2 tweets biochemistry

Serina L Robinson, Barbara R. Terlouw, Megan D. Smith, Sacha J. Pidot, Timothy P. Stinear, Marnix H Medema, Lawrence P. Wackett

Enzymes that cleave ATP to activate carboxylic acids play essential roles in primary and secondary metabolism in all domains of life. Class I adenylate-forming enzymes share a conserved structural fold but act on a wide range of substrates to catalyze reactions involved in bioluminescence, nonribosomal peptide biosynthesis, fatty acid activation, and β-lactone formation. Despite their metabolic importance, the substrates and catalytic functions of the vast majority of adenylate-forming enzymes are unknown without tools available to accurately predict them. Given the crucial roles of adenylate-forming enzymes in biosynthesis, this also severely limits our ability to predict natural product structures from biosynthetic gene clusters. Here we used machine learning to predict adenylate-forming enzyme function and substrate specificity from protein sequence. We built a web-based predictive tool and used it to comprehensively map the biochemical diversity of adenylate-forming enzymes across >50,000 candidate biosynthetic gene clusters in bacterial, fungal, and plant genomes. Ancestral enzyme reconstruction and sequence similarity networking revealed a hub topology suggesting radial divergence of the adenylate-forming superfamily from a core enzyme scaffold similar to contemporary aryl-CoA ligases. Our classifier also predicted β-lactone synthetases in novel biosynthetic gene clusters conserved across >90 different strains of Nocardia . To validate our method, we purified a candidate β-lactone synthetase from Nocardia brasiliensis and reconstituted the complete biosynthetic pathway in vitro to link the gene cluster to the β-lactone natural product, nocardiolactone. We anticipate our machine learning approach will aid in functional classification of enzymes and advance natural product discovery.

69: Spatial control of nucleoporin assembly by Fragile X-related proteins
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Posted to bioRxiv 12 Sep 2019

Spatial control of nucleoporin assembly by Fragile X-related proteins
2 tweets cell biology

Arantxa Agote-Aran, Stephane Schmucker Schmucker, Katerina Jerabkova Jerabkova, Ines Jmel Boyer, Alessandro Berto, Laura Pacini, Paolo Ronchi, Charlotte Kleiss, Laurent Guerard, Yannick Schwab, Herve Moine, Jean-Louis Mandel, Sebastien Jacquemont, Claudia Bagni, Izabela Sumara

Nucleoporins (Nups) build highly organized Nuclear Pore Complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs to regulate nucleocytoplasmic exchange. In the cytoplasm, a large excess of soluble Nups has been reported, but how their assembly is restricted to the NE is currently unknown. Here we show that Fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule and dynein-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and Fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup protein condensates. Likewise, several models of Fragile X syndrome (FXS), characterized by a loss of FMRP, also accumulate cytoplasmic Nup aggregates. These aggregate-containing cells display aberrant nuclear morphology and a delay in G1 cell cycle progression. Our results reveal an unexpected role for the FXR protein family and dynein in the spatial regulation of nucleoporin assembly.

70: Slow recovery from inbreeding depression generated by the complex genetic architecture of segregating deleterious mutations
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Posted to bioRxiv 03 Dec 2019

Slow recovery from inbreeding depression generated by the complex genetic architecture of segregating deleterious mutations
2 tweets evolutionary biology

Paula Elizabeth Adams, Anna L Crist, Ellen Marie Young, John H. Willis, Patrick C. Phillips, Janna Lynn Fierst

The deleterious effects of inbreeding have been of extreme importance to evolutionary biology, but it has been difficult to characterize the complex interactions between genetic constraints and selection that lead to fitness loss and recovery after inbreeding. Viruses, bacteria, and the selfing nematode Caenorhabditis elegans have been shown to be capable of rapid recovery from the fixation of novel deleterious mutation, however the potential for fitness recovery from fixation of segregating variation under inbreeding in outcrossing organisms is poorly understood. C. remanei is an outcrossing relative of C. elegans with high polymorphic variation and extreme inbreeding depression. Here we sought to characterize changes C. remanei in patterns of genomic diversity after ~30 generations of inbreeding via brother-sister mating followed by several hundred generations of recovery at large population size. As expected, inbreeding led to a large decline in reproductive fitness, but unlike results from mutation accumulation experiments, recovery from inbreeding at large populations sizes generated only very moderate recovery in fitness after 300 generations. At the genomic level, we found that while 66% of ancestral segregating SNPs were fixed in the inbred population, this was far fewer than expected under neutral processes. Under recovery, 36 SNPs across 30 genes involved in alimentary, muscular, nervous and reproductive systems changed reproducibly across all replicates, indicating that strong selection for fitness recovery does exist but is likely mutationally limited due to the large number of potential targets. Our results indicate that recovery from inbreeding depression via new compensatory mutations is likely to be constrained by the large number of segregating deleterious variants present in natural populations, limiting the capacity for rapid evolutionary rescue of small populations.

71: VIP interneurons selectively enhance weak but behaviorally-relevant stimuli.
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Posted to bioRxiv 29 Nov 2019

VIP interneurons selectively enhance weak but behaviorally-relevant stimuli.
2 tweets neuroscience

Daniel J Millman, Gabriel Ocker, Shiella Caldejon, India Kato, Josh D Larkin, Eric Kenji Lee, Jennifer Luviano, Chelsea Nayan, Thuyanh V Nguyen, Kat North, Sam Seid, Cassandra White, Jerome A Lecoq, R. Clay Reid, Michael A. Buice, Saskia E.J. de Vries

Vasoactive intestinal peptide-expressing (VIP) interneurons in cortex regulate feedback inhibition of pyramidal neurons through suppression of somatostatin-expressing (SST) interneurons and, reciprocally, SST neurons inhibit VIP neurons. Here, we show that VIP neurons in mouse primary visual cortex have complementary contrast tuning to SST neurons and respond synergistically to front-to-back visual motion and locomotion. Network modeling indicates that this VIP-SST mutual antagonism regulates the gain of cortex to achieve both sensitivity to behaviorally-relevant stimuli and network stability.

72: Predictive engineering and optimization of tryptophan metabolism in yeast through a combination of mechanistic and machine learning models
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Posted to bioRxiv 29 Nov 2019

Predictive engineering and optimization of tryptophan metabolism in yeast through a combination of mechanistic and machine learning models
2 tweets bioengineering

Jie Zhang, Soeren D. Petersen, Tijana Radivojevic, Andres Ramirez, Andres Perez, Eduardo Abeliuk, Benjamin J. Sanchez, Zachary Costello, Yu Chen, Mike Fero, Hector G. Martin, Jens B. Nielsen, Jay D. Keasling, Michael Krogh Jensen

In combination with advanced mechanistic modeling and the generation of high-quality multi-dimensional data sets, machine learning is becoming an integral part of understanding and engineering living systems. Here we show that mechanistic and machine learning models can complement each other and be used in a combined approach to enable accurate genotype-to-phenotype predictions. We use a genome-scale model to pinpoint engineering targets and produce a large combinatorial library of metabolic pathway designs with different promoters which, once phenotyped, provide the basis for machine learning algorithms to be trained and used for new design recommendations. The approach enables successful forward engineering of aromatic amino acid metabolism in yeast, with the new recommended designs improving tryptophan production by up to 17% compared to the best designs used for algorithm training, and ultimately producing a total increase of 106% in tryptophan accumulation compared to optimized reference designs. Based on a single high-throughput data-generation iteration, this study highlights the power of combining mechanistic and machine learning models to enhance their predictive power and effectively direct metabolic engineering efforts.

73: The vagus nerve is necessary for the rapid and widespread neuronal activation in the brain following oral administration of psychoactive bacteria
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Posted to bioRxiv 02 Dec 2019

The vagus nerve is necessary for the rapid and widespread neuronal activation in the brain following oral administration of psychoactive bacteria
2 tweets neuroscience

Aadil Bharwani, Christine West, Kevin Champagne-Jorgensen, Karen-Anne McVey Neufeld, Joseph Ruberto, Wolfgang A Kunze, John Bienenstock, Paul Forsythe

There is accumulating evidence that certain gut microbes modulate brain chemistry and have antidepressant-like behavioural effects. However, it is unclear which brain regions respond to bacteria-derived signals or how signals are transmitted to distinct regions. We investigated the role of the vagus in mediating neuronal activation following oral treatment with Lactobacillus rhamnosus (JB-1). Male Balb/c mice were orally administered a single dose of saline or a live or heat-killed preparation of a physiologically active bacterial strain, Lactobacillus rhamnosus (JB-1). 165 minutes later, c-Fos immunoreactivity in the brain was mapped, and mesenteric vagal afferent fibre firing was recorded. Mice also underwent sub-diaphragmatic vagotomy to investigate whether severing the vagus prevented JB-1-induced c-Fos expression. Finally, we examined the ΔFosB response following acute versus chronic bacterial treatment. While a single exposure to live and heat-killed bacteria altered vagal activity, only live treatment induced rapid neural activation in widespread but distinct brain regions, as assessed by c-Fos expression. Sub-diaphragmatic vagotomy abolished c-Fos immunoreactivity in most, but not all, previously responsive regions. Chronic, but not acute treatment induced a distinct pattern of ΔFosB expression, including in previously unresponsive brain regions. These data identify that specific brain regions respond rapidly to gut microbes via vagal-dependent and independent pathways, but suggest long-term exposure is required for the chronic brain activity associated with behavioural changes.

74: Phase separation of Ede1 promotes the initiation of endocytic events
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Posted to bioRxiv 02 Dec 2019

Phase separation of Ede1 promotes the initiation of endocytic events
2 tweets cell biology

Mateusz Kozak, Marko Kaksonen

Clathrin-mediated endocytosis is a major pathway that eukaryotic cells use to produce transport vesicles from the plasma membrane. The assembly of the endocytic coat is initiated by a dynamic network of weakly interacting proteins, but the exact mechanism of initiation is unknown. Ede1, the yeast homologue of mammalian Eps15, is one of the early-arriving endocytic proteins and a key initiation factor. In the absence of Ede1, most other early endocytic proteins lose their punctate localization and the frequency of endocytic initiation is decreased. We show here that in mutants with increased amounts of cytoplasmic Ede1, the excess protein forms large condensates which exhibit properties of phase separated liquid protein droplets. These Ede1 condensates recruit many other early-arriving endocytic proteins. Their formation depends on the core region of Ede1 that contains a coiled coil and a low-complexity domain. We demonstrate that Ede1 core region is essential for the endocytic function of Ede1. The core region can also promote clustering of a heterologous lipid-binding domain into discrete sites on the plasma membrane that initiate endocytic events. We propose that the clustering of the early endocytic proteins and cargo depend on phase separation mediated by Ede1.

75: Frequent extrachromosomal oncogene amplification drives aggressive tumors
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Posted to bioRxiv 28 Nov 2019

Frequent extrachromosomal oncogene amplification drives aggressive tumors
1 tweet cancer biology

Hoon Kim, Nam Nguyen, Kristen Turner, Sihan Wu, Jihe Liu, Viraj Deshpande, Sandeep Namburi, Howard Y. Chang, Christine Beck, Paul S Mischel, Vineet Bafna, Roel GW Verhaak

Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution, but its frequency and clinical impact are not well understood. Here we show, using computational analysis of whole-genome sequencing data from 1,979 cancer patients, that ecDNA amplification occurs in at least 26% of human cancers, of a wide variety of histological types, but not in whole blood or normal tissue. We demonstrate a highly significant enrichment for oncogenes on amplified ecDNA and that the most common recurrent oncogene amplifications arise on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number matched linear DNA, coupled with enhanced chromatin accessibility. Patients whose tumors have ecDNA-based oncogene amplification showed increase of cell proliferation signature activity, greater likelihood of lymph node spread at initial diagnosis, and significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification plays a central role in driving the poor outcome for patients with some of the most aggressive forms of cancers.

76: Whole genome sequencing analysis of the cardiometabolic proteome
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Posted to bioRxiv 27 Nov 2019

Whole genome sequencing analysis of the cardiometabolic proteome
1 tweet genetics

Arthur Gilly, Young-Chan Park, Grace Png, Thea Bjornland, Lorraine Southam, Daniel Suveges, Sonja Neumeyer, Iris Fischer, Andrei Barysenka, Nigel William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Eleftheria Zeggini

The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( P <7.45×10−11) across the allele frequency spectrum, including 44 new cis -acting and 11 new trans- acting loci, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify replicating evidence for rare-variant cis -acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We find causal links between protein biomarkers and cardiovascular, inflammatory and immune-related diseases. We construct and validate polygenic risk scores that explain up to 45% of protein level variation, and find significant correlation between genetically-predicted biomarker levels and cardiovascular disease risk in UK Biobank.

77: Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
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Posted to bioRxiv 26 Nov 2019

Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
1 tweet cell biology

Hugo Poplimont, Antonios Georgantzoglou, Morgane Boulch, Caroline Coombs, Foteini Papaleonidopoulou, Milka Sarris

Neutrophils are major inflammatory cells that rapidly infiltrate injured tissues to provide antimicrobial functions. A key step in their response is the paracrine release of the attractant LTB4, which switches the migration mode from exploratory patrolling to coordinated swarming. This leads to dense clusters that may further disrupt tissue architecture. The coordination mechanism underpinning neutrophil swarms is elusive. Here we show that neutrophils swarms require mutual reinforcement of damage signalling at the wound core. New biosensors and live imaging in zebrafish revealed that neutrophil chemoattractant synthesis is triggered by a sustained calcium flux upon contact with necrotic tissue and sensing of the damage signal ATP. This calcium alarm signal propagates in the nascent neutrophil cluster through connexin-43 hemichannels, which allow release of intracellular ATP. This enables rapid assembly of a centralised, supracellular chemoattractant source, which is instrumental for coordinated recruitment and maximal cell gathering.

78: Undulating changes in human plasma proteome across lifespan are linked to disease
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Posted to bioRxiv 01 Sep 2019

Undulating changes in human plasma proteome across lifespan are linked to disease
1 tweet systems biology

Benoit Lehallier, David Gate, Nicholas Schaum, Tibor Nanasi, Song Eun Lee, Hanadie Yousef, Patricia Moran Losada, Daniela Berdnik, Andreas Keller, Joe Verghese, Sanish Sathyan, Claudio Franceschi, Sofiya Milman, Nir Barzilai, Tony Wyss-Coray

Aging is the predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, pointing to the intriguing possibility that age-related molecular changes in blood can provide novel insight into disease biology. We measured 2,925 plasma proteins from 4,331 young adults to nonagenarians and developed a novel bioinformatics approach which uncovered profound non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways, and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways of aging and disease and offers potential pathways for aging interventions.

79: Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development
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Posted to bioRxiv 26 Nov 2019

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development
1 tweet genomics

Tanzeen Yusuff, Matthew Jensen, Sneha Yennawar, Lucilla Pizzo, Siddharth Karthikeyan, Dagny J Gould, Avik Sarker, Yurika Matsui, Janani Iyer, Zhi-Chun Lai, Santhosh Girirajan

While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten CNVs and 20 neurodevelopmental genes in Drosophila. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including six lines with lethality and 21 lines with severe wing defects. Assessment of 66 lines for tissue-specific effects showed no correlation between the severity of wing and eye-specific defects. We observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further validated with differences in human tissue-specific expression and network connectivity of CNV genes. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

80: CiteFuse enables multi-modal analysis of CITE-seq data
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Posted to bioRxiv 25 Nov 2019

CiteFuse enables multi-modal analysis of CITE-seq data
1 tweet bioinformatics

Hani Jieun Kim, Yingxin Lin, Thomas A Geddes, Jean Yee Hwa Yang, Pengyi Yang

Multi-modal profiling of single cells represents one of the latest technological advancements in molecular biology. Among various single-cell multi-modal strategies, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) allows simultaneous quantification of two distinct species: RNA and surface marker proteins (ADT). Here, we introduce CiteFuse, a streamlined package consisting of a suite of tools for pre-processing, modality integration, clustering, differential RNA and ADT expression analysis, ADT evaluation, ligand-receptor interaction analysis, and interactive web-based visualization of CITE-seq data. We show the capacity of CiteFuse to integrate the two data modalities and its relative advantage against data generated from single modality profiling. Furthermore, we illustrate the pre-processing steps in CiteFuse and in particular a novel doublet detection method based on a combined index of cell hashing and transcriptome data. Collectively, we demonstrate the utility and effectiveness of CiteFuse for the integrative analysis of transcriptome and epitope profiles from CITE-seq data.

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