bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity
Authors: Martino Cameron , Kellman Benjamin P. , Sandoval Daniel R. , Clausen Thomas Mandel , Marotz Clarisse A. , Song Se Jin , Wandro Stephen , Zaramela Livia S. , Salido Benítez Rodolfo Antonio , Zhu Qiyun , Armingol Erick , Vázquez-Baeza Yoshiki , McDonald Daniel , Sorrentino James T. , Taylor Bryn , Belda-Ferre Pedro , Liang Chenguang , Zhang Yujie , Schifanella Luca , Klatt Nichole R. , Havulinna Aki S. , Jousilahti Pekka , Huang Shi , Haiminen Niina , Parida Laxmi , Kim Ho-Cheol , Swafford Austin D. , Zengler Karsten , Cheng Susan , Inouye Michael , Niiranen Teemu , Jain Mohit , Salomaa Veikko , Esko Jeffrey D. , Lewis Nathan E. , Knight Rob 
Published: August 2020

AbstractThe human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age.In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility.Graphical Abstract. Diagram of hypothesis for bacterial mediation of SARS-CoV-2 infection through heparan sulfate (HS).It is well known that host microbes groom the mucosa where they reside. Recent investigations have shown that HS, a major component of mucosal layers, is necessary for SARS-CoV-2 infection. In this study we examine the impact of microbial modification of HS on viral attachment.
Hypoxia triggers collective aerotactic migration inDictyostelium discoideum
Authors: Cochet-Escartin O. , Demircigil M. , Hirose S. , Allais B. , Gonzalo P. , Mikaelian I. , Funamoto K. , Anjard C. , Calvez V. , Rieu J.-P. 
Published: August 2020

AbstractIt is well known that eukaryotic cells can sense oxygen (O2) and adapt their metabolism accordingly. It is less known that they can also move towards regions of higher oxygen level (aerotaxis). Using a self-generated hypoxic assay, we show that the social amoebaDictyostelium discoideumdisplays a spectacular aerotactic behavior. When a cell colony is covered by a coverglass, cells quickly consume the available O2and the ones close to the periphery move directionally outward forming a dense ring keeping a constant speed and density. To confirm that O2is the main molecular player in this seemingly collective process, we combined two technological developments, porphyrin based O2sensing films and microfluidic O2gradient generators. We showed thatDictyosteliumcells exhibit aerotactic and aerokinetic (increased speed at low O2) response in an extremely low range of O2concentration (0-1.5%) indicative of a very efficient detection mechanism. The various cell behaviors under self-generated or imposed O2gradients were modeled with a very satisfactory quantitative agreement using anin silicocellular Potts model built on experimental observations. This computational model was complemented with a parsimonious ‘Go or Grow’ partial differential equation (PDE) model. In both models, we found that the collective migration of a dense ring can be explained by the interplay between cell division and the modulation of aerotaxis, without the need for cell-cell communication.
Host auxin machinery is important in mediating root architecture changes induced byPseudomonas fluorescensGM30 andSerendipita indica
Authors: Matthiadis Anna , Sukumar Poornima , DeLeon Alyssa , Pelletier Dale , Labbé Jessy L. , Tuskan Gerald A , Kalluri Udaya C 
Published: August 2020

AbstractAuxin is a key phytohormone that is integral to plant developmental processes including those underlying root initiation, elongation, and branching. Beneficial microbes have been shown to have an impact on root development, potentially mediated through auxin. In this study, we explore the role of host auxin signaling and transport components in mediating the root growth promoting effects of beneficial microbes. Towards this end, we undertook co-culture studies ofArabidopsis thalianaplants with microbes previously reported to promote lateral root proliferation and produce auxin. Two types of beneficial microbes were included in the present study; a plant growth promoting bacterial species of interest,Pseudomonas fluorescensGM30, and a well-studied plant growth promoting fungal species,Serendipita indica (Piriformospora indica). Following co-culture, lateral root production was found restored in auxin transport inhibitor-treated plants, suggesting involvement of microbe and/or microbially-produced auxin in altering plant auxin levels. In order to clarify the role of host auxin signaling and transport pathways in mediating interactions with bacterial and fungal species, we employed a suite of auxin genetic mutants as hosts in co-culture screens. Our result show that the transport proteins PIN2, PIN3, and PIN7 and the signaling protein ARF19, are required for mediating root architecture effects by the bacterial and/or fungal species. Mutants corresponding to these proteins did not significantly respond to co-culture treatment and did not show increases in lateral root production and lateral root density. These results implicate the importance of host auxin signaling in both bacterial and fungal induced changes in root architecture and serve as a driver for future research on understanding the role of auxin-dependent and auxin-independent pathways in mediating plant-microbe interactions in economically important crop species.
Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis
Authors: McEvoy Caitriona M. , Clotet-Freixas Sergi , Tokar Tomas , Pastrello Chiara , Reid Shelby , Batruch Ihor , RaoPeters Adrien A.E. , Kaths J. Moritz , Urbanellis Peter , Farkona Sofia , Van Julie A.D. , Urquhart Bradley L. , John Rohan , Jurisica Igor , Robinson Lisa A. , Selzner Markus , Konvalinka Ana 
Published: August 2020

AbstractNormothermicex-vivokidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.
Generalized linear models provide a measure of virulence for specific mutations in SARS-CoV-2 strains
Authors: Oulas Anastasis , Zanti Maria , Tomazou Marios , Zachariou Margarita , Minadakis George , Bourdakou Marilena M , Pavlidis Pavlos , Spyrou George M. 
Published: August 2020

AbstractThis study aims to highlight SARS-COV-2 mutations which are associated with increased or decreased viral virulence. We utilize, genetic data from all strains available from GISAID and countries’ regional information such as deaths and cases per million as well as covid-19-related public health austerity measure response times. Initial indications of selective advantage of specific mutations can be obtained from calculating their frequencies across viral strains. By applying modelling approaches, we provide additional information that is not evident from standard statistics or mutation frequencies alone. We therefore, propose a more precise way of selecting informative mutations. We highlight two interesting mutations found in genes N (P13L) and ORF3a (Q57H). The former appears to be significantly associated with decreased deaths and cases per million according to our models, while the latter shows an opposing association with decreased deaths and increased cases per million. Moreover, protein structure prediction tools show that the mutations infer conformational changes to the protein that significantly alter its structure when compared to the reference protein.
Sodium leak channel as a therapeutic target for neuronal sensitization in neuropathic pain
Authors: Zhang Donghang , Zhao Wenling , Liu Jin , Ou Mengchan , Liang Peng , Li Jia , Chen Yali , Liao Daqing , Bai Siqi , Shen Jiefei , Chen Xiangdong , Huang Han , Zhou Cheng 
Published: August 2020

AbstractNeuropathic pain affects up to 10% of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a voltage-independent cation channel, mediates the background Na+leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely reversed by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel therapeutic target for neuropathic pain.
Oxidative Stress Responses and Nutrient Starvation in MCHM TreatedSaccharomyces cerevisiae
Authors: Ayers Michael C. , Sherman Zachary N. , Gallagher Jennifer E.G. 
Published: August 2020

AbstractIn 2014, the coal cleaning chemical 4-methylcyclohexane methanol (MCHM) spilled into the water supply for 300,000 West Virginians. Initial toxicology tests showed relatively mild results, but the underlying effects on cellular biology were underexplored. Treated wildtype yeast cells grew poorly, but there was only a small decrease in cell viability. Cell cycle analysis revealed an absence of cells in S phase within thirty minutes of treatment. Cells accumulated in G1 over a six-hour time course, indicating arrest instead of death. A genetic screen of the haploid knockout collection revealed 329 high confidence genes required for optimal growth in MCHM. These genes encode three major cell processes: mitochondrial gene expression/translation, the vacuolar ATPase, and aromatic amino acid biosynthesis. The transcriptome showed an upregulation of pleiotropic drug response genes and amino acid biosynthetic genes and downregulation in ribosome biosynthesis. Analysis of these datasets pointed to environmental stress response activation upon treatment. Overlap in datasets included the aromatic amino acid genesARO1,ARO3, and four of the fiveTRPgenes. This implicated nutrient deprivation as the signal for stress response. Excess supplementation of nutrients and amino acids did not improve growth on MCHM, so the source of nutrient deprivation signal is still unclear. Reactive oxygen species and DNA damage were directly detected with MCHM treatment, but timepoints showed these accumulated slower than cells arrested. We propose that wildtype cells arrest from nutrient deprivation and survive, accumulating oxidative damage through the implementation of robust environmental stress responses.
Casein Kinase 1G2 Suppresses Necroptosis-Promoted Testis Aging by Inhibiting Receptor-Interacting Kinase 3
Authors: Li Dianrong , Ai Youwei , Guo Jia , Dong Baijun , Li Lin , Cai Gaihong , Chen She , Xu Dan , Wang Fengchao , Wang Xiaodong 
Published: August 2020

AbstractCasein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIP3, thereby attenuating RIP3-mediated necroptosis. The binding of CSNK1G2 to RIP3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and pre-maturing aging of their testis, a phenotype that was rescued by either double knockout of the RIP3 gene or feeding the animal with a RIP1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIP3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIP3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.
Structure of long-range direct and indirect spinocerebellar pathways as well as local spinal circuits mediating proprioception
Authors: Pop Iliodora V. , Espinosa Felipe , Blevins Cheasequah J. , Okafor Portia C. , Ogujiofor Osita W. , Goyal Megan , Mona Bishakha , Landy Mark A. , Dean Kevin M. , Gurumurthy Channabasavaiah B. , Lai Helen C. 
Published: August 2020

AbstractProprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways are wired. Defining the anatomy of secondary neurons in the spinal cord that integrate and relay proprioceptive and potentially cutaneous information from the periphery to the cerebellum is fundamental to understanding how proprioceptive circuits function. Here, we use genetic tools in both male and female mice to define the unique anatomical trajectories of long-range direct and indirect spinocerebellar pathways as well as local intersegmental spinal circuits. We find that Clarke’s column (CC) neurons, a major contributor to the direct spinocerebellar pathway, has mossy fiber terminals that diversify extensively in the cerebellar cortex with axons terminating bilaterally, but with no significant axon collaterals within the spinal cord, medulla, or cerebellar nuclei. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus (spino-LRt) and spino-olivary pathways, are in part, derived from cervicalAtoh1-lineage neurons, while thoracolumbarAtoh1-lineage neurons project mostly locally within the spinal cord. Notably, while cervical and thoracolumbarAtoh1-lineage neurons connect locally with motor neurons, no CC to motor neuron connections were detected. Silencing of caudalAtoh1- lineage neurons results in a subtle motor impairment consistent with a defect in local proprioceptive circuitry. Altogether, we define anatomical differences between long-range direct, indirect, and local proprioceptive subcircuits that likely mediate different components of proprioceptive-motor behaviors.Significance StatementWe define the anatomy of long-range direct and indirect spinocerebellar pathways as well as local spinal proprioceptive circuits. We observe that mossy fiber axon terminals of Clarke’s column (CC) neurons diversify proprioceptive information across granule cells in multiple lobules on both ipsilateral and contralateral sides sending no significant collaterals within the spinal cord, medulla, or cerebellar nuclei. Strikingly, we find that cervical spinal cordAtoh1-lineage neurons form mainly the indirect spino- lateral reticular nucleus and spino-olivary tracts and thoracolumbarAtoh1-lineage neurons project locally within the spinal cord while only a fewAtoh1-lineage neurons form a direct spinocerebellar tract. Altogether, we define the development, anatomical projections, and some behavioral consequences of silencing spinal proprioceptive pathways.
A novel copper-sensing two-component system for activating Dsb genes in bacteria
Authors: Yu Liang , Cao Qiao , Chen Weizhong , Yang Nana , Yang Cai-Guang , Ji Quanjiang , Wu Min , Bae Taeok , Lan Lefu 
Published: August 2020

AbstractCopper is an essential element for biological systems but becomes toxic when present in excess. InPseudomonas aeruginosa, an important human pathogen, the resistance to copper requires the induction ofdsbDEGoperon encoding proteins involved in disulfide-bond formation (Dsb). However, it is unknown how the copper stress induces the transcription of the operon. Here, we report that the exogenous copper induces the transcription of thedsbDEGoperon through a new copper-sensing two-component system named DsbRS. ThedsbRSis divergently transcribed from thedsbDEGoperon, and the response regulator DsbR binds to the intergenic region between the operons. In the absence of copper, the sensor kinase DsbS acts as a phosphatase toward DsbR and thus blocks the transcription of the operons. However, in the presence of copper, the metal ion directly binds to the sensor domain of DsbS, for which the Cys82 residue plays a critical role. The copper-binding appears to inhibit the phosphatase activity of DsbS, leading to activation of DsbR. The copper resistance of thedsbRSknock-out mutant was restored by ectopic expression of thedsbDEGoperon, confirming the critical role of the operon in the resistance to copper. Strikingly, cognates ofdsbRS-dsbDEGpair are widely distributed across eubacteria. Also, a DsbR-binding site, which contains the consensus sequence 5’-TAA-N7-TTAAT-3’, is detected in the promoter region ofdsbDEGhomologs in those species. Thus, regulation of Dsb genes by DsbRS represents a novel mechanism by which bacterial cells cope with copper stress.ImportanceCopper is an essential redox active cofactor that becomes highly cytotoxic when present in excess. Therefore, in order to evade copper toxicity, bacteria must perceive copper stress and tightly regulate genes expression. In the present study, we identify a new copper-sensing two-component system (designated DsbRS) inPseudomonas aeruginosa, an important human pathogen. We provide multiple lines of evidence that upon copper binding to the periplasmic domain of DsbS, its phosphatase activity is blocked, and the phosphorylated DsbR directly activates the transcription of a number of copper-induced genes including those involved in protein disulfide-bond formation (Dsb). This study suggests that regulation of Dsb genes by DsbRS may be an underappreciated regulatory mechanism by which bacteria sense and respond to copper.
Unique roles of vaginalMegasphaeraphylotypes in reproductive health
Authors: Glascock Abigail L. , Jimenez Nicole R. , Boundy Sam , Koparde Vishal N. , Brooks J. Paul , Edwards David J. , Strauss Jerome F. , Jefferson Kimberly K. , Serrano Myrna G. , Buck Gregory A. ,   Vaginal Microbiome Consortium, Fettweis Jennifer M. 
Published: August 2020

ABSTRACTThe composition of the human vaginal microbiome has been extensively studied and is known to influence reproductive health. However, the functional roles of individual taxa and their contributions to negative health outcomes have yet to be well characterized. Here, we examine two vaginal bacterial taxa grouped within the genusMegasphaerathat have been previously associated with bacterial vaginosis (BV) and pregnancy complications. Phylogenetic analyses support the classification of these taxa as two distinct species. These two phylotypes,Megasphaeraphylotype 1 (MP1) andMegasphaeraphylotype 2 (MP2), differ in genomic structure and metabolic potential, suggestive of differential roles within the vaginal environment. Further, these vaginal taxa show evidence of genome reduction and changes in DNA base composition, which may be common features of host dependence and/or adaptation to the vaginal environment. In a cohort of 3,870 women, we observed that MP1 has a stronger positive association with bacterial vaginosis whereas MP2 was positively associated with trichomoniasis. MP1, in contrast to MP2 and other common BV-associated organisms, was not significantly excluded in pregnancy. In a cohort of 52 pregnant women, MP1 was both present and transcriptionally active in 75.4% of vaginal samples. Conversely, MP2 was largely absent in the pregnant cohort. This study provides insight into the evolutionary history, genomic potential and predicted functional role of two clinically relevant vaginal microbial taxa.
An automated framework for efficiently designing deep convolutional neural networks in genomics
Authors: Zhang Zijun , Park Christopher Y. , Theesfeld Chandra L. , Troyanskaya Olga G. 
Published: August 2020

AbstractConvolutional neural networks (CNNs) have become a standard for analysis of biological sequences. Tuning of network architectures is essential for CNN’s performance, yet it requires substantial knowledge of machine learning and commitment of time and effort. This process thus imposes a major barrier to broad and effective application of modern deep learning in genomics. Here, we present AMBER, a fully automated framework to efficiently design and apply CNNs for genomic sequences. AMBER designs optimal models for user-specified biological questions through the state-of-the-art Neural Architecture Search (NAS). We applied AMBER to the task of modelling genomic regulatory features and demonstrated that the predictions of the AMBER-designed model are significantly more accurate than the equivalent baseline non-NAS models and match or even exceed published expert-designed models. Interpretation of AMBER architecture search revealed its design principles of utilizing the full space of computational operations for accurately modelling genomic sequences. Furthermore, we illustrated the use of AMBER to accurately discover functional genomic variants in allele-specific binding and disease heritability enrichment. AMBER provides an efficient automated method for designing accurate deep learning models in genomics.