Rxivist logo

Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 124,632 papers from 535,495 authors.

Most tweeted biology preprints, last 24 hours

*There are gaps in historical Twitter data, most notably in spring 2020. This may result in some preprints appearing with less tweets than they should.

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

81: An updated structural model of the A domain of the Pseudomonas putida XylR regulator exposes a distinct interplay with aromatic effectors
more details view paper

Posted 17 Jan 2021

An updated structural model of the A domain of the Pseudomonas putida XylR regulator exposes a distinct interplay with aromatic effectors
1 tweet bioRxiv microbiology

Pavel Dvorak, Carlos Alvarez-Carreno, Sergio Ciordia, Alberto Paradela, Victor de Lorenzo

A revised model of the aromatic binding A domain of the sigma 54-dependent regulator XylR of Pseudomonas putida mt-2 was produced based on the known 3D structures of homologous regulators PoxR, MopR, and DmpR. The resulting frame was instrumental for mapping the large number of mutations known to alter effector specificity, which were then reinterpreted under a dependable spatial reference. Some of these changes involved the predicted aromatic-binding pocket but others occurred in distant locations, including dimerization interfaces and putative zinc-binding site. The effector pocket was buried within the protein structure and accessible from the outside only through a narrow tunnel. The model was experimentally validated by treating the cells in vivo and the purified protein in vitro with benzyl bromide, which reacts with accessible nucleophilic residues on the protein surface. Proteomic analyses of the thereby tagged peptides confirmed the predicted in/out distribution of residues but also suggested that the fully-folded protein is not accessible by externally added effectors. The data thus suggested that XylR inducers assist the folding and/or the structuring of the A domain in an intramolecular non-repressive form rather than interacting dynamically with the aromatic partner once a fully structured protein is shaped.

82: Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
more details view paper

Posted 08 Sep 2020

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
1 tweet bioRxiv genomics

Eleni P. Mimitou, Caleb A. Lareau, Kelvin Y. Chen, Andre L. Zorzetto-Fernandes, Yusuke Takeshima, Wendy Luo, Tse-Shun Huang, Bertrand Yeung, Pratiksha I. Thakore, James Badger Wing, Kristopher L. Nazor, Shimon Sakaguchi, Leif S. Ludwig, Vijay G. Sankaran, Aviv Regev, Peter Smibert

Recent technological advances have enabled massively parallel chromatin profiling with single-cell Assay for Transposase Accessible Chromatin by sequencing (scATAC-seq) in thousands of individual cells. Here, we extend these approaches and present ATAC with Select Antigen Profiling by sequencing, ASAP-seq, a tool to simultaneously profile accessible chromatin and protein levels in thousands of single cells. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA (mtDNA) for clonal tracking, thus concomitantly capturing three distinct modalities in single cells. Importantly, ASAP-seq uses a novel bridging approach that repurposes antibody:oligo conjugates designed for existing technologies that pair protein measurements with single cell RNA-seq. We demonstrate the utility of ASAP-seq by revealing coordinated and distinct changes in chromatin, RNA, and surface proteins during native hematopoietic differentiation, peripheral blood mononuclear cell stimulation, and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells. ### Competing Interest Statement COMPETING INTERESTS PS is listed as co-inventor on a patent related to this work (US provisional patent application 62/515-180). CAL, LSL, VGS, and AR are listed as co-inventors on a patent related to mtscATAC-seq (US provisional patent application 62/683,502). A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech.

83: Investigating the impact of reference assembly choice on genomic analyses in a cattle breed
more details view paper

Posted 17 Jan 2021

Investigating the impact of reference assembly choice on genomic analyses in a cattle breed
1 tweet bioRxiv genomics

Audald Lloret-Villas, Meenu Bhati, Naveen Kumar Kadri, Ruedi Fries, Hubert Pausch

Background: Reference-guided read alignment and variant genotyping are prone to reference allele bias, particularly for samples that are greatly divergent from the reference genome. A Hereford-based assembly is the widely accepted bovine reference genome. Haplotype-resolved genomes that exceed the current bovine reference genome in quality and continuity have been assembled for different breeds of cattle. Using whole genome sequencing data of 161 Brown Swiss cattle, we compared the accuracy of read mapping and sequence variant genotyping as well as downstream genomic analyses between the bovine reference genome (ARS-UCD1.2) and a highly continuous Angus-based assembly (UOA Angus 1). Results: Read mapping accuracy did not differ notably between the ARS-UCD1.2 and UOA Angus 1 assemblies. We discovered 22,744,517 and 22,559,675 high-quality variants from ARS-UCD1.2 and UOA Angus 1, respectively. The concordance between sequence- and array-called genotypes was high and the number of variants deviating from Hardy-Weinberg proportions was low at segregating sites for both assemblies. More artefactual INDELs were genotyped from UOA Angus 1 than ARS-UCD1.2 alignments. Using the composite likelihood ratio test, we detected 40 and 33 signatures of selection from ARS-UCD1.2 and UOA Angus 1, respectively, but the overlap between both assemblies was low. Using the 161 sequenced Brown Swiss cattle as a reference panel, we imputed sequence variant genotypes into a mapping cohort of 30,499 cattle that had microarray-derived genotypes. The accuracy of imputation (Beagle R2) was very high (0.87) for both assemblies. Genome-wide association studies between imputed sequence variant genotypes and six dairy traits as well as stature produced almost identical results from both assemblies. Conclusions: The ARS-UCD1.2 and UOA Angus 1 assemblies are suitable for reference-guided genome analyses in Brown Swiss cattle. Although differences in read mapping and genotyping accuracy between both assemblies are negligible, the choice of the reference genome has a large impact on detecting signatures of selection using the composite likelihood ratio test. We developed a workflow that can be adapted and reused to compare the impact of reference genomes on genome analyses in various breeds, populations and species.

84: Mechanistic theory predicts the effects of temperature and humidity on inactivation of SARS-CoV-2 and other enveloped viruses
more details view paper

Posted 16 Oct 2020

Mechanistic theory predicts the effects of temperature and humidity on inactivation of SARS-CoV-2 and other enveloped viruses
1 tweet bioRxiv microbiology

Dylan H. Morris, Kwe Claude Yinda, Amandine Gamble, Fernando W. Rossine, Qishen Huang, Trenton Bushmaker, Robert J. Fischer, M. Jeremiah Matson, Neeltje van Doremalen, Peter J. Vikesland, Linsey C. Marr, Vincent Munster, James O. Lloyd-Smith

Environmental conditions affect virus inactivation rate and transmission potential. Understanding those effects is critical for anticipating and mitigating epidemic spread. Ambient temperature and humidity strongly affect the inactivation rate of enveloped viruses, but a mechanistic, quantitative theory of those effects has been elusive. We measure the stability of the enveloped respiratory virus SARS-CoV-2 on an inert surface at nine temperature and humidity conditions and develop a mechanistic model to explain and predict how temperature and humidity alter virus inactivation. We find SARS-CoV-2 survives longest at low temperatures and extreme relative humidities; median estimated virus half-life is over 24 hours at 10 {degrees}C and 40 % RH, but approximately 1.5 hours at 27 {degrees}C and 65 % RH. Our mechanistic model uses simple chemistry to explain the increase in virus inactivation rate with increased temperature and the U-shaped dependence of inactivation rate on relative humidity. The model accurately predicts quantitative measurements from existing studies of five different human coronaviruses (including SARS-CoV-2), suggesting that shared mechanisms may determine environmental stability for many enveloped viruses. Our results indicate scenarios of particular transmission risk, point to pandemic mitigation strategies, and open new frontiers in the mechanistic study of virus transmission.

85: Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
more details view paper

Posted 22 Mar 2019

Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
1 tweet bioRxiv neuroscience

Donna M. Werling, Sirisha Pochareddy, Jinmyung Choi, Joon-Yong An, Brooke K. Sheppard, Minshi Peng, Zhen Li, Claudia Dastmalchi, Gabriel Santpere, Andre M. M. Sousa, Andrew T. N. Tebbenkamp, Navjot Kaur, Forrest O. Gulden, Michael S. Breen, Lindsay Liang, Michael C. Gilson, Xuefang Zhao, Shan Dong, Lambertus Klei, A. Ercument Cicek, Joseph Buxbaum, Homa Adle-Biassette, Jean-Leon Thomas, Kimberly A. Aldinger, Diana R. O’Day, Ian A. Glass, Noah A. Zaitlen, Michael E. Talkowski, Kathryn Roeder, Matthew W. State, Bernie Devlin, Stephan J Sanders, Nenad Sestan

Variation in gene expression underlies neurotypical development, while genomic variants contribute to neuropsychiatric disorders. BrainVar is a unique resource of paired whole-genome sequencing and bulk-tissue RNA-sequencing from the human dorsolateral prefrontal cortex of 176 neurotypical individuals across prenatal and postnatal development, providing the opportunity to assay genomic and transcriptomic variation in tandem. Leveraging this resource, we identified rare premature stop codons with commensurate reduced and allele-specific expression of corresponding genes, and common variants that alter gene expression (expression quantitative trait loci, eQTLs). Categorizing eQTLs by prenatal and postnatal effect, genes affected by temporally-specific eQTLs, compared to constitutive eQTLs, are enriched for haploinsufficiency, protein-protein interactions, and neuropsychiatric disorder risk loci. Expression levels of over 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell type specific genes and neuropsychiatric disorder loci, underscoring the importance of cataloguing developmental trajectories in understanding cortical physiology and pathology.

86: Aminooxadiazolyl kainic acid reveals that kainic acid receptors contribute to astrocytoma glutamate signaling
more details view paper

Posted 18 Jan 2021

Aminooxadiazolyl kainic acid reveals that kainic acid receptors contribute to astrocytoma glutamate signaling
1 tweet bioRxiv neuroscience

Mitra Sadat Tabatabaee, Zhelin Tian, Julien Gibon, Frederic Menard

The excitatory neurotransmitter glutamate triggers a Ca2+ rise and the extension of processes in astrocytes. Our results suggest that kainic acid receptors (KAR) can independently initiate glutamate signaling in astrocytoma U118-MG cells. The natural product kainic acid triggered glioexcitablity in cells and was inhibited by the KAR antagonist CNQX, but its activity was lower than glutamate on KARs. We created a new heteroaryl kainoid based on rational design: aminooxadiazolyl kainic acid 1 (AODKA). AODKA induced a larger calcium influx and a faster processes extension than kainic acid in U118-MG cells. AODKA is a new tool to study KAR activity in the nervous system.

87: Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction
more details view paper

Posted 22 Oct 2020

Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction
1 tweet bioRxiv pathology

Sajad Ahmad Bhat, Adil Yousuf, Zeeshan Mushtaq, Vimlesh Kumar, Abrar Qurashi

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disease manifesting in the premutation (PM) carriers of the FMR1 gene with alleles bearing 55-200 CGG repeats. The discovery of a broad spectrum of clinical and cell developmental abnormalities among PM carriers with or without FXTAS, and in model systems suggests that neurodegeneration seen in FXTAS could be the inevitable end-result of pathophysiological processes set during early development. Hence, it is imperative to trace early pathological abnormalities. Our previous studies have shown that transgenic Drosophila carrying human-derived fragile X premutation-length CGG repeats are sufficient to cause neurodegeneration. Here, we used the same transgenic Drosophila model to understand the effects of fragile X premutation-length CGG repeats on the structure and function of the developing nervous system. We show that presynaptic expression of the premutation length CGG repeats restricts synaptic growth, reduces the number of synaptic boutons, leads to aberrant presynaptic varicosities, and impairs synaptic transmission at the larval neuromuscular junctions (NMJs). The postsynaptic analysis shows both glutamate receptor and subsynaptic reticulum proteins are normal. However, a high percentage of boutons show the reduced density of Bruchpilot protein, a key component of presynaptic active zones required for vesicle release. The electrophysiological analysis shows a significant reduction in the quantal content, a measure of total synaptic vesicles released per excitation potential. Together these findings endorse that synapse perturbation caused by rCGG repeats mediate presynaptically during larval NMJ development. ### Competing Interest Statement The authors have declared no competing interest.

88: Isolation and characterization of a novel phage SaGU1 that infects Staphylococcus aureus clinical isolates from patients with atopic dermatitis
more details view paper

Posted 24 Oct 2020

Isolation and characterization of a novel phage SaGU1 that infects Staphylococcus aureus clinical isolates from patients with atopic dermatitis
1 tweet bioRxiv microbiology

Yuzuki Shimamori, Ajeng K Pramono, Tomoe Kitao, Tohru Suzuki, Shin-ichi Aizawa, Tomoko Kubori, Hiroki Nagai, Shigeki Takeda, Hiroki Ando

The bacterium Staphylococcus aureus, which grows on healthy human skin, may cause diseases such as atopic dermatitis (AD). Treatment for such AD cases involves antibiotic use; however, alternate treatments are preferred owing to the development of antimicrobial resistance. This study aimed to characterize the novel bacteriophage SaGU1 as a potential agent for phage therapy to treat S. aureus infections. SaGU1 that infects S. aureus strains previously isolated from the skin of patients with AD was screened from sewage samples in Gifu, Japan. Its genome was sequenced and analyzed using bioinformatics tools, and the morphology, lytic activity, stability, and host range of the phage were determined. The SaGU1 genome consisted of 140,909 bp with an average GC content of 30.2%. The viral chromosome contained putative 225 protein-coding genes and four tRNA genes, carrying neither toxic nor antibiotic resistance genes. Electron microscopy analysis revealed that SaGU1 belongs to the Myoviridae family. Stability tests showed that SaGU1 was heat-stable under physiological and acidic conditions. Host-range testing revealed that SaGU1 could infect a broad range of S. aureus clinical isolates present on the skin of patients with AD, whereas it did not kill strains of Staphylococcus epidermidis, which are symbiotic bacteria in the human skin microbiota. Our data suggest that SaGU1 is a potential candidate for developing a phage therapy to treat AD caused by pathogenic S. aureus. ### Competing Interest Statement The authors have declared no competing interest.

89: Muscle fiber type differences in nitrate and nitrite storage and nitric oxide signaling in rats
more details view paper

Posted 02 Jun 2020

Muscle fiber type differences in nitrate and nitrite storage and nitric oxide signaling in rats
1 tweet bioRxiv physiology

Gary M Long, Derrick A Gray, Ashley D Troutman, Amanda Fisher, Mary Beth Brown, Andrew R Coggan

Recent studies have emphasized the importance of the nitric oxide synthase (NOS)-independent, nitrate (NO3-) → nitrite (NO2-) → nitric oxide (NO) pathway in skeletal muscle. In particular, it has been hypothesized that this pathway is especially active in type II, or fast-twitch, muscle fibers, necessitating greater NO3- and NO2- storage. We therefore measured NO3- and NO2- concentrations in the predominantly fast-twitch vastus lateralis and predominantly slow-twitch soleus muscles of rats. Contrary to the above hypothesis, we found that NO3- and NO2- concentrations were 3.4-fold and 1.8 fold higher, respectively, in the soleus. On the other hand, NO signaling (i.e., cyclic guanosine monophosphate (cGMP) level) was comparable in the two muscles. Although the physiological significance of these observations remains to be determined, we speculate that NO production via the NO3- → NO2-- → NO pathway is normally higher in slow-twitch muscles, thus helping compensate for their inherently lower NOS activity. ### Competing Interest Statement The authors have declared no competing interest.

90: PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes
more details view paper

Posted 30 May 2020

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes
1 tweet bioRxiv biochemistry

Daniel Zaidman, Nir London

Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol - PRosettaC - to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts. ### Competing Interest Statement The authors have declared no competing interest.

91: A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine
more details view paper

Posted 07 Nov 2020

A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine
1 tweet bioRxiv developmental biology

Reegan J Willms, Jennifer C Hocking, Edan Foley

Gut microbial products direct growth, differentiation and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence, or absence, of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome, that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered transduction of vascular endothelial growth factor-dependent signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type. ### Competing Interest Statement The authors have declared no competing interest.

92: Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals
more details view paper

Posted 27 May 2020

Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals
1 tweet bioRxiv immunology

Nina Le Bert, Anthony T Tan, Kamini Kunasegaran, Christine Y. L. Tham, Morteza Hafezi, Adeline Chia, Melissa Chng, Meiyin Lin, Nicole Tan, Martin Linster, Wan Ni Chia, Mark I-Cheng Chen, Lin-Fa Wang, Eng Eong Ooi, Shirin Kalimuddin, Paul Anantharajal Tambyah, Jenny Guek-Hong Low, Yee-Joo Tan, Antonio Bertoletti

Memory T cells induced by previous infections can influence the course of new viral infections. Little is known about the pattern of SARS-CoV-2 specific pre-existing memory T cells in human. Here, we first studied T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in convalescent from COVID-19 (n=24). In all of them we demonstrated the presence of CD4 and CD8 T cells recognizing multiple regions of the NP protein. We then show that SARS-recovered patients (n=23), 17 years after the 2003 outbreak, still possess long-lasting memory T cells reactive to SARS-NP, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we observed a differential pattern of SARS-CoV-2 specific T cell immunodominance in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=18). Half of them (9/18) possess T cells targeting the ORF-1 coded proteins NSP7 and 13, which were rarely detected in COVID-19- and SARS-recovered patients. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to "common cold" human coronaviruses but conserved among animal betacoranaviruses. Thus, infection with betacoronaviruses induces strong and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection is of paramount importance for the management of the current COVID-19 pandemic. ### Competing Interest Statement A.B. is a cofounder of Lion TCR, a biotech company developing T cell receptors for treatment of virus-related diseases and cancers. None of the other authors has any competing interest related to the study.

93: Data-Driven Extraction of a Nested Structure of Human Cognition
more details view paper

Posted 02 Feb 2017

Data-Driven Extraction of a Nested Structure of Human Cognition
1 tweet bioRxiv neuroscience

Taylor Bolt, Jason S. Nomi, B. T. Thomas Yeo, Lucina Q. Uddin

Decades of cognitive neuroscience research have revealed two basic facts regarding task-driven brain activation patterns. First, distinct patterns of activation occur in response to different task demands. Second, a superordinate, dichotomous pattern of activation/de-activation, is commonly observed across a variety of task demands. We explore the possibility that a hierarchical model incorporates these two observed brain activation phenomena into a unifying framework. We apply a latent variable approach, exploratory bi-factor analysis, to a large set of brain activation patterns to determine the potential existence of a nested structure of factors that underlies a variety of commonly observed activation patterns. We find that a general factor, associated with a superordinate brain activation/de-activation pattern, explained the majority of the variance (52.37%). The bi-factor analysis also revealed several sub-factors that explained an additional 31.02% of variance in brain activation patterns, associated with different manifestations of the superordinate brain activation/de-activation pattern, each emphasizing different contexts in which the task demands occurred. Importantly, this nested factor structure provided better overall fit to the data compared with a non-nested factor structure model. These results point to domain-general psychological process, representing a 'focused awareness' process or 'attentional episode' that is variously manifested according to the sensory modality of the stimulus and degree of cognitive processing. This novel model provides the basis for constructing a biologically-informed, data-driven taxonomy of psychological processes.

94: Functional Genetic Biomarkers Of Alzheimer's Disease And Gene Expression From Peripheral Blood
more details view paper

Posted 18 Jan 2021

Functional Genetic Biomarkers Of Alzheimer's Disease And Gene Expression From Peripheral Blood
1 tweet bioRxiv bioinformatics

Amish Sethi, Andrew Warren Ni

Detecting Alzheimer's Disease (AD) at the earliest possible stage is key in advancing AD prevention and treatment but is challenged by normal aging processes in addition to other confounding neurodegenerative diseases. Recent genome-wide association studies (GWAS) have identified associated alleles, but it has been difficult to transition from non-coding genetic variants to underlying mechanisms of AD. Here, we sought to reveal functional genetic variants and diagnostic biomarkers underlying AD using machine learning techniques. We first developed a Random Forest (RF) classifier using microarray gene expression data sampled from the peripheral blood of 744 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. After initial feature selection, 5-fold cross-validation of the 100-gene RF classifier achieved an accuracy of 99.04%. The high accuracy of the RF classifier supports the possibility of a powerful and minimally invasive tool for screening of AD. Next, unsupervised clustering was used to validate and identify relationships among differentially expressed genes (DEGs) the RF selected revealing 3 distinct AD clusters. Results suggest downregulation of global sulfatase and oxidoreductase activities in AD through mutations in SUMF1 and SMOX respectively. Then, we used Greedy Fast Causal Inference (GFCI) to find potential causes of AD within DEGs. In the causal graph, HLA-DPB1 and CYP4A11 emerge as hub genes, furthering the discussion of the immune system's role in AD. Finally, we used Gene Set Enrichment Analysis (GSEA) to determine the biological pathways and processes underlying the DEGs that were highly correlated with AD. Cell activation in the immune system, glycosaminoglycan (GAG) binding, vascular dysfunction, oxidative stress, and the neuronal apoptotic process were revealed to be significantly enriched in AD. This study further advances the possibility of low-cost and noninvasive genetic screening for AD while also providing potential gene targets for further experimentation

95: Pairtree: fast reconstruction of cancer evolutionary history using pairwise mutation relationships
more details view paper

Posted 08 Nov 2020

Pairtree: fast reconstruction of cancer evolutionary history using pairwise mutation relationships
1 tweet bioRxiv bioinformatics

Jeff A. Wintersinger, Stephanie M. Dobson, John E Dick, Quaid Morris

Cancers are composed of multiple genetically distinct subpopulations of cancer cells. By performing genome sequencing on tissue samples from a cancer, we can infer the existence of these subpopulations, which mutations render them genetically unique, and the evolutionary relationships between subpopulations. This can reveal critical points in disease development and inform treatment. Here we present Pairtree, a new algorithm for constructing evolutionary trees that reveal relationships between genetically distinct cell subpopulations composing a patient's cancer. Pairtree focuses on performing these reconstructions using dozens of cancerous tissue samples per patient, which can be taken from different points in space (e.g., primary tumour and metastasis) or in time (e.g., at diagnosis and at relapse). In concert, these can reveal thirty or more distinct subpopulations, and show how their composition changed between tissue samples. Each additional tissue sample from a patient provides additional constraints on possible evolutionary histories, and so should aid construction of more accurate and precise results. Counterintuitively, we demonstrate using both simulated and real data that existing algorithms actually perform worse as additional tissue samples are provided, often failing to produce any result. Pairtree, conversely, efficiently leverages the information from additional samples to perform progressively better as samples are added. The algorithm's ability to function in these settings enables new biological and clinical applications, which we demonstrate using data from 14 acute lymphoblastic leukemia cancers, with dozens of tissue samples per cancer. Pairtree also produces a useful visual representation of the degree of support underlying evolutionary relationships present in the user's data, allowing users to make accurate inferences from its results. ### Competing Interest Statement The authors have declared no competing interest.

96: Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation
more details view paper

Posted 16 Nov 2020

Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation
1 tweet bioRxiv genomics

Lucy van Dorp, Cedric CS Tan, Su Datt Lam, Damien Richard, Christopher Owen, Dorothea Berchtold, Christine Orengo, François Balloux

Severe acute respiratory coronavirus 2 (SARS-CoV-2), the agent of the ongoing COVID-19 pandemic, jumped into humans from an unknown animal reservoir in late 2019. In line with other coronaviruses, SARS-CoV-2 has the potential to infect a broad range of hosts. SARS-CoV-2 genomes have now been isolated from cats, dogs, lions, tigers and minks. SARS-CoV-2 seems to transmit particularly well in mink farms with outbreaks reported in Spain, Sweden, the Netherlands, Italy, the USA and Denmark. Genomic data from SARS-CoV-2 isolated from infected minks provides a natural case study of a secondary host jump of the virus, in this case from humans to animals, and occasionally back again. We screened published SARS-CoV-2 genomes isolated from minks for the presence of recurrent mutations common in mink but infrequent in SARS-CoV-2 genomes from human infections. We identify 23 recurrent mutations including three nonsynonymous mutations in the Receptor Binding Domain of the SARS-CoV-2 spike protein that independently emerged at least four times but are only very rarely observed in strains circulating in humans. The repeat emergence of mutations across phylogenetically distinct lineages of the virus isolated from minks points to ongoing adaptation of SARS-CoV-2 to a new host. The rapid acquisition and spread of SARS-CoV-2 mutations in minks suggests that if a similar phenomenon of host adaptation had occurred upon its jump into humans, those human-specific mutations would likely have reached fixation already before the first SARS-CoV-2 genomes were generated. ### Competing Interest Statement The authors have declared no competing interest.

97: A hybrid open-top light-sheet microscope for multi-scale imaging of cleared tissues
more details view paper

Posted 08 May 2020

A hybrid open-top light-sheet microscope for multi-scale imaging of cleared tissues
1 tweet bioRxiv bioengineering

Adam K. Glaser, Kevin W. Bishop, Lindsey A. Barner, Robert B. Serafin, Jonathan T.C. Liu

Light-sheet microscopy has emerged as the preferred means for high-throughput volumetric imaging of cleared tissues. However, there is a need for a user-friendly system that can address diverse imaging applications with varied requirements in terms of resolution (mesoscopic to sub-micron), sample geometry (size, shape, and number), and compatibility with tissue-clearing protocols of different refractive indices. We present a hybrid system that combines a novel non-orthogonal dual-objective and conventional open-top light-sheet architecture for highly versatile multi-scale volumetric imaging. ### Competing Interest Statement A.K.G. and J.T.C.L. are co-founders and shareholders of Lightspeed Microscopy Inc.

98: Biological networks and GWAS: comparing and combining network methods to understand the genetics of familial breast cancer susceptibility in the GENESIS study
more details view paper

Posted 05 May 2020

Biological networks and GWAS: comparing and combining network methods to understand the genetics of familial breast cancer susceptibility in the GENESIS study
1 tweet bioRxiv genetics

Héctor Climente-González, Christine Lonjou, Fabienne Lesueur, Dominique Stoppa-Lyonnet, Nadine Andrieu, Chloé-Agathe Azencott, GENESIS study group

Network approaches to disease use biological networks, which model functional relationships between the molecules in a cell, to generate hypotheses about the genetics of complex diseases. Several among them jointly consider gene scores, representing the association between each gene and the disease, and the biological context of each gene, modeled by a network. Here, we study six such network methods using gene scores from GENESIS, a genome-wide association study (GWAS) on French women with non-BRCA familial breast cancer. We provide a critical comparison of these six methods, discussing the impact of their mathematical formulation and parameters. Using a biological network yields more compelling results than standard GWAS analyses. Indeed, we find significant overlaps between our solutions and the genes identified in the largest GWAS on breast cancer susceptibility. We further propose to combine these solutions into a consensus network, which brings further insights. The consensus network contains COPS5 , a gene related to multiple hallmarks of cancer, and 14 of its neighbors. The main drawback of network methods is that they are not robust to small perturbations in their inputs. Therefore, we propose a stable consensus solution, formed by the most consistently selected genes in multiple subsamples of the data. In GENESIS, it is composed of 68 genes, enriched in known breast cancer susceptibility genes ( BLM , CASP8 , CASP10 , DNAJC1 , FGFR2 , MRPS30 , and SLC4A7 , P-value = 3 × 10^-4) and occupying more central positions in the network than most genes. The network is organized around CUL3 , which is involved in the regulation of several genes linked to cancer progression. In conclusion, we showed how network methods help overcome the lack of statistical power of GWAS and improve their interpretation. Project-agnostic implementations of all methods are available at https://github.com/hclimente/gwas-tools. ### Competing Interest Statement The authors have declared no competing interest.

99: SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
more details view paper

Posted 02 May 2020

SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
1 tweet bioRxiv evolutionary biology

Shing Hei Zhan, Benjamin E. Deverman, Yujia Alina Chan

In a side-by-side comparison of evolutionary dynamics between the 2019/2020 SARS-CoV-2 and the 2003 SARS-CoV, we were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or parallel branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected. The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence. Any existing pools of SARS-CoV-2 progenitors would be particularly dangerous if similarly well adapted for human transmission. To look for clues regarding intermediate hosts, we analyze recent key findings relating to how SARS-CoV-2 could have evolved and adapted for human transmission, and examine the environmental samples from the Wuhan Huanan seafood market. Importantly, the market samples are genetically identical to human SARS-CoV-2 isolates and were therefore most likely from human sources. We conclude by describing and advocating for measured and effective approaches implemented in the 2002-2004 SARS outbreaks to identify lingering population(s) of progenitor virus. ### Competing Interest Statement Shing Hei Zhan is a Co-founder and lead bioinformatics scientist at Fusion Genomics Corporation, which develops molecular diagnostic assays for infectious diseases.

100: Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2
more details view paper

Posted 30 Apr 2020

Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2
1 tweet bioRxiv evolutionary biology

B Korber, WM Fischer, S Gnanakaran, H Yoon, J Theiler, W Abfalterer, B Foley, EE Giorgi, T Bhattacharya, MD Parker, DG Partridge, CM Evans, TM Freeman, Thushan I de Silva, on behalf of the Sheffield COVID-19 Genomics Group, CC LaBranche, DC Montefiori

We have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike (S) protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified fourteen mutations in Spike that are accumulating. Mutations are considered in a broader phylogenetic context, geographically, and over time, to provide an early warning system to reveal mutations that may confer selective advantages in transmission or resistance to interventions. Each one is evaluated for evidence of positive selection, and the implications of the mutation are explored through structural modeling. The mutation Spike D614G is of urgent concern; after beginning to spread in Europe in early February, when introduced to new regions it repeatedly and rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections. These finding have important implications for SARS-CoV-2 transmission, pathogenesis and immune interventions. ### Competing Interest Statement The authors have declared no competing interest.

Previous page 1 2 3 4 5 6 7 8 Next page

PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News