bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of significant molecules and signaling pathways between 2D and 3D culture methods of renal cancer cells
Authors: Wang Mengyao , Guo Hongmei , Gu Hanming , Zhang Mason 
Published: February 2022

AbstractThe majority of cancer studies are conducted with the two-dimensional (2D) culture method, which does not reflect tumor in vivo structure. The 3D culture method can form free bundles of cancer cells and spheroid, which mimics the tumor microenvironment in vivo. However, the molecules and signaling pathways between the 2D and 3D culture methods are still unknown. In this study, we aim to identify the key molecules and signaling pathways by analyzing the RNA-seq data. The GSE190296 was created by the BGISEQ-500 (Homo sapiens). The KEGG and GO analyses indicated sulfur compound metabolic process and regulation of leukocyte mediated immunity are the major differences between 2D and 3D renal cancer cell cultures. Moreover, we figured out several interactive genes including MYC, EGF, VEGFA, STAT3, NOTCH1, CAT, CCND1, HSPA8, DLG4, and HSPA5. Our study may provide new knowledge on the differences between 2D and 3D cancer cell cultures.
AlphaFold2 and RoseTTAFold Predict Posttranslational modifications. Chromophore Formation in GFP-like Proteins
Authors: Hartley Sophia M. , Tiernan Kelly A. , Ametaj Gjina , Cretu Adriana , Zhuang Yan , Zimmer Marc 
Published: February 2022

AbstractAlphaFold2 and RoseTTAfold are able to predict, based solely on their sequence whether GFP-like proteins will post-translationally form a chromophore or not. Their training has not only taught them protein structure and folding, but also chemistry. The structures of 21 sequences of GFP-like fluorescent proteins that will post-translationally form a chromophore and of 23 GFP-like non-fluorescent proteins that do not have the residues required to form a chromophore were determined by AlphaFold2 and RoseTTAfold. The resultant structures were mined for a series of geometric measurements that are crucial to chromophore formation. Statistical analysis of these measurements showed that both programs conclusively distinguished between chromophore forming and non-chromophore forming proteins. A clear distinction between sequences capable of forming a chromophore and those that do not have the residues required for chromophore formation can be obtained by examining a single measurement - the RMSD of the overlap of the central alpha helices of the crystal structure of S65T GFP and the AlphaFold2 determined structure.
A high-quality genome assembly and annotation of the European earwig Forficula auricularia
Authors: Bhattarai Upendra R. , Katuwal Mandira , Poulin Robert , Gemmell Neil J. , Dowle Eddy 
Published: February 2022

AbstractThe European earwig Forficula auricularia is an important model for studies of maternal care, sexual selection, sociality and host-parasite interactions. However, detailed genetic investigations of this species are hindered by a lack of genomic resources. Here we present a high-quality hybrid genome assembly for F. auricularia. The genome was assembled using nanopore long-reads and 10x chromium link-reads. The final assembly is 1.06Gb in length with 31.03% GC content. It consists of 919 scaffolds with an N50 of 12.55Mb. Half of the genome is present in only 20 scaffolds. Benchmarking Universal Single-Copy Orthologs scores are ~90% from three sets of single-copy orthologs (eukaryotic, insect, and arthropod). The total repeat elements in the genome are 64.62%. The MAKER2 pipeline annotated 12,876 protein-coding genes and 21,031 mRNAs. A phylogenetic analysis revealed the isolate used in our genomic analysis belongs to Subspecies B, one of the two known genetic subspecies of F. auricularia. The genome assembly, annotation, and associated resources will be of high value to a large and diverse group of researchers working on Dermapterans.
ImmunoTyper-SR: A Novel Computational Approach for Genotyping Immunoglobulin Heavy Chain Variable Genes using Short Read Data
Authors: Ford Michael , Hari Ananth , Rodriguez Oscar , Xu Junyan , Lack Justin , Oguz Cihan , Zhang Yu , Weber Sarah , Magglioco Mary , Barnett Jason , Xirasagar Sandhya , Samuel Smilee , Imberti Luisa , Bonfanti Paolo , Biondi Andrea , Dalgard Clifton L. , Chanock Stephen , Rosen Lindsey , Holland Steven , Su Helen , Notarangelo Luigi ,   NIAID COVID Consortium, Vishkin Uzi , Watson Corey , Sahinalp S. Cenk 
Published: February 2022

AbstractHuman immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which, together with the joining genes (IGHJ), diversity genes (IGHD), constant genes (IGHC) and immunoglobulin light chains, code for antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype through the use of standard short read sequencing technologies. Here we introduce ImmunoTyper-SR, an algorithmic method for genotype and CNV analysis of the germline IGHV genes using Illumina whole genome sequencing (WGS) data. ImmunoTyper-SR is based on a novel combinatorial optimization formulation that aims to minimize the total edit distance between reads and their assigned IGHV alleles from a given database, with constraints on the number and distribution of reads across each called allele. We have validated ImmunoTyper-SR on 12 individuals with Illumina WGS data from the 1000 Genomes Project, whose IGHV allele composition have been studied extensively through the use of long read and targeted sequencing platforms, as well as nine individuals from the NIAID COVID Consortium who have been subjected to WGS twice. We have then applied ImmunoTyper-SR on 585 samples from the NIAID COVID Consortium to investigate associations between distinct IGHV alleles and anti-type I IFN autoantibodies which have been linked to COVID-19 severity.
Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome
Authors: Bitto Alessandro , Grillo Anthony S. , Stanaway Ian B. , Nguyen Bao M. G. , Ying Kejun , Tung Herman , Smith Kaleb , Tran Ngoc , Velikanje Gunnar , Urfer Silvan R. , Snyder Jessica M. , Kayser Ernst-Bernhard , Wang Lu , Smith Daniel L. , Thompson J. Will , DuBois Laura , DePaolo William , Kaeberlein Matt 
Published: February 2022

SummaryMitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological aging process. Rapamycin, a drug that increases lifespan and health during normative aging also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh Syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh Syndrome. Here we show that another drug that extends lifespan and delays normative aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.
Three models of vaccination strategies against cryptococcosis in immunocompromised hosts using heat-killedCryptococcus neoformansΔsgl1
Authors: Normile Tyler G. , Del Poeta Maurizio 
Published: February 2022

AbstractVaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuatedCryptococcus neoformansΔsgl1mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because liveC. neoformansΔsgl1-vaccinated mice challenged more than once with WT strain had a significant decrease in lung fungal burden, we testedC. neoformansΔsgl1as an immunotherapeutic. We found that therapeutic administrations of HKC. neoformansΔsgl1subsequent to WT challenge significantly improve the lung fungal burden. Similarly, therapeutic administration of HKC. neoformansΔsgl1post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK Δsgl1is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma usingC. neoformansΔgcs1. Remarkably, we show that administration of HK Δsgl1prevents mice from reactivating Δgcs1upon inducing immunosuppression with corticosteroids or by depleting CD4+T cells. Our results suggest that HK Δsgl1represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.ImportanceCryptococcosis results in ∼180,000 global deaths per year in immunocompromised individuals. Current antifungal treatment options are potentially toxic, lacking in areas of need, and exhibit limited efficacy. In addition to these lackluster therapeutic options, no fungal vaccines are currently available for clinical use. Due to the increasing rate of immunocompromised individuals, there is a dire need for the development of improved antifungal therapeutics. Presently, we have demonstrated the high efficacy of a clinically relevant heat-killed mutant strain ofCryptococcus neoformansin inducing advantageous host protection in three models of vaccination against cryptococcosis during immunodeficiencies most associated with this disease.
Robotic-Assisted Gait for lower-limb Rehabilitation: Evidence of Altered Neural Mechanisms in Stroke
Authors: Mayor-Torres Juan Manuel , O’Callaghan Ben , Korik Attila , Del Felice Alessandra , Coyle Damien , Murphy Sean , Lennon Olive 
Published: February 2022

AbstractRobotic-Assisted Gait training (RAGT) offers an innovative therapeutic option for restoration of functional gait in stroke survivors, complementing existing physical rehabilitation strategies. However, there is a limited understanding of the neurophysiological response induced by this training in end-users. Neural desynchronization and Cortico-Muscular Coherence (CMC) are two biomarkers that define the level of muscle-cortex association during gait phases and can be used to estimate induced user’s adaptation during RAGT. In this study, we measure Event-Related Spectral Perturbation (ERSP) and CMC from three healthy individuals and three stroke survivors during overground-gait with and without an exoskeleton. Results show that (1) the use of the exoskeleton in healthy individuals is associated with a different and more refined motor-control represented in a highθ-desynchronization, (2) altered and noisy ERSP and lower and non-focalβ-CMC patterns are observed in Stroke patients when performing overground-gait both with and without the Exoskeleton, and (3) Exoskeleton use in stroke survivors is associated with a reduction in swing-time during gait-cycle, but this effect is not correlated with an increment ofθ-desynchronization and/orβ-CMC. ERSP and CMC demonstrated evidence of neural modulation in able-bodied users during RAGT, which could not be detected in subacute stroke survivors during RAGT. These results suggest that the gait-parameters changes observed during exoskeleton use in subacute stroke survivors are unlikely to be neurally driven.
Diagnostic Utility of Exome Sequencing for Polycystic Kidney Disease
Authors: Chang Alexander R. , Moore Bryn , Luo Jonathan Z. , Sartori Gino , Fang Brian , Jacobs Steven , Abdalla Yoosif , Taher Mohammed ,   Regeneron Genetics Center, Carey David J. , Triffo William , Singh Gurmukteshwar , Mirshahi Tooraj 
Published: February 2022

AbstractImportanceMost studies of ADPKD genetics have used select cohorts, focusing onPKD1andPKD2and more recently several other cystic genes. However, the population prevalence of ADPKD and the contribution of each cystic gene to ADPKD are not well understood.ObjectiveDetermine the prevalence of ADPKD, contribution ofPKD1, PKD2, and other cystic genes to ADPKD in a large, unselected cohort.Design, Setting, and ParticipantsWe determined the prevalence of ADPKD In an unselected health system-based cohort of 173,954 subjects with the existing exome sequencing and extensive electronic health records, including abdominal imaging. The presence of genetic variants inPKD1, PKD2, and eleven other cystic genes was evaluated. Rare genetic variants were identified in patients with chart review confirmed diagnosis of ADPKD.Main OutcomesDiagnosis of ADPKD and presences of rare (AF<0.0001) missense, protein-truncating variants (PTVs), or copy number variants deletions (CNV) inPKD1, PKD2, or PTVs and CNVs in the following 11 genes:ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, LRP5, PKHD1, PRKCSH, SEC61B, andSEC63.ResultsAmong 173,954 patients, there were 235 patients with chart review confirmed ADPKD (0.135%). Among patients with PTV or CNV inPKD1, 66/70 (94.2%) had ADPKD and 43/44 (97.7%) of patients with PTV or CNV inPKD2had ADPKD. In contrast, only 24/77 (31.2%) patients with a PKD1 missense variant previously classified as “likely pathogenic” had ADPKD. A rare variant was identified in a cystic gene in 180/235 (76.6%) of ADPKD patients, with the most common genes implicatedPKD1(127) andPKD2(34) and thenIFT140(7),PKHD1(3),GANAB(4),HNF1B(2),ALG8(1),ALG9(1),IFT140+PKHD1(1). The yield for a genetic determinant of ADPKD was 91.3% among those with a family history compared to 50.6% among those without a family history (p<0.0001). We report several previously unreported variants where pedigree data suggest pathogenicity. Atypical cystic genesALG8, ALG9, GANAB, HNF1B, IFT140, andSEC63were associated with having any kidney or liver cystic ICD code, but not diagnosed ADPKD.ConclusionsExome sequencing established the molecular diagnosis for the vast majority of patients with ADPKD, revealed a wider range of ADPKD with atypical cystic genes. Additional population-based research cohorts are needed to carefully curate missensePKD1variants and variants in atypical cystic genes.
Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help
Authors: Kuehn Julia , Schleifenbaum Susanne , Hellige Antje , Park Carolin , Hinze Claas , Wittkowski Helmut , Holzinger Dirk , Foell Dirk , Kessel Christoph 
Published: February 2022

ObjectiveSystemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFNγ-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization.MethodsCells or sera were obtained from healthy controls (HC, n=26) and sJIA patients (n=61). Isolated naïve Th cells were cultured under Th1, Th17, and T follicular or T peripheral helper (Tf/ph) polarizing conditions and were partly co-cultured with allogenic memory B cells. Surface marker, transcription factor, and/or cytokine expression in peripheral or polarized Th cells or sera as well as B cellular plasma blast generation were studied by flow cytometry, multiplexed bead array assays, ELISA and retrospective RNA profiling analyses.ResultsSJIA naive Th cell differentiation towards Th1 resulted in low IFNγ and Eomesodermin expression. Instead, developing sJIA Th1 cells revealed elevated IL-21 release that negatively correlated with cellular IFNγ and Eomesodermin expression. Both In vitro and ex vivo, IL-21 together with PD-1, ICOS and CXCR5 expression indicated naïve sJIA Th cell differentiation to rather polarize towards a Tf/ph phenotype. Retrospective analysis of whole blood RNA sequencing data demonstrated sJIA-specific overexpression of Bcl-6 as respective master transcription factor. Compared to controls, in vitro generated sJIA Tf/ph cells promoted enhanced B cellular plasma-blast generation.ConclusionIn sJIA pathogenesis skewing of sJIA naïve Th cell differentiation towards a Tf/ph phenotype may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.
Predicting Respiratory Decompensation in Mechanically Ventilated Adult ICU Patients
Authors: Tan Yvette , Young Michael , Girish Akanksha , Hu Beini , Kurian Zina , Greenstein Joseph L , Kim Han , Winslow Raimond , Fackler James , Bergmann Jules 
Published: February 2022

ABSTRACTBackgroundMechanical ventilation is a life-saving treatment in the Intensive Care Unit (ICU), but often causes patients to be at risk of further respiratory complication. We created a statistical model utilizing electronic health record and physiologic vitals data to predict the Center for Disease Control and Prevention (CDC) defined Ventilator Associated Complications (VACs).MethodsWe constructed a random forest model to predict occurrence of VACs using health records and chart events from adult patients in the Medical Information Mart for Intensive Care III (MIMIC-III) database. We trained the machine learning models on two patient populations of 1921 and 464 based on low and high frequency data availability. Model features were generated using both basic statistical summaries and tsfresh, an automated python feature generation library. Classification to determine whether a patient will experience VAC one hour after 36 hours of ventilation was performed using a random forest classifier. Two different sample spaces conditioned on five varying feature extraction techniques were evaluated to identify the most optimal selection of features resulting in the best VAC discrimination. Each dataset was assessed using K-folds cross-validation (k = 10), giving average area under the receiver operating curves (AUROC) s and accuracies.FindingsAfter feature selection, hyperparameter tuning, and feature extraction, the best performing model used automatically generated features on high frequency data and achieved an average Area Under Receiver Operating Characteristic Curve (AUC) of 0·83 ± 0·11 and an average accuracy of 0·69 ± 0·10.InterpretationWe constructed a promising model to predict VACs 1 hour prior to occurrence with 36 hours of ICU patient data. The model provides early warnings of VACs, which may allow actionable therapies to prevent or mitigate ventilator associated complications.FundingN/A
Neutrophil Extracellular Trap Biomarker Titers and Delayed Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage
Authors: Witsch Jens , Spalart Valérie , Martinod Kimberly , Schneider Hauke , Oertel Joachim , Geisel Jürgen , Hendrix Philipp , Hemmer Sina 
Published: February 2022

BackgroundMyeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps, have been associated with arterial and venous thrombosis. Their role in patients with aneurysmal subarachnoid hemorrhage (aSAH) is unknown. Here, we sought to explore whether serum MPO-DNA-complexes are present in patients with aSAH, and whether these levels are associated with delayed cerebral ischemia (DCI).MethodsWe performed a post-hoc analysis of a prospective, blinded, observational single-center biomarker study that enrolled consecutive patients with spontaneous SAH between July 2018 and September 2020. Serum samples obtained on admission and on hospital day 4 were analyzed for concentrations of MPO-DNA complexes. The primary outcome was the occurrence of DCI defined as new infarction on brain CT-scan. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial doppler parameters. We used Wilcoxon’s signed-rank-test to assess for differences between paired measures.ResultsAmong 100 patients with spontaneous SAH, mean age 59 (SD+13) years, 55% women, 78 patients had an aneurysmal SAH and complete DCI information. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/ml (IQR, 18-43 ng/ml) on admission, and 22 ng/ml (IQR, 11-31 ng/ml) on day 4 (Mann-Whitney test: p=0.015). In the primary outcome analysis, we found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test, p=0.036) but not in those without DCI (p=0.171). The secondary analysis showed a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p=0.006), but not in those without clinical vasospasm (p=0.473).ConclusionsMPO-DNA-complexes are detectable in peripheral serum samples of patients with aSAH. A pronounced reduction in MPO-DNA levels over the first days after aSAH might herald DCI. The potential of MPO-DNA levels to serve as a biomarker of DCI requires further exploration.
Integrated genomic and histopathological analysis of low grade serous ovarian carcinoma identifies clinically distinct disease subtypes
Authors: Thomson John P , Hollis Robert L , van Baal Juliette , Ilenkovan Narthana , Churchman Michael , van de Vijver Koen , Dijk Frederike , Meynert Alison M , Bartos Clare , Rye Tzyvia , Croy Ian , Diana Patricia , van Gent Mignon , Creedon Helen , Nirsimloo Rachel , Nussey Fiona , Lok Christianne , Herrington C. Simon , Gourley Charlie 
Published: February 2022

AbstractBackgroundLow-grade serous ovarian carcinoma (LGSOC) is a distinct, under-investigated and relatively chemotherapy-resistant ovarian cancer type. Understanding the molecular landscape is crucial to maximise the impact of molecularly-targeted therapy.MethodsWhole exome sequencing and copy number data were integrated with histopathological patterns, ER/PR expression, and detailed clinical annotation, including survival, in a carefully curated LGSOC cohort.Results63 tumours were analysed in the largest comprehensive genomic LGSOC study to date. Three genomic subgroups were identified: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated mutation (27%, 14 MAPK-associated genes) and MAPK wild-type (MAPKwt: 21%). MAPKwt patients were younger at diagnosis (median 47 versus 62 years in the cMAPKm subgroup) and demonstrated shorter survival [multivariable HR (mHR) 4.17]. The inferior survival in the MAPKwt subgroup was due to shorter post-relapse survival (mHR 5.22) rather than shorter time to first progression (mHR 1.15). Patients in the MAPK-associated mutation subgroup had similar survival to cMAPKm cases. The cMAPKm subgroup more frequently demonstrated macropapillary invasion. Desmoplasia and micropapillary invasion were independently associated with poor survival. NOTCH pathway activation occurred independently of MAPK subgroup.ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical, molecular and histopathological features. True MAPKwt cases represent around a fifth of patients: they are younger but have poorer survival. New therapeutic strategies with activity in this subgroup are urgently required. NOTCH inhibitors represent a therapeutic strategy worthy of exploration.