bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide meta-analysis of insomnia in over 2.3 million individuals implicates involvement of specific biological pathways through gene-prioritization
Authors: Watanabe Kyoko , Jansen Philip R. , Savage Jeanne E. , Nandakumar Priyanka , Wang Xin ,   23andMe Research Team, Hinds David A. , Gelernter Joel , Levey Daniel F. , Polimanti Renato , Stein Murray B. , Van Someren Eus J.W. , Smit August B. , Posthuma Danielle 
Published: December 2020

AbstractInsomnia is a heritable, highly prevalent sleep disorder, for which no sufficient treatment currently exists. Previous genome-wide association studies (GWASs) with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested many more loci to be discovered. The current study almost doubled the sample size to over 2.3 million individuals thereby increasing statistical power. We identified 554 risk loci (confirming 190 previously associated loci and detecting 364 novel), and capitalizing on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and information on functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289. For these, we find brain-tissue expression specificity and enrichment in specific gene-sets of synaptic signaling functions and neuronal differentiation. We show that the novel gene prioritization strategy yields specific hypotheses on causal mechanisms underlying insomnia, which would not fully have been detected using traditional approaches.
Single-cell RNA sequencing revealsin vivosignatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’
Authors: Fischer David S. , Ansari Meshal , Wagner Karolin I. , Jarosch Sebastian , Huang Yiqi , Mayr Christoph H. , Strunz Maximilian , Lang Niklas J. , D’Ippolito Elvira , Hammel Monika , Mateyka Laura , Weber Simone , Wolff Lisa S. , Witter Klaus , Fernandez Isis E. , Leuschner Gabriela , Milger Kathrin , Frankenberger Marion , Nowak Lorenz , Heinig-Menhard Katharina , Koch Ina , Stoleriu Mircea G. , Hilgendorff Anne , Behr Jürgen , Pichlmair Andreas , Schubert Benjamin , Theis Fabian J. , Busch Dirk H. , Schiller Herbert B. , Schober Kilian 
Published: December 2020

ABSTRACTThein vivophenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells requirein vitroantigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we used single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induced transcriptional shifts by antigenic stimulationin vitroand took advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allowed identification of SARS-CoV-2-reactive TCRs and revealed phenotypic effects introduced by antigen-specific stimulation. We characterized transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and showed correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.
Characterization and safety profile of Imuno TF®, a nutritional supplement for immune system regulation containing transfer factors
Authors: Polonini Hudson , de Souza Schmidt Gonçalves Any Elisa , Dijkers Eli , de Oliveira Ferreira Anderson 
Published: December 2020

AbstractImuno TF®is a nutritional supplement composed of isolated transfer factors (TF) from porcine spleen. It is composed of a specific mixture of molecules that impact functions of the biological systems, and historically is linked to the immune system regulation. In this study, we demonstrate for the first time its proteomic analysis, nutritional composition, and safety profile in terms of mutagenic potential and acute oral dose (LD50). The obtained analysis indicated the product is a complex set of oligo- and polypeptides constituted of 163 different peptides which can potentially act on multiple mechanisms on the immune system pathways. The chemical composition showed low fat and low sugar content, saturated fatty acids-free and the presence of 10 vitamins and 11 minerals. No mutagenic effect was observed, and the LD50was 5,000 mg kg-1body weight. This accounts for a safe product to be used by oral route, with potential benefits for the immune system.
Systematic comparison of incomplete-supervision approaches for biomedical imaging classification
Authors: Boushehri Sayedali Shetab , Qasim Ahmad Bin , Waibel Dominik , Schmich Fabian , Marr Carsten 
Published: December 2020

ABSTRACTDeep learning based classification of biomedical images requires manual annotation by experts, which is time-consuming and expensive. Incomplete-supervision approaches including active learning, pre-training and semi-supervised learning address this issue and aim to increase classification performance with a limited number of annotated images. Up to now, these approaches have been mostly benchmarked on natural image datasets, where image complexity and class balance typically differ considerably from biomedical classification tasks. In addition, it is not clear how to combine them to improve classification performance on biomedical image data.We thus performed an extensive grid search combining seven active learning algorithms, three pre-training methods and two training strategies as well as respective baselines (random sampling, random initialization, and supervised learning). For four biomedical datasets, we started training with 1% of labeled data and increased it by 5% iteratively, using 4-fold cross-validation in each cycle. We found that the contribution of pre-training and semi-supervised learning can reach up to 25% macro F1-score in each cycle. In contrast, the state-of-the-art active learning algorithms contribute less than 5% to macro F1-score in each cycle. Based on performance, implementation ease and computation requirements, we recommend the combination of BADGE active learning, ImageNet-weights pre-training, and pseudo-labeling as training strategy, which reached over 90% of fully supervised results with only 25% of annotated data for three out of four datasets.We believe that our study is an important step towards annotation and resource efficient model training for biomedical classification challenges.
Early induction of antibacterial activities distinguishes response of mice to infection with non-permissive from response to permissiveSalmonella
Authors: Yadav Jitender , Qadri Ayub 
Published: December 2020

AbstractSalmonella entericaserovar Typhi (S. Typhi), the causative agent of typhoid in humans, shares very high homology with closely related serovar,S. Typhimurium. Yet, unlikeS. Typhimurium,S. Typhi does not establish infection in mice, the reasons for which are not well understood. Here, we present evidence that unlikeS. Typhimurium,S. Typhi brings about induction of extracellular and intracellular antibacterial activities in mice. Cell-free peritoneal fluids fromS. Typhi but notS. Typhimurium-infected mice inhibited replication ofSalmonella ex vivo. The production of this activity was reduced in presence of serine protease inhibitor, phenylmethylsulfonlyl fluoride (PMSF). PMSF also inhibited generation of antibacterial activity released fromin vitro S. Typhi - infected peritoneal macrophages in a cell death – dependent manner. Intracellularly, infection withS. Typhiin vitroas well asin vivoresulted in increased mRNA levels of iron-regulating molecules, ferroportin and lipocalin. These results suggest that induction of antibacterial molecules early on in mice in response toS. Typhi may prevent establishment of infection with thisSalmonellaserovar.
Sequence determinants of the aggregation of proteins within condensates generated by liquid-liquid phase separation
Authors: Vendruscolo Michele , Fuxreiter Monika 
Published: December 2020

AbstractThe transition between the native and amyloid states of proteins can proceed via a deposition pathway via oligomeric intermediates or via a condensation pathway via liquid droplet intermediates generated through liquid-liquid phase separation. Here we investigate the sequence determinants of aggregation from within the droplet state based on generic interactions. We describe a model in which these sequence determinants can be captured by three features, the droplet-promoting propensity, the aggregation-promoting propensity and the binding mode entropy. By using this approach, we propose a formula to identify aggregation-promoting mutations in droplet-forming proteins. This analysis provides insights into the amino acid code for the conversion of proteins between liquid-like and solid-like condensates.
Different correlation patterns between EEG and memory after E/I balance adjustment in normal middle-aged mice and AD model mice
Authors: Zhou Zheng , Li Liane , Duan Mengsi , Sun Huaying , Yi Hu , Fu Yu 
Published: December 2020

AbstractAlzheimer’s disease (AD) is correlated with brain atrophy, neuronal loss, neurotransmitter imbalance, and cognitive decline, which also occur in normal aging. Thus, comparing the differences between normal aging and AD is of interest in order to test the accelerated aging hypothesis of AD. An imbalance between excitatory/inhibitory (E/I) neurotransmission, especially in gamma-aminobutyric acid (GABA) inhibition dysfunction, is involved in both AD and normal aging. In the present study, we performed correlation analyses between electroencephalograms (EEGs) and memory in middle-aged (∼12 months old) wild-type mice (WT) and AD model mice (APP/PS1) after E/I balance adjustment via GABAAagonist muscimol and antagonist bicuculline administration (0.1 mg/kg intraperitoneally). Specifically, EEGs of the hippocampus and prefrontal cortex were recorded during Y-maze performance. Overall, WT and AD mice showed different correlation patterns between EEG activity and behavioral memory performance. Significant correlations were observed in EEG activity across a wider range of frequency bands (2–100 Hz, except 4–8 Hz) in WT mice, but were mainly observed in low frequency bands (delta-theta, 2–8 Hz) in AD mice. In addition, muscimol and bicuculline treatment contributed to better brain function in AD mice; in contrast, bicuculline administration resulted in poorer brain function in WT mice. Thus, our study suggests that AD shows a distinct pattern of disrupted brain function, rather than accelerated aging. Importantly, this work reveals new insights into future AD treatment by influencing low-frequency EEG activity through E/I balance adjustment, thereby aiding cognitive recovery.
rt-me-fMRI: A task and resting state dataset for real-time, multi-echo fMRI methods development and validation
Authors: Heunis Stephan , Breeuwer Marcel , Caballero-Gaudes César , Hellrung Lydia , Huijbers Willem , Jansen Jacobus FA , Lamerichs Rolf , Zinger Svitlana , Aldenkamp Albert P 
Published: December 2020

AbstractA multi-echo fMRI dataset (N=28 healthy participants) with four task-based and two resting state runs was collected, curated and made available to the community. Its main purpose is to advance the development of methods for real-time multi-echo functional magnetic resonance imaging (rt-me-fMRI) analysis with applications in neurofeedback, real-time quality control, and adaptive paradigms, although the variety of experimental task paradigms supports a multitude of use cases. Tasks include finger tapping, emotional face and shape matching, imagined finger tapping and imagined emotion processing. This work provides a detailed description of the full dataset; methods to collect, prepare, standardize and preprocess it; quality control measures; and data validation measures. A web-based application is provided as a supplementary tool with which to interactively explore, visualize and understand the data and its derivative measures:https://rt-me-fmri.herokuapp.com/. The dataset itself can be accessed via a data use agreement on DataverseNL athttps://dataverse.nl/dataverse/rt-me-fmri. Supporting information and code for reproducibility can be accessed athttps://github.com/jsheunis/rt-me-fMRI.
Identification of potential coagulation pathway abnormalities in SARS-Cov-2 infection; insights from bioinformatics analysis
Authors: Arjmand Sareh , Hosseinkhan Nazanin 
Published: December 2020

AbstractAbnormal coagulation parameters have been explored in a significant number of severe COVID-19 patients, linked to poor prognosis and increased risk of organ failure. Here, to uncover the potential abnormalities in coagulation pathways, we analyzed the RNA-seq data (GEO147507) obtained from the treatment of three pulmonary epithelial cell lines with SARS-CoV-2. The significant differentially expressed genes (DEGs) were subjected to Enrichr database for KEGG pathway enrichment analysis and gene ontology (GO) functional annotation. The STRING database was used to generate PPI networks for identified DEGs. We found three upregulated procoagulant genes (SERPINE1, SERPINA5, and SERPINB2) belong to the serine protease inhibitor (serpin) superfamily that inhibit tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) in the fibrinolysis process. In conclusion, we suggest the fibrinolysis process, especially the blockage of t-PA and u-PA inhibitors, a potential target for more study in treating coagulopathy in severe COVID-19 cases.
Comparative profiling of N-respirasomes predicts aberrant mitochondrial bioenergetics at single-cell resolution
Authors: Bertan Fabio , Wischhof Lena , Scifo Enzo , Guranda Mihaela , Jackson Joshua , Marsal-Cots Anaïs , Piazzesi Antonia , Stork Miriam , Peitz Michael , Prehn Jochen H. M. , Ehninger Dan , Nicotera Pierluigi , Bano Daniele 
Published: December 2020

AbstractMitochondria sustain the energy demand of the cell. The composition and functional state of the mitochondrial oxidative phosphorylation system are informative indicators of organelle homeostasis and bioenergetic capacity. Here we describe a highly sensitive and reproducible method for single-cell visualization and quantification of mitochondrial respiratory supercomplexes as a novel means of measuring mitochondrial respiratory chain integrity. We apply a proximity ligation assay (PLA) and perform comparative studies of mitochondrial CI, CIII and CIV-containing supercomplexes (or N-respirasomes) in fixed human and mouse brain tissues, tumorigenic cells, iPSCs and iPSC-derived NPCs and neurons. Our optimized approach enables a quantitativein-situassessment of even subtle mitochondrial lesions associated with aberrant respiration. By combining quantitative proteomics with single cell imaging analysis, we also report the mechanistic contribution of the MICOS complex subunit CHCHD3 in regulating N-respirasomes. Overall, our PLA-based profiling of N-respirasomes establishes a sensitive and complementary technique for detecting cell-type specific mitochondrial perturbations in fixed materials.
Proteasomal degradation of human SERINC4: a potent host anti-HIV-1 factor that is antagonized by Nef
Authors: Qiu Xusheng , Eke Ifeanyichukwu E. , Johnson Silas F. , Ding Chan , Zheng Yong-Hui 
Published: December 2020

AbstractThe serine incorporator (SERINC) protein family has five paralogous members with 9-11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4 expression and antiviral mechanisms. Unlike its four paralogs, human SERINC4 is subjected to proteasome-mediated turnover, resulting in ~250-fold lower expression than SERINC5. However, when expression was normalized, human SERINC4 restricted HIV-1 replication as effectively as SERINC5, and SERINC4 was also antagonized by Nef via the lysosomal pathway. Although SERINC4 proteins are conserved within primates or rodents, their N-terminal regions are highly variable across species. Interestingly, unlike human SERINC4, murine SERINC4 was stably expressed but had a very poor antiviral activity. We created stable SERINC4 chimeras by replacing the N-terminal region and found that the 1-34 and 35-92 amino acids determine SERINC4 antiviral activity or protein expression, respectively. Using these chimeras, we demonstrate that SERINC4 is incorporated into HIV-1 virions and restricts Tier 1 HIV-1 more effectively than Tier 3 HIV-1. Importantly, SERINC4 increases HIV-1 sensitivity to broadly neutralizing antibodies. Thus, human SERINC4 strongly restricts HIV-1 replication when it is overexpressed, which reflects a potential antiviral activity of this gene product under physiological conditions.HighlightsIdentification of another potent anti-HIV-1 host factor SERINC4 from the SERINC familyIdentification of two N-terminal domains that regulate SERINC4 expression and antiviral activityUnderstanding the natural degradation of human SERINC4 by the proteasomal pathwayUnderstanding the important role of the lysosomal pathway in Nef antagonism of host restriction
GLI3 Processing by the Primary Cilium Regulates Muscle Stem Cell Entry into GAlert
Authors: Brun Caroline E. , Sincennes Marie-Claude , Lin Alexander Y.T. , Hall Derek , Jarassier William , Feige Peter , Ritso Morten , Le Grand Fabien , Rudnicki Michael A. 
Published: December 2020

ABSTRACTSatellite cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite cells possess a primary cilium, a structure that regulates the processing of the GLI family of transcription factors. Here we find that GLI3, specifically, plays a critical role in satellite cell activation. Primary cilia-mediated processing of GLI3 is required to maintain satellite cells in a G0dormant state. Strikingly, satellite cells lacking GLI3 enter GAlertin the absence of injury. Furthermore, GLI3 depletion or inhibition of its processing stimulates symmetrical division in satellite cells and expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced long-term regenerative capacity. Therefore, our results reveal an essential role for primary cilia processing of GLI3 in regulating muscle stem cell activation and fate.
Quantifying phase separation property of chromatin associated proteins under physiological conditions using anti-1,6-hexanediol index
Authors: Shi Minglei , You Kaiqiang , Chen Taoyu , Hou Chao , Liang Zhengyu , Liu Mingwei , Wang Jifeng , Wei Taotao , Qin Jun , Chen Yang , Zhang Michael Q. , Li Tingting 
Published: December 2020

AbstractBackgroundLiquid–liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent.ResultsHere, by combing chromatin associated protein pull-down, quantitative proteomics and 1,6-hexanediol treatment, we developed Hi-MS and defined anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantitative measurement of LLPS property of chromatin-associated proteins in their endogenous state and physiological abundance. The AICAP values were verified by previously reported experiments and were reproducible across different MS platforms. Moreover, the AICAP values were highly correlate with protein functions. Proteins act in active/regulatory biological process often exhibit low AICAP values, while proteins act in structural and repressed biological process often exhibit high AICAP values. We further revealed that chromatin organization changes more in compartment A than B, and the changes in chromatin organization at various levels, including compartments, TADs and loops are highly correlated to the LLPS properties of their neighbor nuclear condensates.ConclusionsOur work provided the first global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure, and demonstrate that the active/regulatory chromatin components, both protein (trans) and DNA (cis), exhibit more hydrophobicity-dependent LLPS properties than the repressed/structural chromatin components.
Evaluating optimal purchasing and selling decisions of beef cattle replacement females
Authors: Boyer Christopher N. , Griffith Andrew P. , DeLong Karen L. 
Published: December 2020

PurposeThe objective of this research was to determine the optimal age and pregnancy status for buying and selling replacement of beef females for risk-neutral and risk-averse producers.Design/methodology/approachA hedonic pricing model was estimated to measure how age, pregnancy status, breed and cull cow prices impact the sale price of these cattle. Data came from an annual heifer and cow sale in Tennessee between 2009 and 2018. A financial simulation model was developed to generate distributions of net present value (NPV) for buying replacement females at various ages and pregnancy status and then selling that female at various ages and pregnancy status.FindingsThe hedonic pricing model indicates sale prices were highest for five-year-old cows that were between four to five months pregnant. NPV was higher for buying heifers versus buying cows and for buying an open female versus a pregnant female. Regardless of age and pregnancy status when purchased, NPV was higher when the female was sold as pregnant prior to the end of her productive life. The risk analysis showed that risk aversion, buying older open cows and selling them as pregnant earlier in their productive life was preferredOriginality/valueThis research offers unique insight into how pregnancy status and age at sale impacts the animal's NPV while considering risk. These results have implications for educating producers on purchasing and selling decisions of heifers and cows as well as for lenders who finance these purchases.
Generating customer engagement in electronic-brand communities: a stimulus–organism–response perspective
Authors: Naqvi Muhammad Hasnain Abbas , Jiang Yushi , Naqvi Mishal 
Published: December 2020

PurposeThis article investigates the factors in customer engagement with electronic brand (e-brand) communities and the mechanism behind their effects. The aim is to investigate the influence of various characteristics of e-brand communities on customer engagement, satisfaction through brand loyalty, and Recommendation.Design/methodology/approachA survey questionnaire was administered to 320 Facebook users in Pakistan. The aim is to investigate the influence of various characteristics of e-brand communities on customer engagement, satisfaction through brand loyalty and recommendation. The data were analyzed using PLS-SEM to test a model developed under the stimulus–organism–response perspective.FindingsEach community attribute significantly affected customer engagement, which was further found to mediate the relationship from these attributes through to customer satisfaction and then to brand loyalty and recommendation.Originality/valueAn original model hypothesized from the stimulus–organism–response framework was validated among an emerging market sample, highlighting the role of customer engagement with e-brand communities in mediating the effects of information and service quality on customer satisfaction.