bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised study of a new inline respiratory function monitor (Juno) to improve mask seal and delivered ventilation with neonatal manikins
Authors: Tracy Mark , Hinder Murray , Morakeas Stephanie , Lowe Krista , Priyadarshi Archana , Crott Matthew , Boustred Matthew , Culcer Mihaela 
Published: September 2023

ABSTRACTBackgroundRespiratory function monitors (RFM) have been used extensively in manikin and infant studies yet have not become the standard of training. We report the outcomes of a new portable, lightweight resuscitation monitor (Juno) designed to show mask leak and deflation tidal volume to assist in positive pressure ventilation (PPV) competency training using manikins.MethodsTwo leak-free manikins (Preterm and Term) were used. Participants provided positive pressure ventilation to manikins using two randomized devices self-inflating bag (SIB) and T-piece resuscitator (TPR) with Juno display initially blinded then unblinded in four 90-second paired sequences, aiming for adequate chest wall rise and target minimal mask leak with appropriate target delivered volume when using the monitor.Results49 experienced neonatal staff delivered 15,569 inflations to the term manikin and 14,580 inflations to the preterm. Comparing blinded to unblinded RFM display there were significant reductions in all groups in the number of inflations out of target range volumes (Preterm: SIB 22.6% to 6.6%, TPR: 7.1% to 4.2% and Term: SIB 54.8% to 37.8%, TPR 67.2 to 63.8%). The percentage of mask leak inflations >60% was reduced in Preterm: SIB 20.7% to 7.2%, TPR 23.4% to 7.4% and in Term: SIB 8.7% to 3.6%, TPR 23.5% to 6.2%).ConclusionsUsing the Juno monitor during simulated resuscitation significantly improved mask leak and delivered ventilation amongst otherwise experienced staff, using both preterm and term manikins. The Juno is a novel RFM that may assist in teaching and self-assessment of resuscitation technique.Key messagesWhat is already known on this topicMask leak is common, can be large in magnitude and produce ineffective ventilation.Excessive tidal volumes may injure vulnerable preterm lungs and brain.The optimum use of RFMs used in manikin training is not determined.What this study addsMask leaks in excess of 60 % significantly reduces delivered tidal volumes.Optimising mask seal reduces high leak inflations in manikin models.Optimising mask seal alone with TPR improves targeted volume delivery in manikin models.How this study might affect research, practice or policyInline RFM monitors with simple GUI can improve the delivery of resuscitation training at all levels of skill.Further research to guide policy how often to train to retain skills is needed.Further research will determine the effectiveness of this RFM as a tool for self-directed learning in rural or remote settings.
Pleiotropic Genetic Effects between Multiple Sclerosis and Musculoskeletal Traits
Authors: Jeong Sohyun , Tsai Ming-Ju , Shen Changbing , Hsu Yi-Hsiang 
Published: September 2023

AbstractBackgroundMusculoskeletal disorders were commonly reported in patients with multiple sclerosis. However, the underlying etiology linking Multiple Sclerosis (MS) and musculoskeletal disorders is not well studied. With large-scale Genome-Wide Association Studies (GWAS) publicly available, we conducted genetic correlation analysis to identify shared pleiotropic genetic effects between MS and musculoskeletal traits. We also conducted Mendelian Randomization (MR) to estimate the causal relation between MS and increased risks of musculoskeletal disorders.MethodsLinkage Disequilibrium Score Regression (LDSR) analysis was performed to estimate heritability and genetic correlation. Univariable, multivariable, and bidirectional MR analyses were conducted to estimate the causal relation. These analyses were done by utilizing the recent GWAS summary statistics of MS, fracture, frailty, falls, and several musculoskeletal risk factors, including bone mineral density, lean mass, grip strengths, and vitamin D.ResultsLDSR analysis showed a moderate genetic correlation of MS with falls (RG=0.10,p=0.01) but not with fracture and frailty. Genetic variants (rs13191659) inLINC00240gene which is associated with iron status biomarkers was found to be associated with both MS and falls. In MR analyses after excluding outlier SNPs with potential pleiotropic effects and correcting for multiple testing, MS presented no causal association with fracture and frailty but a minimal association with falls. Falls showed causally increased risks of fracture and frailty.ConclusionOur study suggests a potential genetic correlation with shared pleiotropic genetic effects between MS and falls. However, we didn’t find evidence to support the causal relation between MS and increased risks of falls, fracture, and frailty.
Transcriptomics and weighted protein network analysis of the LRRK2 protein interactome reveal distinct molecular signatures for sporadic and LRRK2 Parkinson’s Disease
Authors: Zhao Yibo , Bracher-Smith Matthew , Harvey Kirsten , Escott-Price Valentina , Lewis Patrick A , Manzoni Claudia 
Published: September 2023

AbstractMutations in the LRRK2 gene are the most common genetic cause for familial Parkinson’s Disease (LRRK2-PD) and an important risk factor for sporadic PD (sPD). Multiple clinical trials are ongoing to evaluate the benefits associated with the therapeutical reduction of LRRK2 kinase activity. In this study, we described the changes on transcriptomic profiles (whole blood mRNA levels) of LRRK2 protein interactors in the sPD and LRRK2-PD cases as compared to healthy controls with the aim of comparing the two PD conditions. We went on to model the protein-protein interaction (PPI) network around LRRK2, which was weighted to reflect the transcriptomic changes in the network based on the expression and co-expression levels. Our results showed that LRRK2 interactors present both similar but also different alterations in expression levels and co-expression behaviours in the sPD and LRRK2-PD cases. The similar changes result in decreased connectivity within a topological cluster of the LRRK2 PPI network associated with ribosomal functions and DNA/RNA metabolism in both the sPD and LRRK2-PD scenario; while the connectivity within the autophagy/mitophagy/neurotransmitter-transport related cluster was increased exclusively in the LRRK2-PD condition as compared to the healthy controls. These results suggest that, albeit being classified as the same disease based on clinical features, LRRK2-PD and sPD show some significant differences from a molecular perspective.
Nucleoporin-binding nanobodies that either track or inhibit nuclear pore complex assembly
Authors: Colom Mireia Solà , Fu Zhenglin , Güttler Thomas , Trakhanov Sergei , Srinivasan Vasundara , Gregor Kathrin , Pleiner Tino , Görlich Dirk 
Published: September 2023

AbstractNuclear pore complex (NPC) biogenesis is a still enigmatic example of protein self-assembly. We now introduce several cross-reacting anti-Nup nanobodies for imaging intact NPCs from frog to human. We further report a simplified assay that directly tracks postmitotic NPC assembly by added labeled anti-Nup nanobodies. In interphase, NPCs are inserted into a pre-existing nuclear envelope. This makes it difficult to monitor this process as newly-assembled NPCs must be distinguished from pre-existing ones. We solved this problem by insertingXenopusNPCs into human nuclear envelopes and using frog-specific anti-Nup nanobodies for detection. We also asked whether anti-nucleoporin (Nup) nanobodies could serve as NPC assembly inhibitors. A first generation, selected from immune libraries againstXenopusNups, comprised only bright stainers of intact NPCs but no inhibitors, perhaps because the immune response was biased towards non-conserved and, thus, functionally-irrelevant epitopes. To overcome this bias, we selected for crossreactivity betweenXenopusand human Nups and obtained anti-Nup93, Nup98, and Nup155 nanobodies that block Nup-Nup interfaces and arrest NPC assembly. We solved structures of nanobody-target complexes and identified roles for the Nup93-α-solenoid in recruiting Nup358 and the Nup214·88·62 complex, and for Nup155 and the Nup98 autoproteolytic domain in NPC-scaffold assembly. The latter suggests an assembly checkpoint linking pore formation to permeability barrier assembly.
Gastric emptying and nutrient absorption of pea protein products differing in heat treatment and texture: a randomizedin vivocrossover trial andin vitrodigestion study
Authors: Roelofs Julia J.M. , van Eijnatten Elise J.M. , Prathumars Patteela , de Jong Joris , Wehrens Ron , Esser Diederik , Janssen Anja E.M. , Smeets Paul A.M. 
Published: September 2023

AbstractBackgroundPea protein is an interesting alternative for animal-based proteins due to its good availability, low cost and relatively balanced amino acid (AA) profile. Its digestibility may be affected by heat treatment and food texture.ObjectivesTo studyin-vivoAA absorption kinetics and gastric behavior of pea protein products differing in heat treatment and texture and compare this within-vitrodigestion.DesignFourteen males participated in a randomized crossover trial. Iso-caloric and iso-volumetric treatments were a 420-mL heated drink, 420-mL unheated drink and 105-g heated gel (semi-solid) consumed with 315 mL water, all containing 20 g pea protein. Gastric MRI scans were made until 90 minutes post-prandial. Blood samples were collected at baseline and up to five hours. All treatments were tested with anin-vitrodigestion model (INFOGEST).ResultsHeat treatment did not alter AA absorption kinetics and gastric emptying. Time to maximum peak was delayed for the gel treatment (total AAs: 66.9 versus 48.0 min for both drinks, essential AAs: 75.4 versus 50.0 and 46.6 min for the drinks). For the gel treatment initial emptying was faster due to the rapid passage of water.In-vitro, the degree of hydrolysis was highest for the unheated drink in the gastric phase and for the gel treatment in the intestinal phase.ConclusionHeat treating pea protein products does not affect digestion. In contrast, texture of pea protein products can be altered to influence the rate of gastric emptying and AA absorption without affecting total AA absorption.
COST AND UTILIZATION TRENDS OF ENDOMYOCARDIAL BIOPSY IN HEART TRANSPLANT PATIENTS: A 4-YEAR CLAIMS DATA ANALYSIS
Authors: Vilalta Adrian 
Published: September 2023

ABSTRACTObjectiveThis study evaluated patterns of utilization, complications, and costs of endomyocardial biopsies (EMB) in heart transplant patients.MethodsThe IBM®Treatment Pathways®tool was used to analyze claims data selected from the IBM®’sMarketScan®de-identified, HIPAA-compliant dataset. Differences in EMB paid amounts and utilization patterns were assessed for commercial payers and Medicare for years 2016 to 2019. Type, frequency, and overall cost of complications of the EMB procedure in these patients were also evaluated.ResultsA total of 8,170 records (6,385 commercial payers and 1,785 Medicare) of heart transplant patients with evidence of EMB procedures performed between 2016 and 2019 were identified in the database. In 2019, the median paid amount for an outpatient EMB in a heart transplant patient was US $7,918 (commercial) and US $2,980 (Medicare). Heart transplant patients received between 4.6 and 6.8 (median; Medicare, commercial) EMBs the first year after the transplant. Approximately 25% of EMB procedures were associated with complications. In 2019 the total cost of EMB complications per patient was US $9,049.DiscussionAnalysis showed that the paid amount for the EMB procedure increased by almost 25% from 2016 to 2019 for commercial payers. Given the high frequency of complications after the EMB procedure and the associated cost of the complications it is estimated that the median paid amounts are closer to US $10,000 per patient per EMB. Given the number of EMBs provided, the associated risks, and the paid amount trends, non-invasive alternatives to EMB should be considered for the surveillance of heart transplant patients.
Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects
Authors: Wang Hui , Dombroski Beth A , Cheng Po-Liang , Tucci Albert , Si Ya-Qin , Farrell John J , Tzeng Jung-Ying , Leung Yuk Yee , Malamon John S ,   The Alzheimer’s Disease Sequencing Project, Wang Li-San , Vardarajan Badri N , Farrer Lindsay A , Schellenberg Gerard D , Lee Wan-Ping 
Published: September 2023

AbstractStructural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer’s disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05,P=0.03), particularly for singletons (OR=1.12,P=0.0002) and homozygous events (OR=1.10,P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs inABCA7,APP,PLCG2, andSORL1, were associated with AD (SKAT-OP=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R2=0.99) with rs143080277 (chr2:105749599) inNCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.Search TermsAlzheimer’s disease, Structural variation, Copy number variation
Trajectories and correlates of poor mental health in India over the course of the COVID-19 pandemic: a nation-wide survey
Authors: Nichols Emma , Petrosyan Sarah , Khobragade Pranali , Banerjee Joyita , Angrisani Marco , Dey Sharmistha , Bloom Prof David E. , Schaner Simone , Dey AB , Lee Jinkook 
Published: September 2023

AbstractIntroductionThe COVID-19 pandemic had large impacts on mental health; however, most existing evidence is focused on the initial lockdown period and high-income contexts. By assessing trajectories of mental health symptoms in India over two years, we aim to understand the effect of later time periods and pandemic characteristics on mental health in a lower-middle income context.MethodsWe used data from the Real-Time Insights of COVID-19 in India (RTI COVID-India) cohort study (N=3,662). We used covariate-adjusted linear regression models with generalized estimating equations to assess associations between mental health (PHQ-4 score) and pandemic periods as well as pandemic characteristics (COVID-19 cases and deaths, government stringency, self-reported financial impact, COVID-19 infection in the household) and explored effect modification by age, gender, and rural/urban residence.ResultsMental health symptoms dropped immediately following the lockdown period but rose again during the delta and omicron waves. Associations between mental health and later pandemic stages were stronger for adults 45 years of age and older (p<0.001). PHQ-4 scores were significantly and independently associated with all pandemic characteristics considered, including estimated COVID-19 deaths (PHQ-4 difference of 0.041 SD units; 95% Confidence Interval 0.030 - 0.053), government stringency index (0.060 SD units; 0.048 - 0.072), self-reported major financial impacts (0.45 SD units; 0.41-0.49), and COVID-19 infection in the household (0.11 SD units; 0.07-0.16).ConclusionWhile the lockdown period and associated financial stress had the largest mental health impacts on Indian adults, the effects of the pandemic on mental health persisted over time, especially among middle-age and older adults. Results highlight the importance of investments in mental health supports and services to address the consequences of cyclical waves of infections and disease burden due to COVID-19 or other emerging pandemics.
Expanded statistical analysis plan for legacy and long-term effects of aspirin in the ASPREE-XT observational follow-up study of participants in the ASPREE randomized trial
Authors: Wolfe Rory , Broder Jonathan , Chan Andrew , Murray Anne , Orchard Suzanne , Polekhina Galina , Ryan Joanne , Tonkin Andrew , Webb Katherine , Woods Robyn 
Published: September 2023

ABSTRACTThe ASPREE randomized controlled trial (2010-2017) of 19,114 community-dwelling older adults without cardiovascular disease and significant disability compared daily 100mg aspirin to placebo. A total of 16,317 (93%) of 17,546 surviving and non-withdrawn participants agreed to continue regular study follow-up visits in the post-trial phase, named ASPREE-XT (2017-2024). We present a statistical analysis plan to underpin three main papers to report aspirin effects through to the fourth post-trial ASPREE-XT study visit with focus areas of: (1) death, dementia, and disability, (2) CVD events and bleeding, and (3) cancer. The focus of the plan is to estimate long-term (entire timespan of RCT plus post-trial) and legacy (post-trial period only) effects of aspirin in the setting of primary prevention for older individuals. Preliminary insights to these effects are presented that are based on data that has been reported to the study’s observational study monitoring board however formal data lock is not expected until October 2023.
Leucine zipper-based sorting system enables generation of multi-functional CAR T cells
Authors: James Scott E. , Chen Sophia , Ng Brandon D. , Fischman Jacob S. , Jahn Lorenz , Boardman Alexander P. , Rajagopalan Adhithi , Elias Harold K. , Massa Alyssa , Manuele Dylan , Nichols Katherine B. , Lazrak Amina , Lee Nicole , Fei Teng , DeWolf Susan , Peled Jonathan U. , Vardhana Santosha A. , Klebanoff Christopher A. , van den Brink Marcel R. M. 
Published: September 2023

AbstractResistance to chimeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms including antigen-loss escape and tumor-induced immune suppression. Expression of multiple CARs may overcome multi-antigen-loss escape. Similarly, expression of switch receptors that convert inhibitory immune checkpoint signals into positive costimulatory signals may enhance CAR T cell activity in the tumor microenvironment. Engineering multiple features into one cell product, however, is limited by transgene packaging constraints of current vector systems. Here, we describe a leucine zipper-based cell sorting methodology that enables selective single-step immunomagnetic purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This “Zip-sorting” system facilitated generation of T cells simultaneously expressing up to four CARs and co-expressing up to three switch receptors. These multi-CAR multi-Switch receptor arrays enabled T cells to eliminate antigenically heterogeneous syngeneic leukemia populations co-expressing multiple inhibitory ligands. Zip-sorted multi-CAR multi-Switch receptor T cells represent a potent therapeutic strategy to overcome multiple mechanisms of CAR T cell resistance.
APP substrate ectodomain defines Aβ length by restraining γ-secretase processivity and facilitating product release
Authors: Koch Matthias , Enzlein Thomas , Chen Shu-Yu , Petit Dieter , Lismont Sam , Zacharias Martin , Hopf Carsten , Chávez-Gutiérrez Lucía 
Published: September 2023

AbstractSequential proteolysis of the amyloid precursor protein (APP) by γ-secretases (GSECs) generates amyloid-β (Aβ) and defines the proportion of short-to-long Aβ peptides, which is tightly connected to Alzheimer’s disease (AD) pathogenesis.Here, we study the mechanism controlling substrate processing by GSECs and defining product length. We found that polar interactions established by the APPC99ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of GSEC processive cleavage by destabilizing enzyme-substrate (E-S) interactions. We show that increasing hydrophobicity at APPC99-ECD – due to mutation or ligand binding – attenuates this substrate-driven product release mechanism, and rescues the effects that AD pathogenic variants exert on Aβ profiles. In addition, our study reveals that APPC99-ECD facilitates the paradoxical production of longer Aβs caused by some GSEC inhibitors that act as high-affinity competitors to the substrate.These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by GSEC and suggest it as a sweet spot for the potential design of APP targeting compounds selectively promoting its processing by GSEC.
CD81 represses NF-κB in HCV-expressing hepatoma cells
Authors: Bunz Maximilian , Eisele Mona , Hu Dan , Ritter Michael , Kammerloher Julia , Lampl Sandra , Schindler Michael 
Published: September 2023

AbstractThe tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV protein expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as aregulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might serve as viral mechanism to maintain persistent infection, ultimately causing chronic inflammation and HCC.HighlightsCD81 is downregulated and transcriptionally silenced upon HCV genome replicationLoss of CD81 is associated with increased cell growth and HCV expressionCD81 suppresses NF-κB signaling.CD81 interferes with p65 activation and nuclear translocation
No evidence for phylogenetic structure or environmental filtering of springtail microbiomes
Authors: Veres Róbert , Romahn Juliane , Schneider Clément , Bálint Miklós 
Published: September 2023

AbstractMicroorganisms play crucial roles in the lives of metazoans and can significantly impact host fitness. However, recent evidence suggests that many species may lack microorganisms that are positively associated with host fitness. Assessing the prevalence of host-specific microbiomes in animals has proven challenging due to limited studies in most higher taxa, with most investigations focusing on microbes in mammals, cephalopods, fish, and corals. This knowledge gap extends to springtails (Arthropoda: Collembola), which are widespread and abundant hexapods found in terrestrial and semi-aquatic habitats, contributing to important ecological functions. Here we investigated taxonomic bycatch in genome sequences generated from entire individuals of 70 springtail species. We aimed to understand whether microbial and other taxa associated with springtails are influenced by host phylogeny and environmental parameters. The analyses revealed high richness of bacteria and other taxa in the analyzed sequences, but detected no phylosymbiotic or environmental filtering signal in community composition. The findings suggest that springtails may be one of potentially many animal groups lacking distinct microbiomes. The study demonstrates how entire eukaryotic groups can be tested for phylosymbiotic patterns with taxonomic bycatch from genome sequences.