bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shapes and Genescapes: Mapping Multivariate Phenotype-Biological Process Associations for Craniofacial Shape
Authors: Aponte J. David , Katz David C. , Roth Daniela M. , Garcia Marta Vidal , Liu Wei , Andrade Fernando , Roseman Charles C. , Murray Stephen A. , Cheverud James , Graf Daniel , Marcucio Ralph S. , Hallgrímsson Benedikt 
Published: November 2020

AbstractRealistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait—craniofacial shape — in a sample ofn= 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.
Neuraminidase inhibitors rewire neutrophil functionin vivoin murine sepsis andex vivoin COVID-19
Authors: de Oliveira Formiga Rodrigo , Amaral Flávia C. , Souza Camila F. , Mendes Daniel A. G. B. , Wanderley Carlos W. S. , Lorenzini Cristina B. , Santos Adara A. , Antônia Juliana , Faria Lucas F. , Natale Caio C. , Paula Nicholas M. , Silva Priscila C. S. , Fonseca Fernanda R. , Aires Luan , Heck Nicoli , Starick Márick R. , Queiroz-Junior Celso M. , Santos Felipe R. S. , de Souza Filipe R. O. , Costa Vivian V. , Barroso Shana P. C. , Morrot Alexandre , Van Weyenbergh Johan , Sordi Regina , Alisson-Silva Frederico , Cunha Fernando Q. , Rocha Edroaldo L. , Chollet-Martin Sylvie , Hurtado-Nedelec Maria Margarita , Martin Clémence , Burgel Pierre-Régis , Mansur Daniel S. , Maurici Rosemeri , Macauley Matthew S. , Báfica André , Witko-Sarsat Véronique , Spiller Fernando 
Published: November 2020

ABSTRACTNeutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils.In vivo, treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections.At a GlanceIn a severe systemic inflammatory response, such as sepsis and COVID-19, neutrophils play a central role in organ damage. Thus, finding new ways to inhibit the exacerbated response of these cells is greatly needed. Here, we demonstrate thatin vitrotreatment of whole blood with the viral neuraminidase inhibitors Oseltamivir or Zanamivir, inhibits the activity of human neuraminidases as well as the exacerbated response of neutrophils. In experimental models of severe sepsis, oseltamivir decreased neutrophil activation and increased the survival rate of mice. Moreover, Oseltamivir or Zanamivirex vivotreatment of whole blood cells from severe COVID-19 patients rewire neutrophil function.
Conformational dynamics regulate SHANK3 actin and Rap1 binding
Authors: Salomaa Siiri I , Miihkinen Mitro , Kremneva Elena , Paatero Ilkka , Lilja Johanna , Jacquemet Guillaume , Vuorio Joni , Antenucci Lina , Hassani-Nia Fatemeh , Hollos Patrik , Isomursu Aleksi , Vattulainen Ilpo , Coffey Eleanor T. , Kreienkamp Hans-Jürgen , Lappalainen Pekka , Ivaska Johanna 
Published: November 2020

AbstractActin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology and specific biological function of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators and small GTPases. SHANK3 is a multifunctional scaffold protein, interacting with several actin-binding proteins, and a well-established autism risk gene. Recently, SHANK3 was demonstrated to sequester integrin-activating small GTPases Rap1 and R-Ras to inhibit integrin activity via its N-terminal SPN domain. Here, we demonstrate that SHANK3 interacts directly with actin using its SPN domain. Actin binding can be inhibited by an intramolecular closed conformation of SHANK3, where the adjacent ARR domain covers the actin-binding interface of the SPN domain. Actin and Rap1 compete with each other for binding to SHANK3 and loss of SHANK3-actin binding augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for filopodia formation in cancer cells, dendritic spine morphology in neurons and autism-linked phenotypesin vivo.
Pipefish locally adapted to low salinity in the Baltic Sea retain phenotypic plasticity to cope with ancestral salinity levels
Authors: Goehlich Henry , Sartoris Linda , Wagner Kim Sara , Wendling Carolin C. , Roth Olivia 
Published: November 2020

AbstractGenetic adaptation and phenotypic plasticity facilitate the invasion of new habitats and enable organisms to cope with a rapidly changing environment. In contrast to genetic adaptation that spans multiple generations as an evolutionary process, phenotypic plasticity allows acclimation within the life-time of an organism. Genetic adaptation and phenotypic plasticity are usually studied in isolation, however, only by including their interactive impact, we can understand acclimation and adaptation in nature. We aimed to explore the contribution of adaptation and plasticity in coping with an abiotic (salinity) and a biotic (Vibrio bacteria) stressor using six different populations of the broad-nosed pipefish Syngnathus typhle that originated from either high or low saline environments. We hypothesized that wild S. typhle populations are locally adapted to the salinity and prevailing pathogens of their native environment, and that short-term acclimation of parents to a novel salinity may aid in buffering offspring phenotypes in a matching environment. To test these hypotheses, we exposed all wild caught animals, to either high or low salinity, representing native and novel salinity conditions and allowed animals to mate. After male pregnancy, offspring was split and each half was exposed to one of the two salinities and infected with Vibrio alginolyticus bacteria that were evolved at either of the two salinities in a fully reciprocal design. We investigated life history traits of fathers (offspring survival, offspring size) and expression of 47 target genes in mothers and offspring.Pregnant males originating from high salinity exposed to low salinity were highly susceptible to opportunistic fungi infections resulting in decreased offspring size and number. In contrast, no signs of fungal infection were identified in fathers originating from low saline conditions suggesting that genetic adaptation has the potential to overcome the challenging conditions of low salinity. Genetic adaptation increased survival rates of juveniles from parents in lower salinity (in contrast to those from high salinity). Juvenile gene expression indicated patterns of local adaptation, trans-generational plasticity and developmental plasticity. The results of our study suggest that pipefish locally adapted to low salinity retain phenotypic plasticity, which allows them to also cope with ancestral salinity levels and prevailing pathogens.
Mental Health Status of Adolescents During the COVID-19 Pandemic: A Cross-sectional Survey among the Bangladeshi Graduate Students at Dhaka City
Authors: Husain Taha , Uddin Mohammad Main , Chowdhury Saber Ahmed , Kalimullah Nazmul Ahsan 
Published: November 2020

AbstractObjectivesTo identify the level of Mental Health Status of Adolescents During the COVID-19 Pandemic among the Bangladeshi Graduate Student at DhakaMethodA cross-sectional survey was conducted with 330 students from different public and Private Universities in Dhaka, Bangladesh between April 01, 2020 and July 31, 2020 amid the COVID-19 lockdown period in Bangladesh. A standard, self-administered online questionnaire consisting of questions on socio-demographic variables, mental health status, as well as stress management sent to the respondents through social networking platforms. Data were analyzed using descriptive statistics, t-test, one-way ANOVA and correlation tests.ResultsThe mean score of mental health status was 2.08 based on four points scale. They felt problem in decision making (3.04), in doing the things well (2.92), in enjoying normal day to day life (2.88), in playing a useful part in life (2.85), in doing their task (2.75), living in perfectly well and in good health (2.70). The respondents also developed a suicidal tendency (2.55), felt nervous in strung-up (2.24), took longer time to do things (2.14), felt tightness and pressure in head (2.12), and found themselves pressurized by various stuff (2.05). This study also found a significant positive relationship between mental health status and age, living with parents, and parents’ attitude. Finally, this study revealed that the respondents managed their stress by chatting with their friends, parents and siblings, and by sleeping.ConclusionMental health status of adolescents was found moderate in this study. This study suggests further large-scale study including different socio-economic settings in order to figure out the real scenario of adolescents’ mental health status of the country during the pandemic.
Oxygen-dependent changes in HIF binding partners and post-translational modifications regulate stability and transcriptional activity
Authors: Daly Leonard , Brownridge Philip J. , Sée Violaine , Eyers Claire E. 
Published: November 2020

AbstractAdaption of cells to low oxygen environments is an essential process mediated in part by the Hypoxia Inducible Factors (HIFs). Like other transcription factors, the stability and transcriptional activity of HIFs, and consequently the hypoxic response, are regulated by post-translational modification (PTM) and changes in biomolecular interactions. However, our current understanding of PTM-mediated regulation of HIFs is primarily based on in vitro protein fragment-based studies, with validation typically having been conducted by in cellulo fragment expression and hypoxia mimicking drugs. Consequently, we still lack an understanding of true oxygen deprivation signaling via HIFα. Using an immunoprecipitation-based, mass spectrometry approach, we characterize the regulation of in cellulo expressed full-length HIF-1α and HIF-2α, in terms of both PTM and binding partners, in response to normoxia (21% oxygen) and hypoxia (1% oxygen). These studies revealed that a change in oxygen tension significantly alters the complexity and composition of HIF-α protein interaction networks, with HIF-2α in particular having an extended hypoxia-induced interactome, most notably with mitochondrial-associated proteins. Both HIFα isoforms are heavily covalently modified: we define ~40 different sites of PTM on each of HIF-1α and HIF-2α, comprising 13 different PTM types, including multiple cysteine modifications and a highly unusual phosphocysteine. Over 80% of the PTMs identified are novel, and approximately half exhibit oxygen-dependency under these conditions. Combined with domain and evolutionary analysis of >225 vertebrate species, we validate Ser31 phosphorylation on HIF-1α as a regulator of transcription, and propose functional roles for Thr406, Thr528 and Ser581 on HIF-2α.
Identifying and prioritizing potential human-infecting viruses from their genome sequences
Authors: Mollentze Nardus , Babayan Simon A. , Streicker Daniel G. 
Published: November 2020

AbstractDetermining which animal viruses may be capable of infecting humans is currently intractable at the time of their discovery, precluding prioritization of high-risk viruses for early investigation and outbreak preparedness. Given the increasing use of genomics in virus discovery and the otherwise sparse knowledge of the biology of newly-discovered viruses, we developed machine learning models that identify candidate zoonoses solely using signatures of host range encoded in viral genomes. Within a dataset of 861 viral species with known zoonotic status, our approach outperformed models based on the phylogenetic relatedness of viruses to known human-infecting viruses (AUC = 0.773), distinguishing high-risk viruses within families that contain a minority of human-infecting species and identifying putatively undetected or so far unrealized zoonoses. Analyses of the underpinnings of model predictions suggested the existence of generalisable features of viral genomes that are independent of virus taxonomic relationships and that may preadapt viruses to infect humans. Our model reduced a second set of 645 animal-associated viruses that were excluded from training to 272 high and 41 very high-risk candidate zoonoses and showed significantly elevated predicted zoonotic risk in viruses from non-human primates, but not other mammalian or avian host groups. A second application showed that our models could have identified SARS-CoV-2 as a relatively high-risk coronavirus strain and that this prediction required no prior knowledge of zoonotic SARS-related coronaviruses. Genome-based zoonotic risk assessment provides a rapid, low-cost approach to enable evidence-driven virus surveillance and increases the feasibility of downstream biological and ecological characterisation of viruses.
96-Well Oxygen Control Using a 3D-Printed Device
Authors: Szmelter Adam , Jacob Jason , Eddington David 
Published: November 2020

ABSTRACTOxygen concentration varies tremendously within the body and has proven to be a critical variable in cell differentiation, proliferation, and drug metabolism among many other physiological processes. Currently, researchers study the gas’s role in biology using low-throughput gas-control incubators or hypoxia chambers in which all cells in a vessel are exposed to a single oxygen concentration. Here, we introduce a device which can simultaneously deliver 12 unique oxygen concentrations to cells in a 96-well plate and seamlessly integrate into biomedical research workflows. The device inserts into 96-well plates and delivers gas to the headspace thus avoiding undesirable contact with media. This simple approach isolates each well using gas-tight pressure resistant gaskets effectively creating 96 “mini-incubators”. Each of the twelve columns of the plate is supplied by a distinct oxygen concentration from a gas-mixing gradient generator supplied by two feed gases. The wells within each column are then supplied by an equal flow-splitting distribution network. Using equal feed flow rates, concentrations ranging from 0.6% to 20.5% were generated within a single plate. A549 lung carcinoma cells were then used to show that O2levels below 9% caused a stepwise increase in cell death for cells treated with the hypoxia-activated anti-cancer drug Tirapirizamine (TPZ). Additionally, the 96-well plate was further leveraged to simultaneously test multiple TPZ concentrations over an oxygen gradient and generate a 3D dose response landscape. The results presented here show how microfluidic technologies can be integrated into, rather than replace, ubiquitous biomedical labware allowing for increased throughput oxygen studies.
New Insights and Enhanced Human Norovirus Cultivation in Human Intestinal Enteroids
Authors: Ettayebi Khalil , Tenge Victoria R , Cortes-Penfield Nicolas W. , Crawford Sue E. , Neill Frederick H. , Zeng Xi-Lei , Yu Xiaomin , Ayyar B. Vijayalakshmi , Burrin Douglas , Ramani Sasirekha , Atmar Robert L. , Estes Mary K. 
Published: November 2020

AbstractHuman noroviruses (HuNoVs) are the leading cause of epidemic and sporadic acute gastroenteritis worldwide. We previously demonstrated human intestinal stem cell-derived enteroids (HIEs) support cultivation of several HuNoV strains. However, HIEs did not support virus replication from every HuNoV-positive stool sample, which led us to test and optimize new media conditions, identify characteristics of stool samples that allow replication, and evaluate consistency of replication over time. Optimization of our HIE-HuNoV culture system has shown that: 1) A new HIE culture media made with conditioned medium from a single cell line and commercial media promote robust replication of HuNoV strains that replicated poorly in HIEs grown in our original culture media made with conditioned media from 3 separate cell lines; 2) GI.1, eleven GII genotypes (GII.1, GII.2, GII.3, GII.4, GII.6, GII.7, GII.8, GII.12, GII.13, GII.14 and GII.17) and six GII.4 variants, can be cultivated in HIEs; 3) successful replication is more likely with virus in stools with higher virus titers; 4) GII.4_Sydney_2012 virus replication was reproducible over three years; and 5) HuNoV infection is restricted to the small intestine, based on replication in duodenal and ileal HIEs but not colonoids from the same donors. These results improve the HIE culture system for HuNoV replication. Use of HIEs by several laboratories worldwide to study the molecular mechanisms that regulate HuNoV replication confirms the usefulness of this culture system and our optimized methods for virus replication will advance the development of effective therapies and methods for virus control.ImportanceHuman noroviruses (HuNoVs) are highly contagious and cause acute and sporadic diarrheal illness in all age groups. In addition, chronic infections occur in immunocompromised cancer and transplant patients. These viruses are antigenically and genetically diverse and there are strain-specific differences in binding to cellular attachment factors. In addition, new discoveries are being made on strain-specific differences in virus entry and replication and the epithelial cell response to infection in human intestinal enteroids. Human intestinal enteroids are a biologically-relevant model to study HuNoVs; however, not all strains can be cultivated at this time. A complete understanding of HuNoV biology thus requires cultivation conditions that will allow the replication of multiple strains. We report optimization of HuNoV cultivation in human intestinal enteroid cultures to increase the numbers of cultivatable strains and the magnitude of replication, which is critical for testing antivirals, neutralizing antibodies and methods of virus inactivation.
Non-transmissibility of Pepper whitefly borne vein yellows virus (PeWBVYV) by the Mediterranean species ofBemisia tabaciand identification of a candidate insect receptor protein for poleroviruses
Authors: Ghosh Saptarshi , Bello Vinicius Henrique , Ghanim Murad 
Published: November 2020

AbstractRecent reports of transmission of poleroviruses by whiteflies is indicative of evolution of new virus-vector relationships. Pepper whitefly-borne vein yellows virus (PeWBVYV), was the first report of a polerovirus infecting pepper in Israel which was transmitted by whiteflies (MEAM1) and not aphids. This study reports the inability of the Mediterranean species (MED, Q biotype) ofB. tabacito transmit PeWBVYV. However we show that non-transmission of PeWBVYV by MED is not due to the lack of interaction with the GroEL protein of theHamiltonellasymbiont. Although not transmitted by MED, PeWBVYV was detected in its hemolymph, indicating its translocation across the MED midgut barrier. The aphid transmittedPepper vein yellows virus 2(PeVYV-2) was also detected in the hemolymph of MEAM1 whiteflies but PeWBVYV could not be detected in the aphid hemolymph. Interestingly, relative amounts of PeWBVYV in the hemolymph of the, MED was much lower than in hemolymph of MEAM1 whiteflies. We also identified a candidate receptor protein, complement component 1Q sub-complement binding protein (C1QBP) which interacts with the capsid proteins of PeWBVYV and PeVYV-2 but not with the whitefly transmittedTomato yellow leaf curl virusby a yeast two-hybrid approach using the minor capsid protein (RTD) as bait to screen for interacting proteins against the whitefly cDNA library. C1QBP, is a known receptor of bacterial and viral pathogens but this is the first report of its interaction with a plant virus.
Nucleotide-resolution bacterial pan-genomics with reference graphs
Authors: Colquhoun Rachel M , Hall Michael B , Lima Leandro , Roberts Leah W , Malone Kerri M , Hunt Martin , Letcher Brice , Hawkey Jane , George Sophie , Pankhurst Louise , Iqbal Zamin 
Published: November 2020

AbstractBackgroundBacterial genomes follow a U-shaped frequency distribution whereby most genomic loci are either rare (accessory) or common (core); the union of these is the pan-genome. The alignable fraction of two genomes from a single species can be low (e.g. 50-70%), such that no single reference genome can access all single nucleotide polymorphisms (SNPs). The pragmatic solution is to choose a close reference, and analyse SNPs only in the core genome. Given much bacterial adaptability hinges on the accessory genome, this is an unsatisfactory limitation.ResultsWe present a novel pan-genome graph structure and algorithms implemented in the softwarepandora, which approximates a sequenced genome as a recombinant of reference genomes, detects novel variation and then pan-genotypes multiple samples. The method takes fastq as input and outputs a multi-sample VCF with respect to an inferred data-dependent reference genome, and is available athttps://github.com/rmcolq/pandora.Constructing a reference graph from 578E. coligenomes, we analyse a diverse set of 20E. coliisolates. We showpandorarecovers at least 13k more rare SNPs than single-reference based tools, achieves equal or better error rates with Nanopore as with Illumina data, 6-24x lower Nanopore error rates than other tools, and provides a stable framework for analysing diverse samples without reference bias. We also show that our inferred recombinant VCF reference genome is significantly better than simply picking the closest RefSeq reference.ConclusionsThis is a step towards comprehensive cohort analysis of bacterial pan-genomic variation, with potential impacts on genotype/phenotype and epidemiological studies.