bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Trial of Laparoscopic Nissen Versus Anterior 180 Degree Partial Fundoplication – Late Clinical Outcomes at 15 to 20 years
Authors: Rudolph-Stringer Victoria , Bright Tim , Irvine Tanya , Thompson Sarah K. , Devitt Peter G. , Game Philip A. , Jamieson Glyn G. , Watson David I. 
Published: November 2020

Objective:
To determine very late clinical outcomes at up to 20 years follow-up from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication.

Summary Background Data:
Nissen fundoplication for gastroesophageal reflux can be followed by troublesome side effects. To address this, partial fundoplications have been proposed. Previously reports from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication at up to 10 years follow-up showed good outcomes for both procedures.

Methods:
One hundred seven participants were randomized to Nissen versus anterior 180-degree partial fundoplication. Fifteen to 20 year follow-up data was available for 79 (41 Nissen, 38 anterior). Outcome was assessed using a standardized questionnaire with 0 to 10 analog scores and yes/no questions to determine reflux symptoms, side-effects, and satisfaction with surgery.

Results:
After anterior fundoplication heartburn (mean score 3.2 vs 1.4, P = .001) and proton pump inhibitor use (41.7% vs 17.1%, P = .023) were higher, offset by less dysphagia for solids (mean score 1.8 vs 3.3, P = .015), and better ability to belch (84.2% vs 65.9%, P = .030). Measures of overall outcome were similar for both groups (mean satisfaction score 8.4 vs 8.0, P = .444; 86.8% vs 90.2% satisfied with outcome). Six participants underwent revision after anterior fundoplication (Nissen conversion for reflux – 6), and 7 underwent revision after Nissen fundoplication (Nissen to partial fundoplication for dysphagia – 5; redo Nissen for reflux – 1; paraesophageal hernia –1).

Conclusions:
At 15 to 20 years follow-up Nissen and anterior 180-degree partial fundoplication achieved similar success, but with trade-offs between better reflux control versus more side-effects after Nissen fundoplication.
Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS
Authors: Nunns Geoffrey R. , Vigneshwar Navin , Kelher Marguerite R. , Stettler Gregory R. , Gera Lajos , Reisz Julie A. , D’Alessandro Angelo , Ryon Joshua , Hansen Kirk C. , Gamboni Fabia , Moore Ernest E. , Peltz Erik D. , Cohen Mitchell J. , Jones Kenneth L. , Sauaia Angela , Liang Xiayuan , Banerjee Anirban , Ghasabyan Arsen , Chandler James G. , Rodawig Sophia , Jones Carter , Eitel Andrew , Hom Patrick , Silliman Christopher C. 
Published: November 2020

Objectives:
Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients.

Methods:
Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS.

Results:
After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS (P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally.
Murine Cytomegalovirus–induced Complement-fixing Antibodies Deposit in Murine Renal Allografts During Acute Rejection
Authors: Saunders Ute , Li Mao , Boddeda Srinivasa R. , Maher Sonya , Ghere Jessica , Kaptsan Irina , Dhital Ravi , Velazquez Victoria , Guo Lingling , Chen Bo , Zeng Qiang , Schoeb Trenton R. , Cianciolo Rachel , Shimamura Masako 
Published: November 2020

Background.
Human cytomegalovirus (CMV) infection is associated with renal allograft dysfunction and loss, particularly in combination with acute rejection. Emerging literature suggests that non-HLA antibodies may contribute to antibody-mediated rejection, but pathogen-induced antibodies have not been investigated in this context. This study examines the presence of CMV-induced antibodies in murine CMV (MCMV)–infected renal allografts during acute rejection.

Methods.
Intragraft immunoglobulin G (IgG) and complement C3 immunostaining were compared among allogeneic MCMV D−/R−, D+/R−, and D+/R+ renal transplants. Intragraft antibody deposition was examined in B cell–deficient recipients treated with MCMV immune sera. Antibody binding and complement-dependent cytotoxicity (CDC) of D−/R− and D+/R+ sera against infected renal tubular epithelial cells (TECs) were measured in vitro. IgG immunostaining was performed in D+/R+ allografts and native kidneys and in D+/R− allografts treated with ganciclovir to inhibit viral replication.

Results.
D+/R− and D+/R+ transplants had more abundant IgG and C3 deposition compared with D−/R− recipients. Greater IgG deposition was associated with more severe allograft injury in B cell–deficient recipients treated with MCMV immune sera compared with nonimmune sera. D+/R+ sera induced greater CDC of infected TECs compared with D−/R− sera. Native kidneys had lower IgG deposition compared with allografts, despite similar organ viral loads. Ganciclovir-treated allografts had reduced IgG deposition compared with untreated allografts.

Conclusions.
In this murine model, complement-fixing antibodies can deposit into MCMV-infected renal allografts, are associated with allograft damage, and can induce CDC of MCMV-infected renal TECs. The allogeneic response and viral replication may also contribute to intragraft antibody deposition.
scDesign2: a transparent simulator that generates high-fidelity single-cell gene expression count data with gene correlations captured
Authors: Sun Tianyi , Song Dongyuan , Li Wei Vivian , Li Jingyi Jessica 
Published: November 2020

AbstractIn the burgeoning field of single-cell transcriptomics, a pressing challenge is to benchmark various experimental protocols and numerous computational methods in an unbiased manner. Although dozens of simulators have been developed for single-cell RNA-seq (scRNA-seq) data, they lack the capacity to simultaneously achieve all the three goals: preserving genes, capturing gene correlations, and generating any number of cells with varying sequencing depths. To fill in this gap, here we propose scDesign2, a transparent simulator that achieves all the three goals and generates high-fidelity synthetic data for multiple scRNA-seq protocols and other single-cell gene expression count-based technologies. Compared with existing simulators, scDesign2 is advantageous in its transparent use of probabilistic models and is unique in its ability to capture gene correlations via copula. We verify that scDesign2 generates more realistic synthetic data for four scRNA-seq protocols (10x Genomics, CEL-Seq2, Fluidigm C1, and Smart-Seq2) and two single-cell spatial transcriptomics protocols (MERFISH and pciSeq) than existing simulators do. Under two typical computational tasks, cell clustering and rare cell type detection, we demonstrate that scDesign2 provides informative guidance on deciding the optimal sequencing depth and cell number in single-cell RNA-seq experimental design, and that scDesign2 can effectively benchmark computational methods under varying sequencing depths and cell numbers. With these advantages, scDesign2 is a powerful tool for single-cell researchers to design experiments, develop computational methods, and choose appropriate methods for specific data analysis needs.
cancerAlign: Stratifying tumors by unsupervised alignment across cancer types
Authors: Gao Bowen , Luo Yunan , Ma Jianzhu , Wang Sheng 
Published: November 2020

ABSTRACTTumor stratification, which aims at clustering tumors into biologically meaningful subtypes, is the key step towards personalized treatment. Large-scale profiled cancer genomics data enables us to develop computational methods for tumor stratification. However, most of the existing approaches only considered tumors from an individual cancer type during clustering, leading to the overlook of common patterns across cancer types and the vulnerability to the noise within that cancer type. To address these challenges, we proposed cancerAlign to map tumors of the target cancer type into latent spaces of other source cancer types. These tumors were then clustered in each latent space rather than the original space in order to exploit shared patterns across cancer types. Due to the lack of aligned tumor samples across cancer types, cancerAlign used adversarial learning to learn the mapping at the population level. It then used consensus clustering to integrate cluster labels from different source cancer types. We evaluated cancerAlign on 7,134 tumors spanning 24 cancer types from TCGA and observed substantial improvement on tumor stratification and cancer gene prioritization. We further revealed the transferability across cancer types, which reflected the similarity among them based on the somatic mutation profile. cancerAlign is an unsupervised approach that provides deeper insights into the heterogeneous and rapidly accumulating somatic mutation profile and can be also applied to other genome-scale molecular information.Availabilityhttps://github.com/bowen-gao/cancerAlign
Genetic and environmental regulation of caudate nucleus transcriptome: insight into schizophrenia risk and the dopamine system
Authors: Benjamin Kynon JM , Feltrin Arthur S , Barbosa André Rocha , Jaffe Andrew E , Collado-Torres Leonardo , Burke Emily E , Shin Joo Heon , Ulrich William S , Deep-Soboslay Amy , Tao Ran ,   the BrainSeq Consortium, Hyde Thomas M , Kleinman Joel E , Erwin Jennifer A , Weinberger Daniel R , Paquola Apuã CM 
Published: November 2020

AbstractIncreased dopamine (DA) signaling in the striatum has been a cornerstone hypothesis about psychosis for over 50 years. Increased dopamine release results in psychotic symptoms, while D2 dopamine receptor (DRD2) antagonists are antipsychotic. Recent schizophrenia GWAS identified risk-associated common variants near the DRD2 gene, but the risk mechanism has been unclear. To gain novel insight into risk mechanisms underlying schizophrenia, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in postmortem caudate nucleus from a cohort of 444 individuals. Integrating expression quantitative trait loci (eQTL) analysis, transcriptome wide association study (TWAS), and differential expression analysis, we found many new genes associated with schizophrenia through genetic modulation of gene expression. Using a new approach based on deep neural networks, we construct caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. Interestingly, we found that genetic risk for schizophrenia is associated with decreased expression of the short isoform of DRD2, which encodes the presynaptic autoreceptor, and not with the long isoform, which encodes the postsynaptic receptor. This association suggests that decreased control of presynaptic DA release is a potential genetic mechanism of schizophrenia risk. Altogether, these analyses provide a new resource for the study of schizophrenia that can bring insight into risk mechanisms and potential novel therapeutic targets.
Multiple routes of functional diversification of the plant BAHD acyltransferase family revealed by comparative biochemical and genomic analyses
Authors: Kruse Lars H. , Weigle Austin T. , Irfan Mohammad , Martínez-Gómez Jesús , Chobirko Jason D. , Schaffer Jason E. , Bennett Alexandra A. , Specht Chelsea D. , Jez Joseph M. , Shukla Diwakar , Moghe Gaurav D. 
Published: November 2020

ABSTRACTLarge enzyme families catalyze metabolic diversification by virtue of their ability to use diverse chemical scaffolds. How enzyme families attain such functional diversity is not clear. Here, we addressed this question using BAHD acyltransferases as a model, and identified the routes by which duplication, promiscuity and sequence changes influenced BAHD diversification. This fast-evolving family expanded drastically during land plant evolution from 1-5 copies in algae to ∼100 copies in diploid angiosperm genomes.In vitrocharacterization of fourteen BAHDs against a substrate panel and compilation of >160 published activities revealed the wide prevalence of promiscuity among BAHDs. Using phylogenetic analysis, we predicted the substrate classes that the ancestral enzymes were likely capable of using prior to land plant origins. While the anthocyanin acylation activity was fixed in BAHDs later near the origin of angiosperms,in vitrotesting of BAHDs from non-seed plant lineages suggested that the ability to acylate anthocyanins likely existed promiscuously millions of years prior to its fixation. Motif enrichment analysis in anthocyanin-acylating BAHDs identified two motifs fixed in the largest anthocyanin acylating clade. Molecular dynamic simulations and enzyme kinetics revealed the important role of an active site tryptophan, whose bulkiness, hydrophobicity and aromaticity are critical for anthocyanin acylation. Our results thus describe the molecular processes in robust, evolvable enzymes that drive emergence of functional diversity in enzyme families.One sentence summaryUsing a combination of phylogenetics, biochemistry and protein structure analysis, we investigated how the BAHD acyltransferase family evolved to use a structurally diverse array of substrates.
scPretrain: Multi-task self-supervised learning for cell type classification
Authors: Zhang Ruiyi , Luo Yunan , Ma Jianzhu , Zhang Ming , Wang Sheng 
Published: November 2020

ABSTRACTRapidly generated scRNA-seq datasets enable us to understand cellular differences and the function of each individual cell at single-cell resolution. Cell type classification, which aims at characterizing and labeling groups of cells according to their gene expression, is one of the most important steps for single-cell analysis. To facilitate the manual curation process, supervised learning methods have been used to automatically classify cells. Most of the existing supervised learning approaches only utilize annotated cells in the training step while ignoring the more abundant unannotated cells. In this paper, we proposed scPretrain, a multi-task self-supervised learning approach that jointly considers annotated and unannotated cells for cell type classification. scPretrain consists of a pre-training step and a fine-tuning step. In the pre-training step, scPretrain uses a multi-task learning framework to train a feature extraction encoder based on each dataset’s pseudo-labels, where only unannotated cells are used. In the fine-tuning step, scPretrain fine-tunes this feature extraction encoder using the limited annotated cells in a new dataset. We evaluated scPretrain on 60 diverse datasets from different technologies, species and organs, and obtained a significant improvement on both cell type classification and cell clustering. Moreover, the representations obtained by scPretrain in the pre-training step also enhanced the performance of conventional classifiers such as random forest, logistic regression and support vector machines. scPretrain is able to effectively utilize the massive amount of unlabelled data and be applied to annotating increasingly generated scRNA-seq datasets.Availabilityhttps://github.com/ruiyi-zhang/scPretrain\
Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes
Authors: Muelbl Matthew J. , Glaeser Breanna , Shah Alok S. , Chiariello Rachel , Nawarawong Natalie N. , Stemper Brian D. , Budde Matthew D. , Olsen Christopher M. 
Published: November 2020

AbstractTraumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc), and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the BOLD response, and that interhemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional MRI measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.
A global overview of single-cell type selectivity and pleiotropy in complex diseases and traits
Authors: Xue Chao , Jiang Lin , Long Qihan , Chen Ying , Li Xiangyi , Li Miaoxin 
Published: November 2020

AbstractAfter centuries of genetic studies, one of the most fundamental questions, i.e. in what cell types do DNA mutations regulate a phenotype, remains unanswered for most complex phenotypes. The current availability of hundreds of genome-wide association studies (GWASs) and single-cell RNA sequencing (scRNA-seq) of millions of cells provides a unique opportunity to address the question. In the present study, we firstly constructed an association landscape between over 20,000 single cell clusters and 997 complex phenotypes by a cross annotation framework with scRNA-seq expression profiles and GWAS summary statistics. We then performed an extensive overview of cell-type specificity and pleiotropy in human phenotypes and found most phenotypes (>90%) were moderately selectively associated with a limited number of cell types while a small fraction cell types (<10%) had strong pleiotropy in multiple phenotypes (~100). Moreover, we identified three cell type-phenotype mutual pleiotropy blocks in the landscape. The application of the single cell type-phenotype cross annotation framework (named SPA) also explained the T cell biased lymphopenia and suggested important supporting genes in severe COVID-19 from human genetics angle. All the cell type-phenotype association results can be queried and visualized athttp://pmglab.top/spa.
BOSO: a novel feature selection algorithm for linear regression with high-dimensional data
Authors: Valcarcel Luis V. , San José-Enériz Edurne , Cendoya Xabier , Rubio Ángel , Agirre Xabier , Prósper Felipe , Planes Francisco J. 
Published: November 2020

AbstractMotivationWith the frenetic growth of high-dimensional datasets in different biomedical domains, there is an urgent need to develop predictive methods able to deal with this complexity. Feature selection is a relevant strategy in machine learning to address this challenge.ResultsWe introduce a novel feature selection algorithm for linear regression called BOSO (Bilevel Optimization Selector Operator). We conducted a benchmark of BOSO with key algorithms in the literature, finding a superior performance in highdimensional datasets. Proof-of-concept of BOSO for predicting drug sensitivity in cancer is presented. A detailed analysis is carried out for methotrexate, a well-studied drug targeting cancer metabolism.AvailabilityA Matlab implementation of BOSO is available as a Supplementary Material.Contactfplanes@tecnun.esSupplementary InformationSupplementary data are available at Bioinformatics online.
Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity
Authors: Murad John P. , Tilakawardane Dileshni , Park Anthony K. , Kennewick Kelly T. , Lopez Lupita S. , Lee Hee Jun , Gittins Brenna J. , Chang Wen-Chung , Tran Chau P. , Martinez Catalina , Wu Anna M. , Reiter Robert E. , Dorff Tanya B. , Forman Stephen J. , Priceman Saul J. 
Published: November 2020

AbstractChimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed anin vivorequirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.