bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction
Authors: Kanashiro-Takeuchi Rosemeire M. , Takeuchi Lauro M. , Dulce Raul A. , Kazmierczak Katarzyna , Balkan Wayne , Cai Renzhi , Sha Wei , Schally Andrew V. , Hare Joshua M. 
Published: September 2022

AbstractHeart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system, aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-week period. Control animals received no HFD+L-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.
Genome-wide association study of a semicontinuous trait: Illustration of the impact of the modeling strategy through the study of Neutrophil Extracellular Traps levels
Authors: Munsch Gaëlle , Proust Carole , Labrouche-Colomer Sylvie , Aïssi Dylan , Boland Anne , Morange Pierre-Emmanuel , Roche Anne , de Chaisemartin Luc , Harroche Annie , Olaso Robert , Deleuze Jean-François , James Chloé , Emmerich Joseph , Smadja David M , Jacqmin-Gadda Hélène , Trégouët David-Alexandre 
Published: September 2022

AbstractSemicontinuous data, characterized by an excess of zeros followed by a non-negative and right-skewed distribution, are frequently observed in biomedical research. Different statistical models have been proposed to investigate the association of covariates with such outcome. Motivated by the search of genetic factors associated with Neutrophil Extracellular Traps (NETs), a semicontinuous biomarker involved in thrombosis, we here investigated the impact of the selected model for semicontinuous traits in the context of a Genome Wide Association Study (GWAS). We compared three models that jointly model zero and positive values while allowing the estimation of a single association parameter of covariates with the global mean: Tobit, Negative Binomial and Compound Poisson-Gamma. We assessed the fit of these models to a sample of 657 participants of the FARIVE study measured for NETs plasma levels. For each of these three models, we performed a GWAS on NETs in FARIVE participants and results were compared. A simulation study was also conducted to evaluate the control of the type I error. Compound Poisson-Gamma and Negative Binomial models fitted NETs data observed in FARIVE better than the Tobit model. However, the Negative Binomial model suffered from an inflation of its type I error, attributable to extreme positive values of the NETs and low frequency variants. Conversely, the Compound Poisson-Gamma model was robust to both phenomena. Using the latter model, a GWAS identified a genome wide significant locus on chr21q21.3. The lead variant was rs57502213, a deletion of two nucleotides located ∼40kb upstream the non-coding RNA (miR155HG) hosting the miR-155 that was recently highlighted to have a role in NETs formation. This work indicates that the modeling strategy for a semicontinuous outcome in the framework of GWAS studies is crucial. The choice of the model should take into account the nature of the process generating zero values and the presence of extreme values. Our work also suggests that the Compound Poisson-Gamma model, while still marginally employed, can be a robust modeling strategy for GWAS analysis on a semicontinuous trait.
Is the Sars-CoV-2 virus a possible trigger agent for the development of achalasia?
Authors: Furuzawa-Carballeda Janette , Icaza-Chávez María Eugenia , Aguilar-León Diana , Uribe-Uribe Norma , del Carmen Nuñez-Pompa María , Trigos-Díaz Alonso , Areán-Sanz Rodrigo , Fernández-Camargo Dheni A. , Enrique Coss-Adame E , Valdovinos Miguel A. , Briceño-Souza Eduardo , Chi-Cervera Luis A. , Olivares-Flores Miriam , Torres-Villalobos Gonzalo 
Published: September 2022

BACKGROUNDPrevious studies have suggested that achalasia is an autoimmune disease whose probable causal agent is a neurotropic virus that chronically infects the myenteric plexus of the esophagus and, in a genetically susceptible host, induces the disease. The association between achalasia and coronaviruses has not been reported in the literature.AIMSTo evaluate the presence of the SARS-CoV-2 virus, the ACE2 expression, the tissue architecture, and immune response in the lower esophageal sphincter muscle (LESm) of achalasia patients who had SARS-CoV-2 (achalasia-COVID-19) infection before laparoscopic Heller myotomy (LHM) and compare the findings with type II achalasia patients and transplant donors (controls) without COVID-19.METHODSThe LESm of 7 achalasia-COVID-19 patients (diagnosed by PCR), ten achalasia patients, and ten controls without COVID-19 were included. The presence of the virus was evaluated byin situ PCRand immunohistochemistry. ACE2 receptor expression and effector CD4 T cell and regulatory subsets were determined by immunohistochemistry.RESULTSCoronavirus was detected in 6/7 patients-COVID-19. The SARS-CoV-2 was undetectable in the LESm of the achalasia patients and controls. The ACE2 receptor was expressed in all the patients and controls. One patient developed achalasia type II post-COVID-19. The percentage of Th22/Th17/Th1/pDCreg was higher in achalasia and achalasia-COVID-19 pre-HLM vs. controls. The Th2/Treg/Breg cell percentages were higher only in achalasia vs. controls.CONCLUSIONThe presence of the SARS-CoV2 and its receptor in the LESm of type II achalasia-COVID-19 patients but not in the controls suggests that it could affect the myenteric plexus. Unlike achalasia, patients-COVID-19 have an imbalance between effector CD4 T cells and the regulatory mechanisms.
Efficacy of electroacupuncture versus transcutaneous electrical acupoints stimulation on subclinical premature ovarian insufficiency: study protocol for a randomized controlled trial
Authors: Wang Jialing , Dai Linglin , Xu Yani , Zhang Xufen , Zhang Yutong , Tang Ding , Zhan Mingjie , Wang Chao , Wang Zhanglian , Chen Lifang 
Published: September 2022

ABSTRACTIntroduction“Subclinical stage” of premature ovarian insufficiency (POI) refers to menstrual disorders with FSH levels in the range of 15-25 U/L in women under 40 years old caused by diminished ovarian function. Early intervention of subclinical POI may be able to protect ovarian function more effectively and prevent further development to POI. Currently, no standard-of-care exists for subclinical POI. Previous studies have shown effectiveness of electroacupuncture (EA) on POI and transcutaneous electrical acupoint stimulation (TEAS) on diminished ovarian reserve, but no published studies focus on the treatment of subclinical POI. This study aims to assess whether EA or TEAS will be effective in improving ovarian function at the subclinical stage of POI and preventing the progression.Methods114 subclinical POI patients between 25 and 40 years will be randomly assigned to three groups (an EA group, a TEAS group and a waiting for treatment group) in this randomized, controlled, assessor-blinded trial. The treatment will last for three months and the follow-up will last for twelve months. The primary outcomes will be anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH). Secondary outcomes will include serum estradiol (E2), luteinizing hormone (LH), FSH/LH ratio, the menstrual status assessment, and modified Kupperman Menopausal Index. We will also investigate the incidence of adverse events.Trial registrationTrial was registered in the Chinese Clinical Trail Registry (ChiCTR-2100045598); Pre-results.
Therapeutic and Interventional Bronchoscopy Performed in Critically ill COVID-19 patients: A Systematic Review
Authors: Samadder Saikat 
Published: September 2022

AbstractBackgroundCoronavirus disease 2019 (COVID-19) is a highly infectious disease responsible for huge number of deaths in global population. Bronchoscopy was contraindicated for acute respiratory failure in critical patients due to possible transmission of virus to healthcare provider due to aerosol generating procedure (AGP). The safety, efficacy, complication rate, deaths, and transmission rate of virus to healthcare workers due to therapeutic and interventional bronchoscopy performed on COVID-19 patients are accessed.MethodsA systematic review of literature was performed as per PRISMA 2020 guidelines. To obtain literatures available in PubMed, MEDLINE, and Google Scholars with timeline from 1st Jan 2020 – 10th Dec 2021. Databases were searched with MeSH terms bronchoscopy and COVID-19 it fetched 7350 articles. Applying primary inclusion criteria of bronchoscopy in COVID-19 patients. Secondary inclusion criteria therapeutic and interventional bronchoscopy excluding the articles on diagnostic bronchoscopy.ResultTotal 72 clinically relevant literatures were identified and included for further review. 1887/2558 patients underwent bronchoscopy for treatment of severe or critical COVID-19 pneumonia. therapeutic bronchoscopy was performed in 1241/1887 (65.8%) patients and interventional bronchoscopy was performed in 831/1887 (44.03%) patients. Overall, complications observed in 200/1887 (10.5%) patients. Total, 579/1887 (30%) patients died as per the literatures. Total 15 HCW (8%) were found infected during the studies. It led to successful completion of procedures in 924/940 (98.3%) patients. All three types of bronchoscopes were found to be safe for the patients. The safety, efficacy, complication rate to be 97.5%, and 98.3%, and 2.5% respectively in severely SARS-CoV-2 infected patients undergoing bronchoscopy.ConclusionThis study suggests that bronchoscopy is a safe and effective procedure to be performed in patients suffering from COVID-19 pneumonia. Proper use of personal protective equipments (PPE) during bronchoscopic procedure reduced the risk of transmission of the virus from the patients to the healthcare provider.
Host genetic background is a barrier to broadly effective vaccine protection: Relevance to BCG andMycobacterium tuberculosisInfection
Authors: Lai Rocky , Gong Diana , Williams Travis , Ogunsola Abiola F. , Cavallo Kelly , Arlehamn Cecilia S. Lindestam , Acolatse Sarah , Beamer Gillian L. , Ferris Martin T. , Sassetti Christopher M. , Lauffenburger Douglas A. , Behar Samuel M. 
Published: September 2022

SummaryThe heterogeneity of immune responses observed in humans is difficult to model in standard inbred laboratory mice. To capture the diversity inherent in mice and better understand how host variation affects BCG-induced immunity againstMycobacterium tuberculosis, 24 unique Collaborative Cross (CC) recombinant inbred mouse strains and the C57BL/6 reference strain were vaccinated with or without BCG, and then challenged with low-dose aerosolized virulentM. tuberculosis. In contrast to standard lab strains, BCG protected only half of the CC strains tested. Furthermore, BCG efficacy is dissociable from inherent susceptibility to TB. As these strains differed primarily in the genes and alleles they inherited from the CC founder strains, we conclude that the host genetic background has a major influence on whether BCG confers protection againstM. tuberculosisinfection and indicates that host genetics should be considered as an important barrier to vaccine-mediated protection. Importantly, we wished to identify the components of the immune response stimulated by BCG, which were subsequently recalled after Mtb infection and associated with protection. The T cell immune response following BCG vaccination and Mtb challenge was extensively characterized. Although considerable diversity was observed, BCG vaccination had little impact on the composition of T cells recruited and maintained in the lung after infection. Instead, the variability was largely shaped by the genetic background. We developed models to detect vaccine-induced differences, which identified immune signatures associated with BCG-elicited protection against TB. Importantly, even when categorized as susceptible vs. resistant, and protected vs. unprotected, many of the protected CC strains had unique flavors of immunity, indicating multiple paths to protection. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
Eliminating Genes for a Two Component System Increases PHB Productivity in Cupriavidus basilensis 4G11 Under PHB Suppressing, Non-Stress Conditions
Authors: Sander Kyle , Abel Anthony J. , Friedline Skyler , Sharpless William , Skerker Jeffrey , Deutschbauer Adam , Clark Douglas S. , Arkin Adam P. 
Published: September 2022

AbstractSpecies of bacteria from the genus Cupriavidus are known, in part, for their ability to produce high amounts of poly-hydroxybutyrate (PHB) making them attractive candidate bioplastic producers. The native production of PHB occurs during periods of metabolic stress, and the process regulating the initiation of PHB accumulation in these organisms is not fully understood. Screening an RB-TnSeq transposon library of Cupriavidus basilensis 4G11 allowed us to identify two genes of an apparent, uncharacterized two component system which, when omitted from the genome, are capable of increased PHB productivity in balanced, non-stress growth conditions. We observe average increases in PHB productivity of 56% and 41% relative to the wildtype parent strain, upon deleting each of two genes individually from the genome. The increased PHB phenotype disappears, however, in nitrogen-free unbalanced growth conditions suggesting the phenotype is specific to fast-growing, replete, non-stress growth. Bioproduction modeling suggests this phenotype could be due to a decreased reliance on metabolic stress induced by nitrogen limitation to initiate PHB production in the mutant strains. Such strains may allow for the use of single stage, continuous bioreactor systems, which are far simpler than PHB bioproduction schemes used previously. Bioproductivity modeling suggests that omitting this regulation in the cells may increase PHB productivity up to 24% relative to the wildtype organism when using single stage continuous systems. This work furthermore expands our understanding of the regulation of PHB accumulation in Cupriavidus, in particular the initiation of this process upon transition into unbalanced growth regimes.
Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments
Authors: Gupta Akshita , Konnova Angelina , Smet Mathias , Berkell Matilda , Savoldi Alessia , Morra Matteo , Van averbeke Vincent , De Winter Fien , Peserico Denise , Danese Elisa , Hotterbeekx An , Righi Elda ,   mAb ORCHESTRA working group, De Nardo Pasquale , Tacconelli Evelina , Kumar Surbhi Malhotra , Singh Samir Kumar 
Published: September 2022

AbstractThe role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored. Here, we show that patients treated with various anti-SARS-CoV-2 mAb regimens develop evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Mutations develop more frequently in immunocompromised patients and strongly correlate not only with the neutralizing capacity of the therapeutic mAbs, but also with an anti-inflammatory and healing-promoting host milieu. Machine-learning models based on soluble host-derived biomarkers identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy. While our data demonstrate that host-driven immune and non-immune responses are essential for development of mutant SARS-CoV-2, these data could also support point-of-care decision making in reducing the risk of mAb treatment failure and improving mitigation strategies for possible dissemination of escape SARS-CoV-2 mutants.
The Long Noncoding RNA Playrr Regulates Pitx2 Dosage and Protects Against Cardiac Arrhythmias
Authors: Chen Frances L. , Oxford Eva M. , Chou Shao-Pei , Li Na , Leach John P. , Perry Sienna K. , Sanketi Bhargav D. , Cong Christina , Kupiec-Weglinski Sophie A. , Dubowitz Rebecca , Daugherity Erin , Martin James F. , Danko Charles G. , Kurpios Natasza A. 
Published: September 2022

AbstractRationaleThe most significantly associated atrial fibrillation (AF) risk loci in humans map to a noncoding gene desert upstream of the evolutionarily conserved left-right (LR) transcription factor Pitx2, a master regulator of LR asymmetric organ development. Pitx2 dosage is fundamentally linked to the development of sinus node dysfunction (SND) and AF, the most common cardiac arrhythmia affecting adults, but the mechanistic basis for this remains obscure. We identified a conserved long noncoding RNA (lncRNA), Playrr, which is exclusively transcribed on the embryo’s right side, opposite to Pitx2 on the left, that participates in mutually antagonistic transcriptional regulation with Pitx2.ObjectiveThe objective of this study was to investigate a role of Playrr in regulating Pitx2 transcription and protecting against the development of cardiac rhythm disturbances.Methods and ResultsPlayrr expression in the developing heart was analyzed with RNA in situ hybridization. Playrr was expressed asymmetrically (on the right) to Pitx2 (on the left) in developing mouse embryos, including in mouse embryonic sinoatrial node cells. We utilized CRISPR/Cas9 genome editing in mice to target Playrr, generating mice lacking Playrr RNA transcript (PlayrrEx1sj allele). Using qRT-PCR we detected upregulation of the cardiac isoform, Pitx2c, during visceral organ morphogenesis in PlayrrEx1sj mutant embryos. Surface ECG (AliveCor®) and 24-hour telemetry ECG detected bradycardia and irregular interbeat (R-R) intervals suggestive of SND in PlayrrEx1sj mutant adults. Programmed stimulation of PlayrrEx1sj mutant adults resulted in pacing-induced AF. Within the right atrium of PlayrrEx1sj mutant hearts, Masson’s trichrome stain revealed increased collagen deposition indicative of fibrosis, and immunofluorescence demonstrated mis-localization of Connexin 43 in atrial cardiomyocytes. These findings suggested an altered atrial substrate in PlayrrEx1sj adult mice. Finally, transcriptomic analysis by chromatin run-on and sequencing (ChRO-seq) in atria of PlayrrEx1sj mutant mice compared to wild type controls revealed differential expression of genes involved in cell-cell adhesion and motility, fibrosis, and dysregulation of the key cardiac genes Tbx5 and Hcn1.ConclusionsAdult mice lacking functional Playrr lncRNA transcript have baseline bradyarrhythmia and increased susceptibility to AF. These cardiac phenotypes are similar to those observed in Pitx2 heterozygous mice. Interactions between Pitx2 and Playrr may provide a genetic mechanism for modulating Pitx2 dosage and susceptibility to SND and AF.
Dispersal provides trophic-level dependent insurance against a heatwave in freshwater ecosystems
Authors: Vad Csaba F. , Hanny-Endrédi Anett , Kratina Pavel , Abonyi András , Mironova Ekaterina , Murray David S. , Samchyshyna Larysa , Tsakalakis Ioannis , Smeti Evangelia , Spatharis Sofie , Tan Hanrong , Preiler Christian , Petrusek Adam , Bengtsson Mia M. , Ptacnik Robert 
Published: September 2022

AbstractClimate change-related heatwaves are major recent threats to biodiversity and ecosystem functioning. However, our current understanding of the mechanisms governing community resilience (resistance and recovery) to extreme temperature events is still rudimentary. The spatial insurance hypothesis postulates that diverse regional species pools can buffer ecosystem functioning against local disturbances through immigration of better adapted taxa. However, experimental evidence for such predictions from multi-trophic communities and pulse-type disturbances, like heatwaves, are largely missing. We performed an experimental mesocosm study with alpine lake plankton to test whether a dispersal event from natural lakes prior to a simulated heatwave could increase resistance and recovery of local communities. As the buffering effect of dispersal may differ among trophic groups, we independently manipulated dispersal of organisms from lower (microorganisms) and higher (zooplankton) trophic levels. The experimental heatwave suppressed total community biomass by having a strong negative effect on zooplankton biomass, probably due to a heat-induced increase in metabolic costs that in turn caused mortality. Heating thus resulted in weaker top-down control and a subsequent shift to bottom-heavy food webs. While zooplankton dispersal did not alleviate the negative heatwave effects on zooplankton biomass, dispersal of microorganism enhanced biomass recovery at the level of phytoplankton, thereby providing evidence for spatial insurance. The different response of trophic groups may be related to the timing of dispersal, which happened under strongly monopolized resource conditions by zooplankton, creating limited opportunity for competitors to establish. At the same time, the heatwave released phytoplankton from grazing pressure and increased nutrient recycling, which may have facilitated the establishment of new phytoplankton taxa. Our findings clearly show that even a short heatwave can strongly alter energy flow in aquatic ecosystems. Although dispersal can enhance community resilience, the strength of its buffering effects depends on the trophic level.
ShIVA – A user-friendly and interactive interface giving biologists control over their single-cell RNA-seq data
Authors: Aussel Rudy , Asif Muhammad , Chenag Sabrina , Jaeger Sébastien , Milpied Pierre , Spinelli Lionel 
Published: September 2022

AbstractSingle-cell technologies have revolutionised biological research and applications. As they continue to evolve with multi-omics and spatial resolution, analysing single-cell datasets is becoming increasingly complex. For biologists lacking expert data analysis resources, the problem is even more crucial, even for the simplest single-cell transcriptomics datasets.We propose ShIVA, an interface for the analysis of single-cell RNA-seq and CITE-seq data specifically dedicated to biologists. Intuitive, iterative and documented by video tutorials, ShIVA allows biologists to follow a robust and reproducible analysis process, mostly based on the Seurat v4 R package, to fully explore and quantify their dataset, to produce useful figures and tables and to export their work to allow more complex analyses performed by experts.