bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers
Authors: Barton Amber , Hill Jennifer , Bibi Sagida , Chen Liye , Jones Claire , Jones Elizabeth , Camara Susana , Shrestha Sonu , Jin Celina , Gibani Malick M , Dobinson Hazel , Waddington Claire , Darton Thomas C , Blohmke Christoph J , Pollard Andrew J 
Published: March 2021

AbstractBackgroundInfection withSalmonella entericaserovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility.MethodsHuman challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n=176) and/or transcriptionally profiled by RNA-sequencing (n=178).ResultsTwo SNPs withinCAPN14andMIATNBwere identified with p<10−5for association with development of symptoms or bacteraemia following oralS. Typhi orS. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with non-typhoidalSalmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (p=0.012). Genes related to the unfolded protein response and heat shock were over-represented in HLA-B*27:05+participants following challenge (p=0.01). Furthermore, intracellular replication ofS. Typhi is higher in C1R cells transfected with HLA-B*27:05 (p=0.02).ConclusionThese data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive toS. Typhi replication, increasing susceptibility to enteric fever.
Pronounced Genetic Separation Among Varieties of thePrimula cusickianaSpecies Complex, a Great Basin Endemic
Authors: Koontz Austin , Pearse William D. , Wolf Paul 
Published: March 2021

AbstractDistinguishing between unique species and populations with strong genetic structure is a common challenge in population genetics, especially in fragmented habitats where allopatric speciation may be widespread and distinct groups may be morphologically similar. Such is often the case with species complexes across sky island environments. In these scenarios, biogeography may help to explain the relations between species complex members, and RADseq methods are commonly used to compare closely related species across thousands of genetic loci. Here we use RADseq to clarify the relations between geographically distinct but morphologically similar varieties of thePrimula cusickianaspecies complex, and to contextualize past findings of strong genetic structure among populations within varieties. Our genomic analyses demonstrate pronounced separation between isolated populations of this Great Basin endemic, indicating that the current varietal classification of complex members is inaccurate and emphasizing their conservation importance. We discuss how these results correspond to recent biogeographical models used to describe the distribution of other sky island taxa in western North America. Our findings also fit into a wider trend observed for alpinePrimulaspecies complexes, and we consider how heterostylous breeding systems may be contributing to frequent diversification via allopatric speciation in this genus.
Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP
Authors: Soh Ming S. , Bagnall Richard D. , Bennett Mark F. , Bleakley Lauren E. , Syazwan Erlina S. Mohamed , Phillips A. Marie , Chiam Mathew D.F. , McKenzie Chaseley E. , Hildebrand Michael , Crompton Douglas , Bahlo Melanie , Semsarian Christopher , Scheffer Ingrid E. , Berkovic Samuel F. , Reid Christopher A. 
Published: March 2021

AbstractObjectiveTo compare the frequency and impact on channel function ofKCNH2variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-functionKCNH2variants as predictive biomarkers of SUDEP risk.MethodsWe searched forKCNH2variants with a minor allele frequency of < 5%. Functional analysis inXenopus laevisoocytes was performed for allKCNH2variants identified.ResultsKCNH2variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p= 0.11). Loss-of-functionKCNH2variants, defined as causing > 20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominalp= 0.04).KCNH2variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p> 0.99). RareKCNH2variants (< 1% allele frequency) associated with greater loss of function and an ∼11-fold enrichment in the SUDEP cohort (nominalp= 0.03).In silicotools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis.ConclusionsThese data show that loss-of-functionKCNH2variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-functionKCNH2variants that could act as biomarkers of an individual’s SUDEP risk.
Insecticide resistance characteristic ofAnophelesvector species successfully controlled by deployment of pyrethroid and PBO long lasting insecticidal treated nets in Tanzania
Authors: Matowo Johnson , Weetman David , Pignatell Patricia , Wright Alexandra , Charlwood Jacques D , Kaaya Robert , Shirima Boniface , Moshi Oliva , Lukole Eliud , Mosha Jacklin , Manjurano Alphaxard , Mosha Franklin , Rowland Mark , Protopopoff Natacha 
Published: March 2021

AbstractLong lasting insecticidal nets (LLINs) are a proven tool to reduce malaria transmission, but in Africa efficacy is being reduced by pyrethroid resistance in the major vectors. A cluster randomized trial in Muleba district, Tanzania demonstrated that permethrin LLINs co-treated with piperonyl butoxide (PBO), a synergist that can block pyrethroid-metabolizing enzymes in the mosquito, had much greater efficacy than pyrethroid-only nets. Insecticide resistance profiles and underlying mechanisms were investigated inAnopheles gambiaeandAn. funestusfrom Muleba during the trial. Diagnostic dose bioassays using permethrin, together with intensity assays, suggest pyrethroid resistance that is both strong and very common, but not extreme. Transcriptomic analysis found multiple P450 genes over expressed including CYP6M2, CYP6Z3, CYP6P3, CYP6P4, CYP6AA1 and CYP9K1 inAn. gambiaeand CYP6N1, CYP6M7, CYP6M1 and CYP6Z3 inAn. funestus. Indeed, very similar suites of P450 enzymes commonly associated with resistant populations elsewhere in Africa were detected as over expressed suggesting a convergence of mechanisms across Sub-Saharan African malaria vectors. The findings give insight into factors that may correlate with pyrethroid PBO LLIN success, broadly supporting model predictions, but revision to guidelines previously issued by the World Health Organization is warranted.
scDALI: Modelling allelic heterogeneity of DNA accessibility in single-cells reveals context-specific genetic regulation
Authors: Heinen T. , Secchia S. , Reddington J. , Zhao B. , Furlong E.E.M. , Stegle O. 
Published: March 2021

AbstractWhile the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies, using bulk sequencing, ignore much of this heterogeneity, reducing discovery and explanatory power. Single-cell approaches combined with F1 genetic designs provide a new opportunity to address this problem, however suitable computational methods to model these complex relationships are lacking.Here, we developed scDALI, an analysis framework that integrates single-cell chromatin accessibility for unbiased cell state identification with allelic quantifications to assay genetic effects. scDALI builds on Gaussian process regression and can differentiate between homogeneous (pervasive) allelic imbalances and cell state-specific regulation. As a proof-of-principle, we applied scDALI to wholeDrosophilaembryos from F1 crosses, profiling sciATAC-seq at three embryonic stages. Even in these very complex samples, scDALI discovered hundreds of peaks with heterogeneous allelic imbalance, having effects in specific lineages and/or developmental stages. Our study provides a general strategy to identify the cellular context of allelic imbalance, a crucial step in linking genetic traits to cellular phenotypes.
Abi3 regulates microglial ramification and dynamic tissue surveillancein vivo
Authors: Simonazzi Elena , Jones Ruth E. , Chen Fangli , Ranson Adam , Stevenson-Hoare Joshua , Escott-Price Valentina , Sengpiel Frank , Morgan B. Paul , Taylor Philip R. 
Published: March 2021

AbstractA rare coding variant of Abelson-interactor gene family member 3 (Abi3) is associated with increased risk of late-onset Alzheimer’s Disease (AD). Although Abi3 is recognised as a core microglial gene, its role in microglia is largely unknown. Here we demonstrate that Abi3 is crucial for normal microglial morphology, distribution, and homeostatic tissue surveillance activityin vivo.
Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients
Authors: Schweizer Tiziano A. , Shambat Srikanth Mairpady , Vulin Clément , Hoeller Sylvia , Acevedo Claudio , Huemer Markus , Gomez-Mejia Alejandro , Chang Chun-Chi , Baum Jeruscha , Hertegonne Sanne , Hitz Eva , Hofmaenner Daniel A. , Buehler Philipp K. , Moch Holger , Schuepbach Reto A. , Brugger Silvio D. , Zinkernagel Annelies S. 
Published: March 2021

AbstractCritically ill COVID-19 patients are characterized by a severely dysregulated cytokine profile and elevated neutrophil counts, which are thought to contribute to disease severity. However, to date it remains unclear how neutrophils contribute to pathophysiology during COVID-19. Here, we assessed the impact of the dysregulated cytokine profile on the tightly regulated cell death program of neutrophils. We show that in a subpopulation of neutrophils, canonical apoptosis was skewed towards rapidly occurring necroptosis. This phenotype was characterized by abrogated caspase-8 activity and increased RIPK1 levels, favoring execution of necroptosis via the RIPK1-RIPK3-MLKL axis, as further confirmed in COVID-19 biopsies. Moreover, reduction of sFas-L levels in COVID-19 patients and hence decreased signaling to Fas directly increased RIPK1 levels and correlated with disease severity. Our results suggest an important role for Fas signaling in the regulation of cell death program ambiguity via the ripoptosome in neutrophils during COVID-19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome.
Anti-fibrotic activity of an antimicrobial peptide in aDrosophilamodel
Authors: Khalili Dilan , Kalcher Christina , Baumgartner Stefan , Theopold Ulrich 
Published: March 2021

AbstractFibrotic lesions accompany several pathological conditions including tumors. We show that expression of a dominant-active form of the Ras oncogene inDrosophilasalivary glands (SGs) leads to redistribution of components of the basement membrane (BM) and fibrotic lesions. Similar to several types of mammalian fibrosis, the disturbed BM attracts clot components including insect transglutaminase and phenoloxidase. SG epithelial cells show reduced apico-basal polarity accompanied by a loss of secretory activity. Both the fibrotic lesions and the reduced cell polarity are alleviated by ectopic expression of the antimicrobial peptide Drosomycin (Drs), which also restores secretory activity of the SGs. In addition to ECM components, both Drs and F-actin localize to fibrotic lesions.
Long-Term Imaging of Living Adult Zebrafish
Authors: Castranova Daniel , Samasa Bakary , Galanternik Marina Venero , Gore Aniket V. , Weinstein Brant M. 
Published: March 2021

ABSTRACTThe zebrafish has become a widely used animal model due in large part to its accessibility to and usefulness for high-resolution optical imaging. Although zebrafish research has historically focused mostly on early development, in recent years the fish has increasingly been used to study regeneration, cancer metastasis, behavior, and other processes taking place in juvenile and adult animals. However, imaging of live adult zebrafish is extremely challenging, with survival of adult fish limited to a few tens of minutes using standard imaging methods developed for zebrafish embryos and larvae. Here, we describe a new method for imaging intubated adult zebrafish using a specially designed 3D printed chamber for long-term imaging of adult zebrafish on inverted microscope systems. We demonstrate the utility of this new system by nearly day-long observation of neutrophil recruitment to a wound area in living double-transgenic adult casper zebrafish with fluorescently labeled neutrophils and lymphatic vessels.
Influence of the TorD signal peptide chaperone on Tat-dependent protein translocation
Authors: Bageshwar Umesh K. , DattaGupta Antara , Musser Siegfried M. 
Published: March 2021

ABSTRACTThe twin-arginine translocation (Tat) pathway transports folded proteins across energetic membranes. Numerous Tat substrates contain co-factors that are inserted before transport with the assistance of redox enzyme maturation proteins (REMPs), which bind to the signal peptide of precursor proteins. How signal peptides are transferred from a REMP to a binding site on the Tat receptor complex remains unknown. Since the signal peptide mediates both interactions, possibilities include: i) a coordinated hand-off mechanism; or ii) a diffusional search after REMP dissociation. We investigated the binding interaction between substrates containing the TorA signal peptide (spTorA) and its cognate REMP, TorD, and the effect of TorD on thein vitrotransport of such substrates. We found thatEscherichia coliTorD is predominantly a monomer at low micromolar concentrations (dimerizationKD> 50 µM), and this monomer binds reversibly to spTorA (KD≈ 1 µM). While TorD binds to membranes (KD≈ 100 nM), it has no apparent affinity for Tat translocons and it inhibits binding of a precursor substrate to the membrane. TorD has a minimal effect on substrate transport by the Tat system, being mildly inhibitory at high concentrations. These data are consistent with a model in which the REMP-bound signal peptide is shielded from recognition by the Tat translocon, and spontaneous dissociation of the REMP allows the substrate to engage the Tat machinery. Thus, the REMP does not assist with targeting to the Tat translocon, but rather temporarily shields the signal peptide.
Reduced neutralization of SARS-CoV-2 variants by convalescent plasma and hyperimmune intravenous immunoglobulins for treatment of COVID-19
Authors: Tang Juanjie , Lee Youri , Ravichandran Supriya , Grubbs Gabrielle , Huang Chang , Stauft Charles , Wang Tony , Golding Basil , Golding Hana , Khurana Surender 
Published: March 2021

ABSTRACTHyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to different levels by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 (≤2-fold). Again, the CP showed more pronounced loss of cross-neutralization against the VOCs compared with hCoV-2IG. Significant reduction of hCoV-2IG binding was observed to the RBD-E484K followed by RBD-N501Y and minimal loss of binding to RBD-K417N compared with unmutated RBD. This study suggests that post-exposure treatment with hCoV-2IG is preferable to CP. In countries with co-circulating SARS-CoV-2 variants, identifying the infecting virus strain could inform optimal treatments, but would likely require administration of higher volumes or repeated infusions of hCOV-2IG or CP, in patients infected with the emerging SARS-CoV-2 variants.
Revealing the transcription factor regulatory context of human specific cortical development using single-cell multi-omics
Authors: Wu Yan , Lake Blue , Sos Brandon , Chen Song , Duong Thu E. , Yung Yun C. , Dong Weixiu , Limaye Siddarth , Chun Jerold , Zhang Kun 
Published: March 2021

AbstractHuman behaviors are at least partially driven by genomic regions that influence human-specific neurodevelopment. This includes genomic regions undergoing human specific sequence acceleration (Human Accelerated Regions or HARs) and regions showing human-specific enhancer activity (Human Gained Enhancers or HGEs) not present in other primates. However, prior studies on HAR/HGE activities involved mixtures of brain cell types and focused only on putative downstream target genes. Here, we directly measured cell type specific HAR/HGE activity in the developing fetal human brain using two independent single-cell chromatin accessibility datasets with matching single-cell gene expression data. Transcription factor (TF) motif analyses identified upstream TFs binding to HARs/HGEs and identified LHX2, a key regulator of forebrain development, as an active HGE regulator in neuronal progenitors. We integrated our TF motif analyses with published chromatin interaction maps to build detailed regulatory networks where TFs are linked to downstream genes via HARs/HGEs. Through these networks, we identified a potential regulatory role for NFIC in human neuronal progenitor networks via modulating the Notch signaling and cell adhesion pathways. Therefore, by using a single cell multi-omics approach, we were able to capture both the upstream and downstream regulatory context of HARs/HGEs, which may provide a more comprehensive picture of the roles HARs/HGEs play amongst diverse fetal cell types of the developing human brain.
Viscoelasticity and cell jamming state transition
Authors: Pajic-Lijakovic Ivana , Milivojevic Milan 
Published: March 2021

AbstractAlthough collective cell migration (CCM) is a highly coordinated migratory mode, perturbations in the form of jamming state transitions and vice versa often occur even in 2D. These perturbations are involved in various biological processes, such as embryogenesis, wound healing and cancer invasion. CCM induces accumulation of cell residual stress which has a feedback impact to cell packing density. Density-mediated change of cell mobility influences the state of viscoelasticity of multicellular systems and on that base the jamming state transition. Although a good comprehension of how cells collectively migrate by following molecular rules has been generated, the impact of cellular rearrangements on cell viscoelasticity remains less understood. Thus, considering the density driven evolution of viscoelasticity caused by reduction of cell mobility could result in a powerful tool in order to address the contribution of cell jamming state transition in CCM and help to understand this important but still controversial topic. In addition, five viscoelastic states gained within three regimes: (1) convective regime, (2) conductive regime, and (3) damped-conductive regime was discussed based on the modeling consideration with special emphasis of jamming and unjamming states.
Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1
Authors: Gough Rosemarie E. , Jones Matthew C. , Zacharchenko Thomas , Le Shimin , Yu Miao , Jacquemet Guillaume , Muench Ste P. , Yan Jie , Humphries Jonathan D. , Jørgensen Claus , Humphries Martin J. , Goult Benjamin T. 
Published: March 2021

AbstractTalin is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behaviour of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronised phosphorylation of a large number of protein targets. CDK1 activity also maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesiveness that are required for successful completion of mitosis. Using a combination of biochemical, structural and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8 through the use of recombinant fragments. Talin also contains a consensus CDK1 phosphorylation motif centred on S1589; a site that was phosphorylated by CDK1in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of KANK and weakened the mechanical response of the region, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, therefore provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division in multicellular organisms.SummaryThe direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division.