bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automated identification of small drug molecules for Hepatitis C virus through a novel programmatic tool and extensive Molecular Dynamics studies of select drug candidates
Authors: Madaj Rafal , Sanker Akhil , Geoffrey A S Ben , David Host Antony , Verma Shubham , Gracia Judith , Faleti Ayodele Ifeoluwa , Yakubu Abdulbasit Haliru 
Published: July 2020

AbstractWe report a novel python based programmatic tool that automates the dry lab drug discovery workflow for Hepatitis C virus. Firstly, the python program is written to automate the process of data mining PubChem database to collect data required to perform a machine learning based AutoQSAR algorithm through which drug leads for Hepatitis C virus is generated. The workflow of the machine learning based AutoQSAR involves feature learning and descriptor selection, QSAR modelling, validation and prediction. The drug leads generated by the program are required to satisfy the Lipinski’s drug likeness criteria. 50 of the drug leads generated by the program are fed as programmatic inputs to an In Silico modelling package by the program for fast virtual screening and computer modelling of the interaction of the compounds generated as drug leads and the drug target, a viral Helicase of Hepatitis C. The results are stored automatically in the working folder of the user by the program. The program also generates protein-ligand interaction profiling and stores the visualized images in the working folder of the user. Select protein-ligand complexes associated with structurally diverse ligands having lowest binding energy were selected for extensive molecular dynamics simulation studies and subsequently for molecular mechanics generalized-born surface area (MMGBSA) with pairwise decomposition calculations. The molecular mechanics studies predict In Silico that the compounds generated by the program inhibit the viral helicase of Hepatitis C and prevent the replication of the virus. Thus our programmatic tool ushers in the new age of automatic ease in drug identification for Hepatitis C virus through a programmatic tool that completely automates the dry lab drug discovery workflow. The program is hosted, maintained and supported at the GitHub repository link given belowhttps://github.com/bengeof/Automated-drug-identification-programmatic-tool-for-Hepatitis-C-virus
The organizational principles of de-differentiated topographic maps in somatosensory cortex
Authors: Liu Peng , Chrysidou Anastasia , Doehler Juliane , Hebart Martin , Wolbers Thomas , Kuehn Esther 
Published: July 2020

AbstractTopographic maps are a fundamental feature of cortex architecture in the mammalian brain. One common theory is that the de-differentiation of topographic maps links to impairments in everyday behavior due to less precise functional map readouts. Here, we tested this theory by characterizing de-differentiated topographic maps in primary somatosensory cortex (SI) of younger and older adults by means of ultra-high resolution functional magnetic resonance imaging together with perceptual finger individuation and hand motor performance. Older adults’ SI maps showed similar amplitude and size to younger adults’ maps, but presented with less representational similarity between distant fingers. Larger population receptive field sizes in older adults’ maps did not correlate with behavior, whereas reduced cortical distances between D2 and D3 related to worse finger individuation but better motor performance. Our data uncover the drawbacks of a simple de-differentiation model of topographic map function, and motivate the introduction of feature-based models of cortical reorganization.
Identifying Causative Mechanisms Linking Early-Life Stress to Psycho-Cardio-Metabolic Multi-Morbidity: The EarlyCause Project
Authors: Mariani Nicole , Borsini Alessandra , Cecil Charlotte A.M. , Felix Janine F. , Sebert Sylvain , Cattaneo Annamaria , Walton Esther , Milaneschi Yuri , Cochrane Guy , Amid Clara , Rajan Jeena , Giacobbe Juliette , Sanz Yolanda , Agustí Ana , Sorg Tania , Herault Yann , Miettunen Jouko , Parmar Priyanka , Cattane Nadia , Jaddoe Vincent , Lötjönen Jyrki , Buisan Carme , Ballester Miguel A. González , Piella Gemma , Gelpi Josep L. , Lamers Femke , Penninx Brenda WJH , Tiemeier Henning , von Tottleben Malte , Thiel Rainer , Heil Katharina F. , Järvelin Marjo-Riitta , Pariante Carmine , Mansuy Isabelle M. , Lekadir Karim 
Published: July 2020

AbstractIntroductionDepression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards shared risk of these diseases and the development of coordinated preventive and therapeutic interventions.Methods and analysisThis paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union’s Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shape an individual’s physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.Ethics and disseminationThe study has been approved by the Ethics Board of the European Commission. The results will be published in peer-reviewed academic journals, and disseminated to and communicated with clinicians, patient organisations and media.
Intramolecular quality control: HIV-1 Envelope gp160 signal-peptide cleavage as a functional folding checkpoint
Authors: McCaul Nicholas , Quandte Matthias , Bontjer Ilja , van Zadelhoff Guus , Land Aafke , Sanders Rogier W. , Braakman Ineke 
Published: July 2020

SummaryRemoval of the membrane-tethering signal peptides that target secretory proteins to the endoplasmic reticulum is a prerequisite for proper folding. While generally thought to be removed well before translation termination, we here report two novel post-targeting functions for the HIV-1 gp120 signal peptide, which remains attached until gp120 folding triggers its removal. First, the signal peptide improves fidelity of folding by enhancing conformational plasticity of gp120 by driving disulfide isomerization through a redox-active cysteine, at the same time delaying folding by tethering the N-terminus to the membrane, which needs assembly with the C-terminus. Second, its carefully timed cleavage represents intramolecular quality control and ensures release and stabilization of (only) natively folded gp120. Postponed cleavage and the redox-active cysteine both are highly conserved and important for viral fitness. Considering the ∼15% secretory proteins in our genome and the frequency of N-to-C contacts in protein structures, these regulatory roles of the signal peptide are bound to be more common in secretory-protein biosynthesis.
Acto-myosin cross-bridge stiffness depends on the nucleotide state of the myosin II
Authors: Wang Tianbang , Brenner Bernhard , Nayak Arnab , Amrute-Nayak Mamta 
Published: July 2020

AbstractHow various myosin isoforms fulfill the diverse physiological requirements of distinct muscle types remains unclear. Myosin II isoforms expressed in skeletal muscles determines the mechanical performance of the specific muscles as fast movers, or slow movers but efficient force holders. Here, we employed a single-molecule optical trapping method and compared the chemo-mechanical properties of slow and fast muscle myosin II isoforms. Stiffness of the myosin motor is key to its force-generating ability during muscle contraction. We found that acto-myosin (AM) cross-bridge stiffness depends on its nucleotide state as the myosin progress through the ATPase cycle. The strong actin bound ‘AM.ADP’ state exhibited > 2 fold lower stiffness than ‘AM rigor’ state. The two myosin isoforms displayed similar ‘rigor’ stiffness. We conclude that the time-averaged stiffness of the slow myosin is lower due to prolonged duration of the AM.ADP state, which determines the force-generating potential and contraction speed of the muscle, elucidating the basis for functional diversity among myosins.
Calnexin mediates the maturation of GPI-anchors through ER retention
Authors: Guo Xin-Yu , Liu Yi-Shi , Gao Xiao-Dong , Kinoshita Taroh , Fujita Morihisa 
Published: July 2020

AbstractThe protein folding and lipid moiety status of glycosylphosphatidylinositol-anchored proteins (GPI-APs) are monitored in the endoplasmic reticulum (ER), with calnexin playing dual roles in the maturation of GPI-APs. In the present study, we investigated the functions of calnexin in the quality control and lipid remodeling of GPI-APs in the ER. By directly binding the N-glycan on proteins, calnexin was observed to efficiently retain GPI-APs in the ER until they were correctly folded. In addition, sufficient ER retention time was crucial for GPI-inositol deacylation, which is mediated by post-GPI attachment protein 1 (PGAP1). Once the calnexin/calreticulin cycle was disrupted, misfolded and inositol-acylated GPI-APs could not be retained in the ER and were exposed on the plasma membrane. In calnexin/calreticulin deficient cells, endogenous GPI-anchored alkaline phosphatase was expressed on the cell surface, but its activity was significantly decreased. ER stress induced surface expression of misfolded GPI-APs, but proper GPI-inositol deacylation occurred due to the extended time that they were retained in the ER. Our results indicate that calnexin-mediated ER quality control systems for GPI-APs are necessary for both protein folding and GPI-inositol deacylation.
Enhanced COVID-19 data for improved prediction of survival
Authors: Zeng Wenhuan , Gautam Anupam , Huson Daniel H 
Published: July 2020

AbstractThe current COVID-19 pandemic, caused by the rapid world-wide spread of the SARS-CoV-2 virus, is having severe consequences for human health and the world economy. The virus effects individuals quite differently, with many infected patients showing only mild symptoms, and others showing critical illness. To lessen the impact of the pandemic, one important question is which factors predict the death of a patient? Here, we construct an enhanced COVID-19 dataset by processing two existing databases (from Kaggle and WHO) and using natural language processing methods to enhance the data by adding local weather conditions and research sentiment.Author summaryIn this study, we contribute an enhanced COVID-19 dataset, which contains 183 samples and 43 features. Application of Extreme Gradient Boosting (XGBoost) on the enhanced dataset achieves 95% accuracy in predicting patients survival, with country-wise research sentiment, and then age and local weather, showing the most importance. All data and source code are available at http://ab.inf.uni-tuebingen.de/publications/papers/COVID-19.
Requirement of FLCN tumor suppressor gene for mTORC1-mediated inhibition of TFE3 transcriptional activity
Authors: Li Hua , Oh HyoungBin , Viollet Benoit , Schmidt Laura S. , Linehan W. Marston , Krymskaya Vera P. , Hong Seung-Beom 
Published: July 2020

AbstractTFE3 is an oncogenic transcription factor whose subcellular localization and activity are regulated by post-translational modifications. TFE3 is hyper-phosphorylated in the cytoplasm of mammalian cells under normal growth conditions, but becomes hypo-phosphorylated and translocates into the nucleus of cells with genetic inactivation of theFLCNtumor suppressor gene, which is responsible for the development of renal cancer, lung cysts and cutaneous hamartomas in patients with Birt-Hogg-Dubé syndrome (BHD). Since FLCN is suggested to play a role in metabolic signaling through its interaction with energy and nutrient sensing kinases AMPK and mTOR, we investigated whether metabolic signaling regulates TFE3 activity through post-translational modifications and subcellular localization. We found that TFE3 was activated by metabolic stresses, such as glucose or amino acid deprivation, and induced gene expression of lysosomal genes,cathepsins, V-ATPaseandmucolipin-1. AMPK activation and/or mTORC1 inhibition by nutrient deprivation, AMPK activator, mTOR or lysosomal inhibitors induced hypo-phosphorylation and subsequent nuclear localization of TFE3. mTORC1 directly phosphorylated TFE3in vitroand the mutation of a putative mTORC1-dependent TFE3 phosphorylation site, Ser 321, was critical for its interaction with 14-3-3 protein, and retention in the cytoplasm. Direct phosphorylation of TFE3 by AMPK was demonstrated by anin vitrokinase assay and the AMPK-mediated phosphorylation sites were determined by mass spectrometry; however, the physiological significance of AMPK-mediated TFE3 phosphorylation requires further investigation. mTORC1-mediated TFE3 phosphorylation under nutrient and growth factor replete conditions was dependent on FLCN expression. In summary, we have shown that TFE3 induces lysosomal gene expression upon activation of AMPK and inhibition_of mTORC1 activity by metabolic stresses or loss of FLCN, which would play important roles not only in catabolic processes but also in the pathogenicity of human disease including cancer.
Urban living influences the reproductive success of Darwin’s finches in the Galápagos Islands
Authors: Harvey Johanna A. , Chernicky Kiley , Simons Shelby R. , Verrett Taylor B. , Chaves Jaime A. , Knutie Sarah A. 
Published: July 2020

AbstractUrbanization is expanding worldwide and can have major consequences for organisms, anthropogenic factors can reduce the fitness of animals but may also have benefits, such as consistent human food availability. Understanding these trade-offs is critically important in environments with unreliable annual natural food availability, such as the Galápagos Islands where urbanization is rapidly increasing. For example, during dry climatic condition years, the reproductive success of bird species, such as Darwin’s finches, is low because low precipitation reduces food availability. Urban areas in the Galápagos provide supplemental human food to finches, which could improve their reproductive success during years with low natural food availability. However, urban finches might face trade-offs, as the incorporation of anthropogenic debris (e.g. string, hair, plastic) into their nests can increase mortality.In our study, we determined the effect of urbanization on the reproductive effort and success of small ground finches (Geospiza fuliginosa; a species of Darwin’s finch) during a dry year on San Cristóbal Island, Galápagos Islands. We also documented the abundance of anthropogenic debris incorporated in to nests.We quantified nest building, egg laying, hatching, and fledging of small ground finches in an urban and non-urban area. We also qualified the type of anthropogenic debris in finch nests and the quantified the percent of debris comprising total nest mass. We determined whether incorporating these materials into the nest directly led to entanglement- or ingestion-related mortalities.Overall, urban finches built more nests, laid more eggs, and produced more fledglings than non-urban finches. However, every nest in the urban area contained anthropogenic-related material, which resulted in entanglement- or ingestion-related mortalities in 18% of nests with nestlings. Non-urban nests did not contain any anthropogenic-related material.Our study showed that urban living has trade-offs during drier climatic conditions: urban birds have overall higher reproductive success than non-urban birds, but urban birds can also suffer a negative consequence by using anthropogenic-related material for nesting. These results suggest that despite the potential cost of urban living, finches benefit overall from urban living and urbanization may buffer the effects of limited resource availability in the Galápagos Islands.
Speciation and the developmental alarm clock
Authors: Cutter Asher D. , Bundus Joanna D. 
Published: July 2020

AbstractNew species arise as the genomes of populations diverge. The developmental ‘alarm clock’ of speciation sounds off when sufficient divergence in genetic control of development leads hybrid individuals to infertility or inviability, the world awoken to the dawn of new species with intrinsic post-zygotic reproductive isolation. Some developmental stages will be more prone to hybrid dysfunction due to how molecular evolution interacts with the ontogenetic timing of gene expression. Considering the ontogeny of hybrid incompatibilities provides a profitable connection between ‘evo-devo’ and speciation genetics to better link macroevolutionary pattern, microevolutionary process, and molecular mechanisms. Here we explore speciation alongside development, emphasizing their mutual dependence on genetic network features, fitness landscapes, and developmental system drift. We assess models for how ontogenetic timing of reproductive isolation can be predictable. Experiments and theory within this synthetic perspective can help identify new rules of speciation as well as rules in the molecular evolution of development.Impact StatementIntegrating speciation genetics with ontogeny can identify predictable rules in the molecular evolution of developmental pathways and in the accumulation of reproductive isolation as genomes diverge.
Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex
Authors: Glasgow Stephen D. , Wong Edwin W. , Beamish Ian V. , Lancon Kevin , Gibon Julien , Séguéla Philippe , Ruthazer Edward S. , Kennedy Timothy E. 
Published: July 2020

AbstractThe ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that cholinergic activation of muscarinic receptors on entorhinal cortical neurons mediates plasma membrane recruitment of the netrin-1 receptor deleted-in-colorectal cancer (DCC) to promote muscarinic receptor-mediated persistent firing. Conditional deletion of netrin-1 or DCC, which are required for synaptic plasticity, inhibits cholinergic persistent firing, and leads to deficits in spatial working memory. Together, these findings indicate that normal working memory function requires synergistic action of acetylcholine and netrin-1.
Luxury marketing in social media: the role of social distance in a craftsmanship video
Authors: Lee Jung Eun , Youn Song-Yi 
Published: July 2020

PurposeThe purpose of this study is to examine the effect of craftsmanship content and social distance embedded in the craftsmanship content on luxury brand experiences, perceived luxury and brand purchase intentions using a social media video.Design/methodology/approachThe authors conducted a single factor (close social distance vs great social distance vs control group) using a between-subjects experimental design. The social distance was manipulated by the presence (i.e. a close social distance) or absence (i.e. a great social distance) of a consumer scene in a craftsmanship video shown on social media. The control group watched a video with non-craftsmanship content. Then, brand experience, perceived luxury and purchase intentions were measured.FindingsThe results showed that the control group perceived less luxury and had lower brand experiences and purchase intentions than the group that watched the video without a consumer scene. In addition, participants who watched the craftsmanship video that included a consumer scene (i.e. a close social distance) had stronger brand experiences than those who watched the video without the scene (i.e. a great social distance). The brand experience increased perceived luxury and purchase intentions.Originality/valueBy manipulating social distance and providing better brand experiences in social media, experiential marketing allows luxury brands to reconcile two apparently incompatible goals: maintaining an exclusive image while increasing purchase intentions.
Modeling of crack repair using piezoelectric material: XFEM approach
Authors: Kumar Ritesh , Pathak Himanshu , Singh Akhilendra , Tiwari Mayank 
Published: July 2020

PurposeThe purpose of this paper is to analyze the repair of a straight and angular crack in the structure using a piezoelectric material under thermo-mechanical loading by the extended finite element method (XFEM) approach. This provides a general and simple solution for the modeling of crack in the structure to analyze the repair.Design/methodology/approachThe extended finite element method is used to model crack geometry. The crack surface is modeled by Heaviside enrichment function while the crack front is modeled by branch enrichment functions.FindingsThe effectiveness of the repair is measured in terms of stress intensity factor and J-integral. The critical voltage at which patch repair is most effective is evaluated and presented. Optimal patch shape, location of patch, adhesive thickness and adhesive modulus are obtained for effective repair under thermo-mechanical loading environment.Originality/valueThe presented numerical modeling and simulation by the XFEM approach are of great benefit to analyze crack repair in two-dimensional and three-dimensional structures using piezoelectric patch material under thermo-mechanical loading.