bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multidimensional Boolean Patterns in Multi-omics Data
Authors: Golovko George , Reyes Victor , Pinchuk Iryna , Fofanov Yuriy 
Published: January 2021

AbstractMotivationVirtually all biological systems are governed by a set of complex relations between their components. Identification of relations within biological systems involves a rigorous search for patterns among variables/parameters. Two-dimensional (involving two variables) patterns are identified using correlation, covariation, and mutual information approaches. However, these approaches are not suited to identify more complicated multidimensional relations, which simultaneously include 3, 4, and more variables.ResultsWe present a novel pattern-specific method to quantify the strength and estimate the statistical significance of multidimensional Boolean patterns in multiomics data. In contrast with dimensionality reduction and AI solutions, patterns identified by the proposed approach may provide a better background for meaningful mechanistic interpretation of the biological processes. Our preliminary analysis suggests that multidimensional patterns may dominate the landscape of multi-omics data, which is not surprising because complex interactions between components of biological systems are unlikely to be reduced to simple pairwise interactions.
Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis
Authors: Ting Christopher , Aspal Mohit , Vaishampayan Neil , Huang Steven K. , Riemondy Kent A. , Wang Fa , Farver Carol , Zemans Rachel L. 
Published: January 2021

AbstractARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.
DsbA-L protects against diabetic renal injury through the adipo-renal axis
Authors: Zeng Lingfeng , Yang Ming , Hu Chun , Zhao Li , Chen Xianghui , Wei Yaping , Lin Huapeng 
Published: January 2021

AbstractDisulfide-bond A oxidoreductase-like protein (DsbA-L) is an adiponectin-interacting protein that is highly expressed in adipose tissue. The adipo-renal axis involves adipocyte release of signaling molecules that are recruited to kidney and regulate kidney function. We have found that the DsbA-L modulated the progression of diabetic nephropathy, but the precise mechanism of this modulation is unknown. Here, the transgenic mice overexpressing DsbA-L protein in fat (fDsbA-L) were used to verify that the renoprotective role of DsbA-L whether by adipo-renal axis. Mice were divided into four groups: a normal (Control) group, STZ induced diabetic mice, fDsbA-L mice and diabetic fDsbA-L mice (n=6). Diabetes was induced in mice by STZ 100mg/kg and continued HFD feeding for 12 weeks. Compared with the control group, the weight, blood glucose,and urine protein levels and the pathological changes in the kidney tissue of diabetic mice were increased significantly, accompanied by increased NLRP3,caspase-1, IL-1β, IL-18, FN, and Collagen1 mRNA and protein expression, which were reduced in diabetic fDsbA-L mice. Interestingly, the level of adiponectin in serum and kidney expression in diabetic mice was reduced significantly compared to that in the control group. However this change was reversed in diabetic fDsbA-L mice. These data suggest that the overexpression of DsbA-L in the adipocytes of mice can protect against diabetic renal injury through anti-inflammatory mediators,and may be mediated by the adipo-renal axis.
GN1, Glucosamine Analog, attenuate the neuronal hyperactivity of c-fosgene in Adjuvant-Induced Arthritis in Rats
Authors: Jawed Huma , Shah Syed Uzair Ali , Awan Shahid I. , Anjum Shazia , Simjee Shabana U. 
Published: January 2021

ABSTRACTThe anti-inflammatory and anti-arthritic activity of GN1 (6-hydroxymethyl-3-(1-methylene-allylamino)-tetrahydro-pyran-2,4,5-triol), an analog of glucoseamine was investigated in the adjuvant induced arthritis (AIA) in rats. It was observed that the highly increased hind paw swelling was significantly reduced (p <0.001) with no noticeable retardation of body weight in the GN1 treated arthritic rats as compared to arthritic control rats. The histopathological analysis of isolated rat joints by scaling system classification of different stages appear in arthritic inflammatory lesion development, disclosed the suppressive effect in the inflammation processing in the GN1 treated animals. Different predictive markers such as TNF-α, nitric oxide IL-1β, peroxide and glutathione were also determined in the serum samples of the treated and non-treated arthritic rats in order to measure the intensity of inflammation. Our results show that GN-1 treatment in arthritic groups demonstrated marked reduction inc-fosexpression. Results also revealed that GN1 significantly reduces the peroxide production (p < 0.002) and both the pro-inflammatory cytokines TNF-α (p < 0.015) and IL-1β (p < 0.001) in the arthritic rats receiving this treatment. Although, nitric oxide formation was found to be less than the arthritic control, but this reduction was not significant. The level of glutathione was significantly increased in GN1 treated arthritic rats (p < 0.037). These observations suggest that GN1 may help in reducing the inflammation and have anti-arthritic properties.
Modelling tuberculosis drug resistance amplification rates in high-burden settings
Authors: Karmakar Malancha , Ragonnet Romain , Ascher David B. , Trauer James M. , Denholm Justin T. 
Published: January 2021

AbstractBackgroundAntimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used molecular understanding to develop a compartmental epidemiological model ofMycobacterium tuberculosis(Mtb) transmission.MethodsA four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministicMtbtransmission model was developed to explore the progression from DS-to MDR-TB. The model incorporated strain-specific fitness costs and was calibrated using data from national tuberculosis prevalence surveys and drug resistance surveys from Philippines and Viet Nam. Using an adaptive Metropolis algorithm, we estimated drug resistance amplification and transmission rates.ResultsThe posterior estimates for the proportion of isoniazid mono-resistant amplification among treatment failure was 0.75 (0.64 – 0.85) for Philippines and 0.55 (0.39 – 0.63) for Viet Nam. The proportion of rifampicin mono-resistant amplification among treatment failure was 0.05 (0.04 – 0.06) for Philippines and 0.011 (0.010 – 0.012) for Viet Nam. In Philippines, the estimated proportion of primary resistance resulting from transmission was 56% (42 – 68) for INH-R, 48% (34 – 62) for RIF-R and 42% (34 – 50) for MDR-TB. For Viet Nam, the estimated proportion of drug resistance due to transmission was 79% (70 – 86) for INH-R, 68% (58 – 75) for RIF-R and 50% (45 – 53) for MDR-TB.DiscussionRIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which also allow for early detection of INH-R.
Bayesian Variable Selection Utilizing Posterior Probability Credible Intervals
Authors: Du Mengtian , Andersen Stacy L. , Perls Thomas T. , Sebastiani Paola 
Published: January 2021

AbstractIn recent years, there has been growing interest in the problem of model selection in the Bayesian framework. Current approaches include methods based on computing model probabilities such as Stochastic Search Variable Selection (SSVS) and Bayesian LASSO and methods based on model choice criteria, such as the Deviance Information Criterion (DIC). Methods in the first group compute the posterior probabilities of models or model parameters often using a Markov Chain Monte Carlo (MCMC) technique, and select a subset of the variables based on a prespecified threshold on the posterior probability. However, these methods rely heavily on the prior choices of parameters and the results can be highly sensitive when priors are changed. DIC is a Bayesian generalization of the Akaike’s Information Criterion (AIC) that penalizes for large number of parameters, it has the advantage that can be used for selection of mixed effect models but tends to prefer overparameterized models. We propose a novel variable selection algorithm that utilizes the parameters credible intervals to select the variables to be kept in the model. We show in a simulation study and a real-world example that this algorithm on average performs better than DIC and produces more parsimonious models.
Aedes aegyptiAag-2 culture cells enter endoreplication process upon pathogen challenge
Authors: Domínguez-Benítez Christian , Serrato-Salas Javier , Condé Renaud , Lanz-Mendoza Humberto 
Published: January 2021

AbstractMetamorphic insects apparently rely on a finite number of cells after emergence to counterbalance either commensal and pathogen presence. For hematophagous insects, blood-feeding is a crucial step for offspring development, therefore enteric cells repairing molecular mechanisms consists in fine regulated pathways to counterattack biotic and abiotic insults. Nevertheless, recent research suggests that midgut cells are capable to adapt their immune responses to pathogen challenges. Recently,AnophelesandAedesmosquitoes have been observed to increase their DNA cell content upon encounter with parasites, bacteria and virus respectively. Genomic endoreplication is one of the most important processes in larval development for fast transcriptional activity and protein secretion.So, in this paper we explore the ability ofAedes aegyptiAag-2 culture cells to develop a likely endoreplication process to face pathogen presence. Aag-2 cells at 6 and 12 hours post-biotic insult enter a proliferation arrest and increases DNA content, these two phenomena recovers control levels at 24 h post-treatment. It requires more research data about the type of genomic regions that has been replicated in the process, and the concentration that antimicrobial molecules are released into culture media.
Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling
Authors: Ariosa-Morejon Yoanna , Santos Alberto , Fischer Roman , Davis Simon , Charles Philip , Thakker Rajesh , Wann Angus , Vincent Tonia L. 
Published: January 2021

AbstractCollagen-rich tissues have poor reparative capacity that is further impaired with age, predisposing to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, skin and plasma of mice across the life course. We report highly dynamic matrisome turnover in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed epigenetic modulation across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFb in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several of these pathways have been associated with age-related disease. Fewer changes were observed for skin and plasma. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.
Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
Authors: Dou Shuaijie , Li Guoxian , Li Ge , Hou Chunmei , Zheng Yang , Tang Lili , Gao Yang , Mo Rongliang , Li Yuxiang , Wang Renxi , Shen Beifen , Zhang Jun , Han Gencheng 
Published: January 2021

AbstractNuclear Factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering the stress granules (SGs) formation. However, the regulation of the NF90-SGs pathway remain largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SGs mediated antiviral immunity. Vesicular Stomatitis Virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages which in turn recruited the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiated a proteasome-dependent degradation of the NF90 via K48-linked ubiquitination at Lys297. Targeted inactivation of the Tim-3 enhances the NF90 downstream SGs formation by selectively increasing the phosphorylation of PKR and eIF2a, the expression of SGs markers G3BP1 and TIA-1, and protected mice from lethal VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.
De novoprotein fold families expand the designable ligand binding site space
Authors: Pan Xingjie , Kortemme Tanja 
Published: January 2021

AbstractA major challenge in designing proteinsde novoto bind user-defined ligands with high specificity and affinity is finding backbones structures that can accommodate a desired binding site geometry with high precision. Recent advances in methods to generate protein fold familiesde novohave expanded the space of accessible protein structures, but it is not clear to what extendde novoproteins with diverse geometries also expand the space of designable ligand binding functions. We constructed a library of 25,806 high-quality ligand binding sites and developed a fast protocol to place (“match”) these binding sites into both naturally occurring andde novoprotein families with two fold topologies: Rossman and NTF2. 5,896 and 7,475 binding sites could be matched to the Rossmann and NTF2 fold families, respectively.De novodesigned Rossman and NTF2 protein families can support 1,791 and 678 binding sites that cannot be matched to naturally existing structures with the same topologies, respectively. While the number of protein residues in ligand binding sites is the major determinant of matching success, ligand size and primary sequence separation of binding site residues also play important roles. The number of matched binding sites are power law functions of the number of members in a fold family. Our results suggest thatde novosampling of geometric variations on diverse fold topologies can significantly expand the space of designable ligand binding sites for a wealth of possible new protein functions.Author summaryDe novodesign of proteins that can bind to novel and highly diverse user-defined small molecule ligands could have broad biomedical and synthetic biology applications. Because ligand binding site geometries need to be accommodated by protein backbone scaffolds at high accuracy, the diversity of scaffolds is a major limitation for designing new ligand binding functions. Advances in computational protein structure design methods have significantly increased the number of accessible stable scaffold structures. Understanding how many new ligand binding sites can be accommodated by thede novoscaffolds is important for designing novel ligand binding proteins. To answer this question, we constructed a large library of ligand binding sites from the Protein Data Bank (PDB). We tested the number of ligand binding sites that can be accommodated byde novoscaffolds and naturally existing scaffolds with same fold topologies. The results showed thatde novoscaffolds significantly expanded the ligand binding space of their respective fold topologies. We also identified factors that affect difficulties of binding site accommodation, as well as the relationship between the number of scaffolds and the accessible ligand binding site space. We believe our findings will benefit future method development and applications of ligand binding protein design.
Multi-strain fermented milk promotes gut microbiota recovery after Helicobacter pylori therapy: a randomised, controlled trial
Authors: Guillemard Eric , Poirel Marion , Schäfer Florent , Quinquis Laurent , Rossoni Caroline , Keicher Christian , Wagner Frank , Szajewska Hania , Barbut Frédéric , Derrien Muriel , Malfertheiner Peter 
Published: January 2021

AbstractBACKGROUNDHelicobacter pylori (Hp) eradication therapy can alter gut microbiota, provoking gastro-intestinal (GI) symptoms that can be improved by probiotics. The effect on Hp patients of a Test fermented milk containing yogurt and three Lacticaseibacillus (L. paracasei CNCM I-1518, CNCM I-3689, L. rhamnosus CNCM I-3690) strains was assessed on antibiotic associated diarrhea (AAD) (primary aim), GI-symptoms, gut microbiota composition and metabolites. In this aim, a randomized, double-blind, controlled trial was performed in 136 adults under Hp-treatment (14-day amoxicillin, clarithromycin, pantoprazole), who consumed the Test or a Control product for 28 days. Feces were analysed for gut microbiota composition, short chain fatty acids (SCFA), calprotectin, and viability of ingested strains.RESULTSNo effect of Test product was observed on AAD occurrence or duration, rating scores or number of days of GI symptoms. Hp-treatment induced a significant alteration in bacterial and fungal composition, a decrease of bacterial count and alpha-diversity, an increase of Candida and of calprotectin, and a decrease of SCFA concentration. Following Hp treatment, in the Test as compared to Control group, intra-subject beta-diversity distance from baseline was lower (padj=0.02), Escherichia-Shigella (padj=0.0082) and Klebsiella (padj= 0.013) were significantly less abundant, and concentrations of major SCFA (p=0.035) and valerate (p = 0.045) were higher. Viable Lp and Lr strains from the Test product were mainly detected during product consumption in feces.CONCLUSIONSThe study showed that 14-day Hp triple therapy alters gut bacterial and fungal community, their metabolites and gut inflammatory markers. Consumption of a multi-strain fermented milk can induce faster recovery of the microbiota composition and SCFA production and limit the bloom of pathobionts. (ClinicalTrials.gov, NCT02900196; First Posted : September 14, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02900196).
Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray
Authors: Camerini David , Randall Arlo Z. , Trappl-Kimmons Krista , Oberai Amit , Hung Christopher , Edgar Joshua , Shandling Adam , Huynh Vu , Teng Andy A. , Hermanson Gary , Pablo Jozelyn V. , Stumpf Megan M. , Lester Sandra N. , Harcourt Jennifer , Tamin Azaibi , Rasheed Mohammed , Thornburg Natalie J. , Satheshkumar Panayampalli S. , Liang Xiaowu , Kennedy Richard B. , Yee Angela , Townsend Michael , Campo Joseph J. 
Published: January 2021

AbstractThe emergence and rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of varying lengths and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multi-coronavirus arrays to identify specific antibody reactivity. High level IgG, IgM and IgA reactivity to structural proteins S, M and N, as well as accessory proteins, of SARS-CoV-2 were observed that was specific to COVID-19 patients. Overlapping 100, 50 and 30 amino acid fragments of SARS-CoV-2 proteins identified antigenic regions. Numerous proteins of SARS-CoV, MERS-CoV and the endemic human coronaviruses, HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients.