bluuebunny/crossref_metadata_2025_split huggingface dataset:
VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss
Authors: Peng Jiguang , Xiang Jiale , Jin Xiangqian , Meng Junhua , Song Nana , Chen Lisha , Tayoun Ahmad Abou , Peng Zhiyu 
Published: August 2020

AbstractPurposeThe American College of Medical Genetics and Genomics, and the Association for Molecular Pathology (ACMG/AMP) have proposed a set of evidence-based guidelines to support sequence variant interpretation. The ClinGen hearing loss expert panel (HL-EP) introduced further specifications into the ACMG/AMP framework for genetic hearing loss. This study aimed to semi-automate the HL ACMG/AMP rules.MethodsVIP-HL aggregates information from external databases to automate 13 out of 24 ACMG/AMP rules specified by HL-EP, namely PVS1, PS1, PM1, PM2, PM4, PM5, PP3, BA1, BS1, BS2, BP3, BP4, and BP7.ResultsWe benchmarked VIP-HL using 50 variants where 83 rules were activated by the HL expert panel. VIP-HL concordantly activated 96% (80/83) rules, significantly higher than that of by InterVar (47%; 39/83). Of 4948 ClinVar star 2+ variants from 142 deafness-related genes, VIP-HL achieved an overall variant interpretation concordance in 88.0% (4353/4948). VIP-HL is available with a user-friendly web interface at http://hearing.genetics.bgi.com/.ConclusionVIP-HL is an integrated online tool for reliable automated variant classification in hearing loss genes. It assists curators in variant interpretation and provides a platform for users to share classifications with each other.
Continuous variable response, kinetic gating and connectivity that govern IS topology are perturbed in hyperinsulinemia
Authors: Shukla Namrata , Kadam Shantanu , Padinhateeri Ranjith , Kolthur-Seetharam Ullas 
Published: August 2020

AbstractUnderstanding kinetic control of biological processes is as important as identifying components that constitute pathways. Insulin-signaling (IS) is central for almost all metazoans and its perturbations are associated with various diseases and aging. While temporal phosphorylation changes and kinetic constants have provided some insights, constant or variable parameters that establish and maintain signal topology are poorly understood. Our iterative experimental and mathematical simulation-based approaches reveal novel kinetic parameters that encode concentration and nutrient dependent information. Further, we find that pulsatile fasting insulin rewires IS akin to memory and in anticipation of a fed response. Importantly, selective kinetic gating of signals and maximum connectivity, between metabolic and growth-factor arms under normo-insulinemic states, maintains network topology. In addition to unraveling kinetic constraints that determine cascade architecture, our findings will help in identifying novel therapeutic strategies that conserve coupling between metabolic and growth-factor arms, which is lost in diseases and conditions of hyperinsulinemia.
CD40 provides immune privilege to the bone marrow hematopoietic niche
Authors: Bassani Barbara , Gulino Alessandro , Portararo Paola , Botti Laura , Cappetti Barbara , Chiodoni Claudia , Bolli Niccolò , Ciciarello Marilena , Joehrens Korinna , Anagnostopoulos Ioannis , Na Il-Kang , Curti Antonio , Tripodo Claudio , Colombo Mario P. , Sangaletti Sabina 
Published: August 2020

AbstractAllogeneic bone marrow transplantation remains the only therapeutic option for a wide range of hematological malignancies despite the risk of possible adverse, immune-related events, such as infection and acute graft-versus-host disease (aGVHD). aGVHD is characterized by T-cell activation, defective B-cell development and osteoblastic niche destruction in bone marrow (BM) among other issues. Transplant conditioning regimens cause excessive inflammatory cytokines production and impaired regulatory T-cell control of aberrant T-cell activation. Here, we show that mesenchymal cells (MSCs) upregulated CD40 upon irradiation at the expense of mesenchymal markers, and that CD40 endows MSC of regulatory function on Treg homeostasis and fitness. Transplantation of wild type hematopoietic cells into a CD40-null recipient reduces Treg numbers allowing persistent T-cell activation and pro-inflammatory cytokines production causing, impaired B-lymphopoiesis. These evidences find correlation in aGVHD patients showing the loss of CD40+ BM-MSCs along with reduction in cells of the B-lineage. Modeling aGVHD in mice we show that the elimination of CD40+ BM-MSCs relies on their higher expression of MHC-I molecules. Indeed, aGVHD mice compared to MHC-matched controls showed the loss of MHC-I + radio-resistant host BM-MSCs. Our data point to CD40+ MHC-I+BM-MSCs as a key regulator of BM tolerogenic niches.Key pointsCD40 regulates BM immunological tolerance following total body irradiation (TBI) and transplantation (BMT).Loss of CD40+MHC-IhighBM-MSCs is associated to BM manifestation of aGVHD in human and murine model.
Agromonas: a rapid disease assay forPseudomonas syringaegrowth in agroinfiltrated leaves
Authors: Buscaill Pierre , Sanguankiattichai Nattapong , Lee Yoon Joo , Kourelis Jiorgos , Preston Gail , van der Hoorn Renier A. L. 
Published: August 2020

SUMMARYThe lengthy process to generate transformed plants is a limitation in current research on the interactions of the model plant pathogenPseudomonas syringaewith plant hosts. Here we present an easy method called agromonas, where we quantifyP. syringaegrowth in agroinfiltrated leaves ofNicotiana benthamianausing a cocktail of antibiotics to selectP. syringaeon plates. As a proof of concept, we demonstrate that transient expression of PAMP receptors reduces bacterial growth and that transient depletion of a host immune gene and transient expression of a T3 effector increaseP. syringaegrowth in agromonas assays. We show that we can rapidly achieve structure-function analysis of immune components and test the function of immune hydrolases. The agromonas method is easy, fast and robust for routine disease assays with variousPseudomonasstrains without transforming plants or bacteria. The agromonas assay offers reliable opportunity for further comprehensive analysis of plant immunity.One sentence summaryAgromonas is a rapid and robust disease assay to monitorPseudomonas syringaegrowth in agroinfiltrated leaves expressing immune components and their suppressors.
Development of Putative Isospecific Inhibitors for HDAC6 using Random Forest, QM-Polarized docking, Induced-fit docking, and Quantum mechanics
Authors: Joel Ireoluwa Yinka , Adigun Temidayo Olamide , Bankole Olukayode Olusola , Ajibola Ahmeedah Ololade , Ofeniforo Emmanuel Bankole , Auta Faith Beyaan , Ozojiofor Ugochukwu Okechukwu , Remi-Esan Ifelolu Adeseye , Akande Aminat Ifeoluwa 
Published: August 2020

AbstractHistone deacetylases have been recognized as a potential target for epigenetic aberrance reversal in the various strategies for cancer therapy, with HDAC6 implicated in various forms of tumor growth and cancers. Diverse inhibitors of HDAC6 has been developed, however, there is still the challenge of iso-specificity and toxicity. In this study, we trained a Random forest model on all HDAC6 inhibitors curated in the ChEMBL database (3,742). Upon rigorous validations the model had an 85% balanced accuracy and was used to screen the SCUBIDOO database; 7785 hit compounds resulted and were docked into HDAC6 CD2 active-site. The top two compounds having a benzimidazole moiety as its zinc-binding group had a binding affinity of −78.56kcal/mol and −78.21kcal/mol respectively. The compounds were subjected to exhaustive docking protocols (Qm-polarized docking and Induced-Fit docking) in other to elucidate a binding hypothesis and accurate binding affinity. Upon optimization, the compounds showed improved binding affinity (−81.42kcal/mol), putative specificity for HDAC6, and good ADMET properties. We have therefore developed a reliable model to screen for HDAC6 inhibitors and suggested a series of benzimidazole based inhibitors showing high binding affinity and putative specificity for HDAC6.
Human Embryonic Stem Cell-derived Lung Organoids: a Model for SARS-CoV-2 Infection and Drug Test
Authors: Pei Rongjuan , Feng Jianqi , Zhang Yecheng , Sun Hao , Li Lian , Yang Xuejie , He Jiangping , Xiao Shuqi , Xiong Jin , Lin Ying , Wen Kun , Zhou Hongwei , Chen Jiekai , Rong Zhili , Chen Xinwen 
Published: August 2020

AbstractThe coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culturein vitroand model the physiological conditions of natural organs. Here we demonstrated that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids. Ciliated cells, alveolar type 2 (AT2) cells and rare club cells were virus target cells. Electron microscopy captured typical replication, assembly and release ultrastructures and revealed the presence of viruses within lamellar bodies in AT2 cells. Virus infection induced more severe cell death in alveolar organoids than in airway organoids. Additionally, RNA-seq revealed early cell response to SARS-CoV-2 infection and an unexpected downregulation of ACE2 mRNA. Further, compared to the transmembrane protease, serine 2 (TMPRSS2) inhibitor camostat, the nucleotide analog prodrug Remdesivir potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model for SARS-CoV-2 infection and drug discovery.
PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells
Authors: De Smedt Jonathan , van Os Elise Anne , Talon Irene , Ghosh Sreya , Toprakhisar Burak , Da Costa Rodrigo Furtado Madeiro , Zaunz Samantha , Vazquez Marta Aguirre , Boon Ruben , Baatsen Pieter , Smout Ayla , Verhulst Stefaan , van Grunsven Leo A. , Verfaillie Catherine M. 
Published: August 2020

AbstractTo date there is no representativein vitromodel for liver sinusoidal endothelial cells (LSECs), as primary LSECs dedifferentiate very fast in culture and no combination of cytokines or growth factors can induce an LSEC fate in (pluripotent stem cell-derived) endothelial cells (ECs). Furthermore, the transcriptional programs driving an LSEC fate have not yet been described. Here, we first present a computational workflow (CenTFinder) that can identify transcription factors (TFs) that are crucial for modulating pathways involved in cell lineage specification. UsingCenTFinder, we identified several novel LSEC-specific protein markers such as FCN2 and FCN3, which were validated by analysis of previously published single-cell RNAseq data. We also identified PU.1 (encoded by theSPI1gene) as a major regulator of LSEC-specific immune functions. We show thatSPI1overexpression (combined with the general EC transcription factorETV2) in human pluripotent stem cells (PSCs) induces ECs with an LSEC-like phenotype. The ETV2-SPI1-ECs display increased expression of LSEC markers such as CD32B and MRC1 as well as several of the proposed novel markers. More importantly, ETV2-SPI1-ECs acquire LSEC functions, including uptake of FSA-FITC as well as labelled IgG. In conclusion, we present theCenTFindercomputational tool to identify key regulatory TFs within specific pathways, in this work pathways of lineage specification, and we demonstrate its use by the identification and validation of PU.1 as a master regulator for LSEC fating.
Regulation ofCYP94B1by WRKY33 controls apoplastic barrier formation in the roots leading to salt tolerance
Authors: Krishnamurthy Pannaga , Vishal Bhushan , Ho Wan Jing , Lok Felicia Chien Joo , Lee Felicia Si Min , Kumar Prakash P 
Published: August 2020

AbstractSalinity is an environmental stress that causes decline in crop yield.Avicennia officinalisand other mangroves have adaptations such as ultrafiltration at the roots aided by apoplastic cell-wall barriers to thrive in saline conditions. We studied a Cytochrome P450 gene,AoCYP94B1fromA. officinalisand itsArabidopsisorthologAtCYP94B1that are involved in apoplastic barrier formation, and are induced by 30 minutes of salt treatment in the roots. Heterologous expression ofAoCYP94B1inatcyp94b1 Arabidopsismutant and wild-type rice conferred increased NaCl tolerance to seedlings by enhancing root suberin deposition. Histochemical staining and GC-MS/MS quantification of suberin precursors confirmed the role of CYP94B1 in suberin biosynthesis. Using chromatin immunoprecipitation, yeast one-hybrid and luciferase assays, we identified AtWRKY33 as the upstream regulator ofAtCYP94B1inArabidopsis. In addition,atwrky33mutants exhibited reduced suberin and salt sensitive phenotypes, which were rescued by expressing35S::AtCYP94B1inatwrky33mutant. This further confirms that the regulation ofAtCYP94B1by AtWRKY33 is part of the salt tolerance mechanism, and our findings can help in generating salt tolerant crops.One sentence summaryAtWRKY33 transcription factor regulatesAtCYP94B1to increase plant salt tolerance by enhanced suberin deposition in the endodermal cells ofArabidopsisroots
Bioinformatic Analysis Reveals That Some Mutations May Affect On Both Spike Structure Damage and Ligand Binding Site
Authors: Aktas Emre 
Published: August 2020

AbstractThere are some mutations are known related to SARS-CoV-2. Together with these mutations known, I tried to show other newly mutations regionally. According to my results which 4326 whole sequences are used, I found that some mutations occur only in a certain region, while some other mutations are found in each regions. Especially in Asia, more than one mutation(three different mutations are found in QLA46612 isolated from South Korea) was seen in the same sequence. Although I detected a huge number of mutations (more than seventy in Asia) by regions, some of them were predicted that damage spike’s protein structure by using bioinformatic tools.The predicted results are G75V(isolated from North America), T95I(isolated from South Korea), G143V(isolated from North America), M177I(isolated Asia), L293M(isolated from Asia), P295H(isolated from Asia), T393P(isolated from Europe), P507S(isolated from Asia), D614G(isolated from all regions) respectively. Also, in this study, I tried to show how possible binding sites of ligands change if the spike protein structure is damaged and whether more than one mutation affects ligand binding was estimated using bioinformatics tools. Interestingly, mutations that predicted to damage the structure do not affect ligand binding sites, whereas ligands’ binding sites were affected in those with multiple mutations.Focusing on mutations may opens up the window to exploit new future therapeutic targets.
The psychophysics of visual search with heterogeneous distractors
Authors: Mihali Andra , Ma Wei Ji 
Published: August 2020

AbstractVisual search is one of the most ecologically important perceptual task domains. One research tradition has studied visual search using simple, parametric stimuli and a signal detection theory or Bayesian modeling framework. However, this tradition has mostly focused on homogeneous distractors (identical to each other), which are not very realistic. In a different tradition, Duncan and Humphreys (1989) conducted a landmark study on visual search with heterogeneous distractors. However, they used complex stimuli, making modeling and dissociation of component processes difficult. Here, we attempt to unify these research traditions by systematically examining visual search with heterogeneous distractors using simple, parametric stimuli and Bayesian modeling. Our experiment varied multiple factors that could influence performance: set size, task (N-AFC localization vs detection), whether the target was revealed before or after the search array (perception versus memory), and stimulus spacing. We found that performance robustly decreased with increasing set size. When examining within-trial summary statistics, we found that the minimum target-to-distractor feature difference was a stronger predictor of behavior than the mean target-to-distractor difference and than distractor variance. To obtain process-level understanding, we formulated a Bayesian optimal-observer model. This model accounted for all summary statistics, including when fitted jointly to localization and detection. We replicated these results in a separate experiment with reduced stimulus spacing. Together, our results represent a critique of Duncan and Humphrey’s descriptive approach, bring visual search with heterogeneous distractors firmly within the reach of quantitative process models, and affirm the “unreasonable effectiveness” of Bayesian models in explaining visual search.
Ecology and Epidemiology of Wheat Curl Mite and Mite-Transmissible Viruses in Colorado and Insights into the Wheat Virome
Authors: Albrecht Tessa , White Samantha , Layton Marylee , Stenglein Mark , Haley Scott , Nachappa Punya 
Published: August 2020

AbstractThe wheat curl mite (WCM)-transmissible wheat streak disease complex is the most serious disease of wheat in the U.S. Great Plains. In the current study, we determined the genetic variability in WCM and mite-transmitted viruses in Colorado and identified sources of resistance in Colorado wheat germplasm to wheat streak disease complex. We identified two distinct genotypes of WCM, Type 1 and Type 2 based on the ribosomal ITS1 region. Both genotypes were found to co-exist throughout the wheat producing regions of Colorado. Analysis of the whole genome and partial coat protein sequences revealed rich diversity of wheat streak mosaic virus (WSMV) and High Plains wheat mosaic virus (HPWMoV) isolates collected from Colorado, whereas triticum mosaic virus (TriMV) showed low sequence variability. Analysis of WSMV isolates revealed two novel isolates and one that was 100% similar to a new variant of WSMV from Kansas. Interestingly, between 2-4 genotypes of all 8 RNA segments of HPWMoV were identified, which suggests new variants of emaraviruses and co-occurrence of multiple strains within host populations. Several novel viruses including mycoviruses were identified for the first time in Colorado. We found variation in WSMV resistance among wheat varieties; however a variety that harbored dual resistance to mite and WSMV had lower virus titer compared to varieties that contained single resistance gene. This suggests that pyramiding genes will ensure improved and durable resistance. Future research may be aimed at elucidating the dynamics, diversity, and distribution of the new WSMV and HPWMoV isolates and their responses to wheat genotypes.
An Ensemble Learning Approach for Cancer Drug Prediction
Authors: Mandera Darsh , Ritz Anna 
Published: August 2020

AbstractPredicting the response to a particular drug for specific cancer, despite known genetic mutations, still remains a huge challenge in modern oncology and precision medicine. Today, prescribing a drug for a cancer patient is based on a doctor’s analysis of various articles and previous clinical trials; it is an extremely time-consuming process. We developed a machine learning classifier to automatically predict a drug given a carcinogenic gene mutation profile. Using the Breast Invasive Carcinoma Dataset from The Cancer Genome Atlas (TCGA), the method first selects features from mutated genes and then applies K-Fold, Decision Tree, Random Forest and Ensemble Learning classifiers to predict best drugs. Ensemble Learning yielded prediction accuracy of 66% on the test set in predicting the correct drug. To validate that the model is general-purpose, Lung Adenocarcinoma (LUAD) data and Colorectal Adenocarcinoma (COADREAD) data from TCGA was trained and tested, yielding prediction accuracies 50% and 66% respectively. The resulting accuracy indicates a direct correlation between prediction accuracy and cancer data size. More importantly, the results of LUAD and COADREAD show that the implemented model is general purpose as it is able to achieve similar results across multiple cancer types. We further verified the validity of the model by implementing it on patients with unclear recovery status from the COADREAD dataset. In every case, the model predicted a drug that was administered to each patient. This method will offer oncologists significant time-saving compared to their current approach of extensive background research, and offers personalized patient care for cancer patients.
Ectopic expression of a maize gene is induced by Composite Insertions generated through Alternative Transposition
Authors: Su Weijia , Zuo Tao , Peterson Thomas 
Published: August 2020

AbstractTransposable elements (TEs) are DNA sequences that can mobilize and proliferate throughout eukaryotic genomes. Previous studies have shown that in plant genomes, TEs can influence gene expression in various ways such as inserting in introns or exons to alter transcript structure and content, and providing novel promoters and regulatory elements to generate new regulatory patterns. Furthermore, TEs can also regulate gene expression at the epigenetic level by modifying chromatin structure, changing DNA methylation status and generating small RNAs. In this study, we demonstrated thatAc/fActransposable elements are able to induce ectopic gene expression by duplicating and shuffling enhancer elements.Ac/fAcelements belong to thehATfamily of Class II TEs. They can undergo standard transposition events, which involve the two termini of a single transposon, or alternative transposition events which involve the termini of two different, nearby elements. Our previous studies have shown that alternative transposition can generate various genome rearrangements such as deletions, duplications, inversions, translocations and Composite Insertions (CIs). We identified over 50 independent cases of CIs generated byAc/fAcalternative transposition and analyzed 10 of them in detail. We show that these CIs induced ectopic expression of the maizepericarp color 2 (p2)gene, which encodes a Myb-related protein. All the CIs analyzed contain sequences including a transcriptional enhancer derived from the nearbyp1gene, suggesting that the CI-induced activation ofp2is effected by mobilization of thep1enhancer. This is further supported by analysis of a mutant in which the CI is excised andp2expression is lost. These results show that alternative transposition events are not only able to induce genome rearrangements, but also generate Composite Insertions that can control gene expression.SummaryWhen Barbara McClintock originally identified and characterized Transposable Elements (TEs) in maize, she termed them “Controlling Elements” due to their effects on gene expression. Here we show that maizeAc/DsTEs can acquire a genomic enhancer and generate Composite Insertions (CIs) that activate expression of a nearby gene. CIs are structurally variable elements that include TE termini enclosing sequences from an original donor locus, and are formed when the termini of two nearby TEs transpose during S phase from a replicated to unreplicated site. In this way, TEs may acquire genomic enhancers to generate Controlling Elements as described by McClintock.