bluuebunny/crossref_metadata_2025_split huggingface dataset:
High expression of CD38 and MHC class II on CD8+T cells during severe influenza disease reflects bystander activation and trogocytosis
Authors: Jia Xiaoxiao , Chua Brendon Y , Loh Liyen , Koutsakos Marios , Kedzierski Lukasz , Olshanski Moshe , Heath William R , Xu Jianqing , Wang Zhongfang , Kedzierska Katherine 
Published: February 2021

AbstractAlthough co-expression of CD38 and HLA-DR on CD8+T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38+HLA-DR+expression can be associated with severe and fatal disease outcomes. As the expression of CD38+HLA-DR+is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38+MHC-II+phenotype on CD8+T-cells. Our analysis of influenza-specific immunodominant DbNP366+CD8+T-cell responses showed that CD38+MHC-II+co-expression was detected on both virus-specific and bystander CD8+T-cells, with increased numbers of both CD38+MHC-II+CD8+T-cell populations observed in the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8+T-cells recognising the ovalbumin-derived KbSIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II−/−mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38+MHC II+OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38+MHC II+on CD8+T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+CD8+T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+phenotype for CD8+T-cell memory establishment and recall.SummaryCo-expression of CD38 and MHC-II on CD8+T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38+HLA-DR+expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38+MHC-II+CD8+T cell responsesin vivoand the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+CD8+T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+phenotype for CD8+T-cell memory establishment and recall.
Elucidating the patterns of seed-to-seedling transmission ofXanthomonas citripv.malvacearum, the causal agent of cotton bacterial blight
Authors: Mijatović Jovana , Severns Paul M. , Kemerait Robert C. , Walcott Ron R. , Kvitko Brian H. 
Published: February 2021

ABSTRACTCotton bacterial blight (CBB) was a major disease of cotton in the United States in the early part of the 20thcentury. The recent reemergence of CBB, caused byXanthomonas citripv.malvacearum(Xcm) revealed many gaps in our understanding of this important disease. In this study, we employed a field isolate ofXcmfrom Georgia USA (WT) to generate a non- pathogenic,hrcVmutant lacking a functional Type III Secretion System (T3SS-). We tagged the WT and T3SS- strains with an auto-bioluminescent Tn7reporter and compared colonization patterns of susceptible and resistant cotton seedlings using macroscopic image analysis and bacterial load enumeration. Wildtype and T3SS-Xcmstrains colonized cotton cotyledons of resistant and susceptible cotton cultivars. However,Xcmpopulations were significantly higher in susceptible seedlings inoculated with the WT strain. Additionally, WT and T3SS-Xcmstrains systemically colonized true leaves, although at different rates. Finally, we observed that seed-to-seedling transmission ofXcmmay involve systemic spread through the vascular tissue of cotton plants. These findings yield novel insights into potentialXcmreservoirs for CBB outbreaks.
Dual RNA-Seq analysis of SARS-CoV-2 correlates specific human transcriptional response pathways directly to viral expression
Authors: Maulding Nathan D , Seiler Spencer , Pearson Alex , Kreusser Nick , Stuart Josh 
Published: February 2021

AbstractThe SARS-CoV-2 pandemic has challenged humankind’s ability to quickly determine the cascade of health effects caused by a novel infection. Even with the unprecedented speed at which vaccines were developed and introduced into society, identifying therapeutic interventions and drug targets for patients infected with the virus remains important as new strains of the virus may evolve, or future coronaviruses may emerge, that are resistant to current vaccines. The application of transcriptomic RNA sequencing of infected samples may shed new light on the pathways involved in viral mechanisms and host responses. We describe the application of “dual RNA-seq” analysis to consider both the host and pathogen transcriptomes simultaneously, to investigate for the first time theco-regulation of human and SARS-CoV-2 genes. Together with differential expression analysis, we describe the tissue specificity of SARS-CoV-2 expression, an inferred lipopolysaccharide response, and co-regulation ofCXCL’s, SPRR’s, S100’swith SARS-CoV-2 expression. Lipopolysaccharide response pathways in particular offer promise for future therapeutic research and the prospect of subgrouping patients based on chemokine expression that may help explain the vastly different reactions patients have to infection. Taken together these findings illuminate previously unappreciated SARS-CoV-2 expression signatures, identify new therapeutic considerations, and contribute a pipeline for studying multi-transcriptome systems.
Testing for parallel genomic and epigenomic footprints of adaptation to urban life in a passerine bird
Authors: Caizergues Aude E. , Luyer Jeremy Le , Grégoire Arnaud , Szulkin Marta , Senar Juan-Carlos , Charmantier Anne , Perrier Charles 
Published: February 2021

AbstractIdentifying the molecular mechanisms involved in rapid adaptation to novel environments and determining their predictability are central questions in Evolutionary Biology and pressing issues due to rapid global changes. Complementary to genetic responses to selection, faster epigenetic variations such as modifications of DNA methylation may play a substantial role in rapid adaptation. In the context of rampant urbanization, joint examinations of genomic and epigenomic mechanisms are still lacking. Here, we investigated genomic (SNP) and epigenomic (CpG methylation) responses to urban life in a passerine bird, the Great tit (Parus major). To test whether urban evolution is predictable (i.eparallel) or involves mostly non-parallel molecular processes among cities, we analysed three distinct pairs of city and forest Great tit populations across Europe. Results reveal a polygenic response to urban life, with both many genes putatively under weak divergent selection and multiple differentially methylated regions (DMRs) between forest and city great tits. DMRs mainly overlapped transcription start sites and promotor regions, suggesting their importance in the modulation gene expression. Both genomic and epigenomic outliers were found in genomic regions enriched for genes with biological functions related to nervous system, immunity, behaviour, hormonal and stress responses. Interestingly, comparisons across the three pairs of city-forest populations suggested little parallelism in both genetic and epigenetic responses. Our results confirm, at both the genetic and epigenetic levels, hypotheses of polygenic and largely non-parallel mechanisms of rapid adaptation in new environments such as urbanized areas.
The lncRNAEPB41L4A-AS1regulates gene expression in the nucleus and exerts cell type-dependent effects on cell cycle progression
Authors: Samdal Helle , Hegre Siv Anita , Chawla Konika , Liabakk Nina-Beate , Aas Per Arne , Sporsheim Bjørnar , Sætrom Pål 
Published: February 2021

AbstractThe long non-coding RNA (lncRNA)EPB41L4A-AS1is aberrantly expressed in various cancers and has been reported to be involved in metabolic reprogramming and as a repressor of the Warburg effect. Although the biological relevance ofEPB41L4A-AS1is evident, its functional role seems to vary depending on cell type and state of disease. By combining RNA sequencing and ChIP sequencing of cell cycle synchronized HaCaT cells we previously identifiedEPB41L4A-AS1to be one of 59 lncRNAs with potential cell cycle functions. Here, we demonstrate thatEPB41L4A-AS1exists as bright foci and regulates gene expression in the nucleus in bothcisandtrans. Specifically, we find thatEPB41L4A-AS1positively regulates its sense overlapping geneEPB41L4Aand influences expression of hundreds of other genes, including genes involved in cell proliferation. Finally, we show thatEPB41L4A-AS1affects cell cycle phase distribution, though these effects vary between cell types.
Sustained Interleukin-1β overexpression exacerbates Tau pathology in a murine tauopathy model via cyclooxygenase-1
Authors: Ghosh Simantini , Shaftel Solomon S. , Kyrkanides Stephanos , Olschowka John A. , O’Banion M. Kerry 
Published: February 2021

AbstractPathologic accumulation of abnormally phosphorylated tau in neurofibrillary tangles is a hallmark feature of Alzheimer’s disease and other tauopathies. Interleukin-1β ◻◻◻ −1β◻ is a major proinflammatory cytokine in the central nervous system that has been implicated in the pathogenesis of tauopathies as well as Alzheimer’s disease. To explore the role of chronic IL-1β overexpression in tauopathiesin vivowe used an inducible model of IL-1β overexpression developed in our laboratory. The IL-1β (IL-1) mice bear a transcriptional stop flanked by LoxP elements upstream of a human IL-1β gene. Upon delivery of Cre, the IL-1 transgene is locally activated by excision of the stop sequence. The IL-1 mice were bred to JNPL3 (Tau) mice, which overexpress human tau with the P301L mutation. Expression of IL-1β was induced in the dentate gyrus of 8 to 8.5 month old progeny by stereotaxic injection of FIV-Cre. One and three months later, Tau/IL-1 mice demonstrated 2-4 fold increases in phospho-tau and glial activation. To attenuate IL-1β mediated inflammation, we reduced PGE2production via pharmacological inhibition of cyclooxygenase-1 (COX-1) with SC560 in Tau/IL-1 mice, and observed significant reductions in phospho-tau pathology and microglial activation. Further, we found upregulation in active forms of p38MAPK, which was significantly reduced in mice receiving SC560 treatment. Our results demonstrate that IL-1β has a direct exacerbating effect on tau pathologyin vivo, and inhibiting COX-1 can reverse this. COX-1 inhibition can therefore serve as a valuable therapeutic strategy for tauopathies with an advanced inflammatory component.
Pathfinder: A gamified measure to integrate general cognitive ability into the biological, medical, and behavioural sciences
Authors: Malanchini Margherita , Rimfeld Kaili , Gidziela Agnieszka , Cheesman Rosa , Allegrini Andrea G. , Shakeshaft Nicholas , Schofield Kerry , Packer Amy , Ogden Rachel , McMillan Andrew , Ritchie Stuart J. , Dale Philip S. , Eley Thalia C. , Stumm Sophie von , Plomin Robert 
Published: February 2021

AbstractGenome-wide association (GWA) studies have uncovered DNA variants associated with individual differences in general cognitive ability (g), but these are far from capturing heritability estimates obtained from twin studies. A major barrier to finding more of this ‘missing heritability’ is assessment – the use of diverse measures across GWA studies as well as time and cost of assessment. In a series of four studies, we created a 15-minute (40-item), online, gamified measure ofgthat is highly reliable (alpha = .78; two-week test-retest reliability = .88), psychometrically valid and scalable; we called this new measure Pathfinder. In a fifth study, we administered this measure to 4,751 young adults from the Twins Early Development Study. This novelgmeasure, which also yields reliable verbal and nonverbal scores, correlated substantially with standard measures of g collected at previous ages (r ranging from .42 at age 7 to .57 at age 16). Pathfinder showed substantial twin heritability (.57, 95% CIs = .43, .68) and SNP heritability (.37, 95% CIs = .04, .70). A polygenic score computed from GWA studies of five cognitive and educational traits accounted for 12% of the variation ing, the strongest DNA-based prediction ofgto date. Widespread use of this engaging new measure will advance research not only in genomics but throughout the biological, medical, and behavioural sciences.
Establishment of a reverse genetic system from a bovine derived Influenza D virus isolate
Authors: Holwerda Melle , Laloli Laura , Wider Manon , Schönecker Lutz , Becker Jens , Meylan Mireille , Dijkman Ronald 
Published: February 2021

AbstractThe ruminant-associated Influenza D virus (IDV) has a broad host tropism and was shown to have zoonotic potential. To identify and characterize molecular viral determinants influencing the host spectrum of IDV, a reverse genetic system is required. For this, we first performed 5′ and 3′ rapid amplification of cDNA ends (RACE) of all seven genomic segments, followed by assessment of the 5′ and 3′ NCR activity prior to constructing the viral genomic segments of a contemporary Swiss bovine IDV isolate (D/CN286) into the bidirectional pHW-2000 vector. The bidirectional plasmids were transfected in HRT-18G cells followed by viral rescue on the same cell type. Analysis of the segment specific 5′ and 3′ non-coding regions (NCR) highlighted that the terminal 3′ end of all segments harbours an Uracil instead of a Cytosine nucleotide, similar to other Influenza viruses. Subsequent analysis on the functionality of the 5′ and 3′ NCR in a minireplicon assay revealed that these sequences were functional and that the variable sequence length of the 5′ and 3′ NCR influences reporter gene expression. Thereafter, we evaluated the replication efficiency of the reverse genetic clone on conventional cell lines of human, swine and bovine origin by use of an in vitro model recapitulating the natural replicate site of IDV in bovine and swine. This revealed that the reverse genetic clone D/CN286 replicates efficiently in all cell culture models. Combined, these results demonstrate the successful establishment of a reverse genetic system from a contemporary bovine IDV isolate that can be used for future identification and characterization of viral determinants influencing the broad host tropism of IDV.
Cardiopharyngeal deconstruction and ancestral tunicate sessility
Authors: Ferrández-Roldán A. , Fabregà-Torrus M. , Sánchez-Serna G. , Durán-Bello E. , Joaquín-Lluís M. , Garcia-Fernàndez J. , Albalat R. , Cañestro C. 
Published: February 2021

AbstractA key problem in understanding chordate evolution has been the origin of sessility of ascidians, and whether the appendicularian free-living style represents a primitive or derived condition of tunicates. To address this problem, we performed comprehensive developmental and genomic comparative analyses of the cardiopharyngeal gene regulatory network (GRN) between appendicularians and ascidians. Our results reveal that the cardiopharyngeal GRN has suffered a process of evolutionary deconstruction with massive ancestral losses of genes (Mesp,Ets1/2,Gata4/5/6,Mek1/2,Tbx1/10, and RA- and FGF-signaling related genes) and subfunctions (e.g.FoxF,Islet,Ebf,Mrf,Dachand Bmp signaling). These losses have led to the deconstruction of two modules of the cardiopharyngeal GRN that in ascidians are related to early and late multipotent state cells involved in lineage fate determination towards first and secondary heart fields, and siphon muscle. Our results allow us to propose an evolutionary scenario, in which the evolutionary deconstruction of the cardiopharyngeal GRN has had an adaptive impact on the acceleration of the developmental cardiac program, the redesign of the cardiac architecture into an open-wide laminar structure, and the loss of pharyngeal muscle. Our findings, therefore, provide evidence supporting that the ancestral tunicate had a sessile ascidian-like lifestyle, and points to the deconstruction of the cardiopharyngeal GRN in appendicularians as a key event that facilitated the evolution of their pelagic free-living style connected to the innovation of the house.
High-Intensity Interval Training Remodels the Proteome and Acetylome of Human Skeletal Muscle
Authors: Hostrup M , Lemminger AK , Stocks B , Gonzalez-Franquesa A , Larsen JK , Quesada J Prats , Thomassen M , Weinert BT , Bangsbo J , Deshmukh AS 
Published: February 2021

AbstractExercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health.Impact statementHostrup and colleagues identify global proteomic and acetylomic adaptations to high-intensity interval training, demonstrating adaptations to processes regulating metabolism and contraction.
Cas9 targeted enrichment of mobile elements using nanopore sequencing
Authors: McDonald Torrin L. , Zhou Weichen , Castro Christopher , Mumm Camille , Switzenberg Jessica A. , Mills Ryan E. , Boyle Alan P. 
Published: February 2021

AbstractMobile element insertions (MEIs) are highly repetitive genomic sequences that contribute to inter- and intra-individual genetic variation and can lead to genetic disorders. Targeted and whole-genome approaches using short-read sequencing have been developed to identify reference and non-reference MEIs; however, the read length hampers detection of these elements in complex genomic regions. Here, we pair Cas9 targeted nanopore sequencing with computational methodologies to capture active MEIs in human genomes. We demonstrate parallel enrichment for distinct classes of MEIs, averaging 44% of reads on targeted signals. We show an individual flow cell can recover a remarkable fraction of MEIs (97% L1Hs, 93%AluYb, 51%AluYa, 99% SVA_F, and 65% SVA_E). We identify twenty-one non-reference MEIs in GM12878 overlooked by modern, long-read analysis pipelines, primarily in repetitive genomic regions. This work introduces the utility of nanopore sequencing for MEI enrichment and lays the foundation for rapid discovery of elusive, repetitive genetic elements.
CardiacNmnat/NAD+/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in agingDrosophila
Authors: Wen Deng-tai , Zheng Lan , Lu Kai , Hou Wen-qi 
Published: February 2021

AbstractEndurance exercise is an important way to resist and treat a high-fat-diet(HFD)-induced heart defects, but the underlying molecular mechanisms are poorly understood. Here, we usedDrosophilato identify whether cardiac Nmnat/NAD+/SIR2 pathways activation could mediate endurance exercise resistance to heart defects. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXOpathway and Nmnat/NAD+/SIR2/PGC-1αpathway, including up-regulating cardiacNmnat, SIR2, FOXO, PGC-1αexpression, SOD activity, and NAD+level, and it prevented HFD-induced or cardiacNmnatknock-down-induced cardiac lipid accumulation, MDA content and fibrillation increase, and fractional shortening decrease. CardiacNmnatoverexpression activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiacNmnatknockdown flies. Therefore, current results confirmed that cardiac Nmnat/NAD+/SIR2 pathways were important antagonists of HFD-induced heart defects. The cardiacNmnat/NAD+/SIR2pathways activation was the important underlying molecular mechanism of endurance exercise and cardiac Nmnat overexpression against heart defects inDrosophila.
Social capital and individual entrepreneurial orientation: innovativeness, proactivity, and risk-taking in an emerging economy
Authors: Corrêa Victor Silva , Queiroz Maciel M. , Shigaki Helena Belintani 
Published: February 2021

PurposeThis paper investigates if and how entrepreneurs' social capital influences their individual entrepreneurial orientation attributes (innovativeness, proactiveness, and risk-taking).Design/methodology/approachThe research method adopted is an exploratory multiple case study. The case chosen is that of an emerging and under-examined entrepreneur, the religious entrepreneur. The study investigates 20 pastors responsible for small enterprise-churches in Brazil.FindingsSocial capital influences individual entrepreneurial orientation, being characterized by a relative paradox. The networks must be dense enough to stimulate entrepreneurs' individual entrepreneurial orientation but not be so dense as to harm innovativeness, proactivity and risk-taking. Further, data show that individual entrepreneurial orientation influences social capital.Research limitations/implicationsOne limitation relates to the semi-structured interviews' restricted use. A second limitation is associated with the recognition of churches only as productive enterprises.Practical implicationsThis article suggests the significance of incorporating both themes in entrepreneurial education and training programs. It also stresses the appropriateness of religious entrepreneurship as an empirical research field for business scholars.Originality/valueThe contributions are fivefold. First, the authors build exploratory theoretical propositions on the influence of social capital on individual entrepreneurial orientation. Second, they highlight the significance of dense networks for individual entrepreneurial orientation, expanding the literature that supports the relevance of cohesive networks solely to the construct's organizational dimension. Third, the authors suggest that a relative paradox may characterize individual entrepreneurial orientation. Fourth, the authors suggest the existence of recursion between both constructs. Finally, this study is one of the first to examine social capital and individual entrepreneurial orientation, considering innovativeness, proactivity, and risk-taking, which represents a neglected field in benchmarking studies.