bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Optimised GAS-pharyngeal cell biofilm model
Authors: Vyas Heema K. N. , McArthur Jason D. , Sanderson-Smith Martina L. 
Published: November 2020

AbstractGroup A Streptococcus (GAS) causes 700 million infections and accounts for half a million deaths per year. Biofilm formation has been implicated in both pharyngeal and dermal GAS infections. In vitro, plate-based assays have shown that several GAS M-types form biofilms, and multiple GAS virulence factors have been linked to biofilm formation. Although the contributions of these plate-based studies have been valuable, most have failed to mimic the host environment, with many studies utilising abiotic surfaces. GAS is a human specific pathogen, and colonisation and subsequent biofilm formation is likely facilitated by distinct interactions with host tissue surfaces. As such, a host cell-GAS model has been optimised to support and grow GAS biofilms of a variety of GAS M-types. Improvements and adjustments to the crystal violet biofilm biomass assay have also been tailored to reproducibly detect delicate GAS biofilms. We propose 72 h as an optimal growth period for yielding detectable biofilm biomass. GAS biofilms formed are robust and durable, and can be reproducibly assessed via staining/washing intensive assays such as crystal violet with the aid of methanol fixation prior to staining. Lastly, SEM imaging of GAS biofilms formed by this model are resemblant of those previously found on excised tonsils of patients suffering chronic pharyngo-tonsillitis. Taken together, we outline an efficacious GAS biofilm pharyngeal cell model that can support long-term GAS biofilm formation, with biofilms formed closely resembling those seen in vivo.
The kinase specificity of protein kinase inhibitor peptide (PKI)
Authors: Chen Yao , Sabatini Bernardo L. 
Published: November 2020

AbstractG-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested inin vitroassays. We found that in addition to inhibiting PKA activity, both PKI (6-22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities.
A two-state ribosome and protein model can robustly capture the chemical reaction dynamics of gene expression
Authors: Pandey Ayush , Murray Richard M. 
Published: November 2020

AbstractWe derive phenomenological models of gene expression from a mechanistic description of chemical reactions using an automated model reduction method. Using this method, we get analytical descriptions and computational performance guarantees to compare the reduced dynamics with the full models. We develop a new two-state model with the dynamics of the available free ribosomes in the system and the protein concentration. We show that this new two-state model captures the detailed mass-action kinetics of the chemical reaction network under various biologically plausible conditions on model parameters. On comparing the performance of this model with the commonly used mRNA transcript-protein dynamical model for gene expression, we analytically show that the free ribosome and protein model has superior error and robustness performance.
A systematic evaluation of IgM and IgG antibody assay accuracy in diagnosing acute Zika Virus infection in Brazil; lessons relevant to emerging infections
Authors: Medialdea-Carrera Raquel , Levy Flavia , Castanha Priscila , de Sequeira Patricia Carvalho , Brasil Patricia , Lewis-Ximenez Lia L , Turtle Lance , Solomon Tom , de Filippis Ana Maria Bispo , Brown David W. , Griffiths Michael J. 
Published: November 2020

AbstractAccurate diagnostics underpin effective public health responses to emerging viruses. For viruses, such as Zika virus (ZIKV), where the viremia clears quickly, antibody-based (IgM or IgG) diagnostics are recommended for patients who present seven days after symptom onset. However, cross-reactive antibody responses can complicate test interpretation among populations where closely related viruses circulate.We examined the accuracy (proportion of samples correctly categorized as Zika-positive or negative) for antibody-based diagnostics among Brazilian residents (Rio de Janeiro) during the ZIKV outbreak. Four ZIKV ELISAs (IgM and IgG Euroimmun, IgM Novagnost and CDC MAC), two dengue ELISAs (IgM and IgG Panbio), and the ZIKV plaque reduction neutralization test (PRNT) were evaluated. Positive samples were ZIKV PCR confirmed clinical cases collected in 2015-2016 (n=169); Negative samples (n=236) were collected before ZIKV was present in Brazil (≤2013).Among serum samples collected ≥7 days from symptom onset, PRNT exhibited the highest accuracy (93.7%), followed by the Euroimmun IgG ELISA (77.9%). All IgM assays exhibited lower accuracy (<74%). IgG was detected more consistently than IgM among ZIKV cases using Euroimmun ELISAs (68% versus 22%). Anti-DENV IgM ELISA was positive in 41.1% of confirmed ZIKV samples tested.The Euroimmun IgG assay, although misdiagnosing 22% of samples, provided the most accurate ELISA. Anti-ZIKV IgG was detected more reliably than IgM among ZIKV patients, suggesting a secondary antibody response to assay antigens following ZIKV infection. Antibody ELISAs need careful evaluation in their target population to optimise use and minimise misdiagnosis, prior to widespread deployment, particularly where related viruses co-circulate.
Sensing stress responses in potato with whole-plant redox imaging
Authors: Hipsch Matanel , Lampl Nardy , Zelinger Einat , Barda Orel , Rosenwasser Shilo 
Published: November 2020

AbstractEnvironmental stresses are among the major factors that limit crop productivity and plant growth. Plant exposure to various abiotic stress, such as drought, cold temperatures, or high light, results in overproduction of reactive oxygen species (ROS). To avoid oxidative damage, critical mechanisms for their detoxification have evolved, consisting of ROS-scavenging enzymes and small antioxidant molecules, such as glutathione (GSH) and ascorbate. Thus, monitoring redox changes with high spatial and temporal resolution is critical for understanding oxidative stress signaling and has the potential to enable early detection of stress responses in crop plants. In this work, potato plants (‘Solanum tuberosum’) expressing a chloroplast-targeted reduction-oxidation-sensitive green fluorescent protein2 (roGFP2) were generated to report the redox potential of the glutathione (EGSH) in the chloroplast stroma. By applying whole-plant fluorescence imaging, we mapped alteration in the chloroplast EGSH under several stress conditions including, high-light, cold and drought. Extremely high increase in chloroplast EGSH was observed under the combination of high-light and low temperatures, conditions that specifically induce PSI photoinhibition. Intriguingly, whole-plant ratiometric imaging analysis noted a higher reduced state in newly developed as compared to mature leaves, suggesting a graded stress sensitivity as part of the plant strategies for coping with stress conditions. The presented observations suggest that whole-plant redox imaging can serve as a powerful tool for the basic understanding of plant stress responses as well as for applied agricultural research, such as improving phenotyping capabilities in breeding programs and early detection of stress responses in the field.
EpitopeVec: Linear Epitope Prediction Using Deep Protein Sequence Embeddings
Authors: Bahai Akash , Asgari Ehsaneddin , Mofrad Mohammad R.K. , Kloetgen Andreas , McHardy Alice C. 
Published: November 2020

AbstractMotivationB-cell epitopes (BCEs) play a pivotal role in the development of peptide vaccines, immunodiagnostic reagents, and antibody production, and thus generally in infectious disease prevention and diagnosis. Experimental methods used to determine BCEs are costly and time-consuming. It thus becomes essential to develop computational methods for the rapid identification of BCEs. Though several computational methods have been developed for this task, cross-testing of classifiers trained and tested on different datasets revealed their limitations, with accuracies of 51 to 53%.ResultsWe describe a new method called EpitopeVec, which utilizes residue properties, modified antigenicity scales, and a Protvec representation of peptides for linear BCE prediction with machine learning techniques. Evaluating on several large and small data sets, as well as cross-testing demonstrated an improvement of the state-of-the-art performances in terms of accuracy and AUC. Predictive performance depended on the type of antigen (viral, bacterial, eukaryote, etc.). In view of that, we also trained our method on a large viral dataset to create a linear viral BCE predictor.AvailablityThe software is available at https://github.com/hzi-bifo/epitope-prediction under the GPL3.0 license.Contactalice.mchardy@helmholtz-hzi.deSupplementary informationSupplementary data are available at Bioinformatics online.
The full model of the pMHC-TCR-CD3 complex: a structural and kinetics characterization
Authors: Alba Josephine , Acuto Oreste , D’Abramo Marco 
Published: November 2020

AbstractThe machinery involved in cytotoxic T-cell activation requires three main characters such as: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3-complex which is a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied both in experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering process. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3-complex) is still missing, due to insufficient data available on the CD3-chains arrangement around the TCR. The recent determination of the TCR:CD3-complex structure by means of Cryo-EM technique has given a chance to build the entire proteins system essential in the activation of T-cell, and thus in the adaptive immune response. Here, we present the first full model of the pMHC interacting with the TCR:CD3-complex, built in a lipid environment. To describe the conformational behaviour associated with the unbound and the bound states, all atoms Molecular Dynamics simulations were performed for the TCR:CD3-complex and for two pMHC:TCR:CD3-complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of such a region in the propagation of the signal. Moreover, we found that the TCR reduces the flexibility of the MHC I binding groove, confirming our previous results.
High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria
Authors: Cao Huan , Antonopoulos Aristotelis , Henderson Sadie , Wassall Heather , Brewin John , Masson Alanna , Shepherd Jenna , Konieczny Gabriela , Patel Bhinal , Williams Maria-Louise , Davie Adam , Forrester Megan A , Hall Lindsay , Minter Beverley , Tampakis Dimitris , Moss Michael , Lennon Charlotte , Pickford Wendy , Erwig Lars , Robertson Beverley , Dell Anne , Brown Gordon D. , Wilson Heather M. , Rees David C. , Haslam Stuart M. , Rowe J. Alexandra , Barker Robert N. , Vickers Mark A. 
Published: November 2020

AbstractIn both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs withPlasmodium falciparumexpose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.
CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects
Authors: Villa Carlo Emanuele , Cheroni Cristina , López-Tóbon Alejandro , Dotter Christoph P. , Oliveira Bárbara , Sacco Roberto , Yahya Aysan Cerag , Morandell Jasmin , Gabriele Michele , Sommer Christoph , Gabitto Mariano , Testa Giuseppe , Novarino Gaia 
Published: November 2020

AbstractChromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance leads to a significant enlargement of cerebral organoids aligned to the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.
Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins
Authors: Ishida Mizuki , Maki Yuta , Ninomiya Akinori , Takada Yoko , Campeau Philippe , Kinoshita Taroh , Murakami Yoshiko 
Published: November 2020

AbstractGlycosylphosphatidylinositols (GPIs) are glycolipids that anchor many proteins (GPI-APs) on the cell surface. The core glycan of GPI precursor has three mannoses, which in mammals, are all modified by ethanolamine-phosphate (EthN-P). It is postulated that EthN-P on the third mannose (EthN-P-Man3) is the bridge between GPI to the protein and the second (EthN-P-Man2) is removed after GPI-protein attachment. However, EthN-P-Man2 may not be always transient, as mutations of PIGG, the enzyme that transfers EthN-P to Man2, result in inherited GPI deficiencies (IGDs), characterized by neuronal dysfunctions. Here, we show EthN-P on Man2 is the preferential bridge in some GPI-APs, among them, the ect-5’-nucleotidase and netrin G2. We found that CD59, a GPI-AP, is attached via EthN-P-Man2 both in PIGB-knockout cells, in which GPI lacks Man3 and with a small fraction, in wild type cells. Our findings modify the current view of GPI anchoring and provide mechanistic bases of IGDs caused by PIGG mutations.
Retinal glial cells under hypoxia possibly function in mammalian myopia by responding to mechanical stimuli, affecting hormone metabolism and peptide secretion
Authors: Zhang Xuhong , Wen Yingying , Jin Le , Zhang Dongyan , Zhang Liyue , Xie Chen , Guo Dongyu , Tong Jianping , Shen Ye 
Published: November 2020

AbstractPurposeChanges in the retina and the choroid blood vessels are regularly observed in myopia. The aim of this study is to test if the retinal glial cells, which directly contact blood vessels, play a role in mammalian myopia.MethodWe adapted the common form-deprivation myopia mouse model and used the retina slice and whole-mount immunofluorescence technique to evaluate changes in the morphology, and distribution of retinal glial cells. We then searched the Gene Expression Omnibus database for series on myopia and retinal glial cells (astrocytes and Müller cells). Using review articles and the National Center for Biotechnology Information gene database, we obtained clusters of myopia-related gene lists. By searching SwissTargetPrediction, we collected information on atropine target proteins. We then used online tools to find the Gene Ontology analysis enriched clusters, pathways, and proteins that provide correlative evidence.ResultGlial fibrillary acidic protein fluorescence was observed in mice eyes that were covered and deprived of light for five days compared to uncovered eyes, and the cell morphology became more star-like. From in silico experiments, we identified several pathways and proteins that were common to both myopia and retinal glial cells in hypoxic conditions. The common pathways in human astrocytes represented response to mechanical stimuli, peptide secretion, skeletal system development, and monosaccharide binding. In mouse Müller cells, the pathways represented membrane raft and extracellular structure organisation. The proteins common to myopia and hypoxic glial cells were highly relevant to atropine target proteins.ConclusionRetinal astrocytes and Müller cells under hypoxic conditions contribute to the development of myopia, and may be a valid target for atropine.
The FABRIC Cancer Portal: A Ranked Catalogue of Gene Selection in Tumors over the Human Coding Genome
Authors: Kelman Guy , Brandes Nadav , Linial Michal 
Published: November 2020

AbstractWe present The FABRIC Cancer Portal, a comprehensive catalogue of gene selection in cancer covering the entire human coding genome (~18,000 protein-coding genes) across 33 cancer types and pan-cancer. Genes in the portal are ranked according to the strength of evidence for selection in tumor, based on rigorous and robust statistics. Gene selection is quantified by combining genomic data with rich proteomic annotations. The portal includes a selected set of cross-references to the most relevant resources providing genomic, proteomic and cancer-related information. We showcase the portal with known and overlooked cancer genes, demonstrating the usefulness of the portal via its simple visual interface that allows to pivot between gene-centric and cancer-type views. The portal is available at fabric-cancer.huji.ac.il.
Bias invariant RNA-seq metadata annotation
Authors: Wartmann Hannes , Heins Sven , Kloiber Karin , Bonn Stefan 
Published: November 2020

AbstractRecent technological advances have resulted in an unprecedented increase in publicly available biomedical data, yet the reuse of the data is often precluded by experimental bias and a lack of annotation depth and consistency. Here we investigate RNA-seq metadata prediction based on gene expression values. We present a deep-learning based domain adaptation algorithm for the automatic annotation of RNA-seq metadata. We show how our algorithm outperforms existing approaches as well as traditional deep learning methods for the prediction of tissue, sample source, and patient sex information across several large data repositories. By using a model architecture similar to siamese networks the algorithm is able to learn biases from datasets with few samples. Our domain adaptation approach achieves metadata annotation accuracies up to 12.3% better than a previously published method. Lastly, we provide a list of more than 10,000 novel tissue and sex label annotations for 8,495 unique SRA samples.
Constraint-based metabolic control analysis for rational strain engineering
Authors: Tsouka Sophia , Ataman Meric , Hameri Tuure , Miskovic Ljubisa , Hatzimanikatis Vassily 
Published: November 2020

AbstractThe advancements in genome editing techniques over the past years have rekindled interest in rational metabolic engineering strategies. While Metabolic Control Analysis (MCA) is a well-established method for quantifying the effects of metabolic engineering interventions on flows in metabolic networks and metabolic concentrations, it fails to account for the physiological limitations of the cellular environment and metabolic engineering design constraints. We report here a constraint-based framework based on MCA, Network Response Analysis (NRA), for the rational genetic strain design that incorporates biologically relevant constraints, as well as genome editing restrictions. The NRA core constraints being similar to the ones of Flux Balance Analysis, allow it to be used for a wide range of optimization criteria and with various physiological constraints. We show how the parametrization and introduction of biological constraints enhance the NRA formulation compared to the classical MCA approach, and we demonstrate its features and its ability to generate multiple alternative optimal strategies given several user-defined boundaries and objectives. In summary, NRA is a sophisticated alternative to classical MCA for rational metabolic engineering that accommodates the incorporation of physiological data at metabolic flux, metabolite concentration, and enzyme expression levels.
Multimodal neuroimaging markers of variation in cognitive ability in older HIV+ men
Authors: Cruz Ana Lucia Fernandez , Chen Chien-Ming , Sanford Ryan , Collins D. Louis , Brouillette Marie-Josée , Mayo Nancy E. , Fellows Lesley K. 
Published: November 2020

AbstractObjectiveThis study used converging methods to define the structural and functional characteristics of the neural substrates underlying variation in cognitive ability in older men with well-controlled HIV infection.MethodsSeventy-six HIV+ men treated with combination antiretrovirals completed attention and inhibitory control tasks tapping different cortico-subcortical circuits while time-locked high-density EEG was acquired. Fifty-four also underwent structural MRI. We investigated relationships between task-evoked EEG responses, cognitive ability and immunocompromise. MRI suggested a subcortical basis for the observed EEG effects.ResultsEEG activity was associated with cognitive ability at later (P300) but not earlier processing stages of both tasks. However, only the P300 evoked by the attention task was associated with past HIV infection severity. Source localization confirmed that the tasks engaged different brain circuits. Thalamus volumes correlated with P300 amplitudes evoked by the attention task, while globus pallidus volumes were related to the P300 in both tasks.InterpretationThis is the first study to combine structural and functional imaging in an overlapping sample to address the neural circuits related to cognitive dysfunction in HIV. Neural substrates of attention were more affected than those supporting inhibitory control. Preliminary evidence suggests these differences may relate to vulnerability of the thalamus to the effects of HIV. Our results suggest high-yield tasks and circuit targets for future work.