bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common genetic variations in telomere length genes and lung cancer
Authors: Penha Ricardo Cortez Cardoso , Smith-Byrne Karl , Atkins Joshua R , Haycock Philip , Kar Siddhartha , Codd Veryan , Samani Nilesh J , Nelson Christopher P , Milojevic Maja , Gabriel Aurélie AG , Amos Christopher , Brennan Paul , Hung Rayjean J , Kachuri Linda , McKay James D 
Published: August 2022

AbstractBackgroundGenome-wide association studies (GWAS) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Recently, 108 novel genetic loci within genes involved in telomere biology and DNA repair have been linked to LTL in UK Biobank. In the current work, we investigated the relationship between genetically predicted LTL and lung cancer.MethodsTo explore the shared genetic basis between LTL and lung cancer, we performed genetic correlation, Mendelian Randomization (MR), and colocalisation analyses using the largest available GWASs of LTL (N=464,716) and lung cancer (29,239 cases; 56,450 controls). To further characterize the molecular mechanisms underlying this relationship, principal component analysis (PCA) was used to summarize gene expression profiles in lung adenocarcinoma tumours from The Cancer Genome Atlas.ResultsAlthough there was no genome-wide genetic correlation between LTL and lung cancer risk (rg=-0.01, p=0.88), MR analyses using 144 instruments identified a putatively causal association. Longer LTL conferred an increased risk of lung cancer (OR=1.62, 95%CI=1.44-1.83, p=9.9×10−15), lung cancer in never smokers (OR=2.02, 95%CI=1.45-2.83, p=3.78×10−05), and lung adenocarcinoma (OR=2.43, 95%CI=2.02-2.92, p=3.8×10−21). Of these 144 LTL genetic instruments, 12 showed evidence of colocalisation with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6 (rs2303262), PRPF6 (rs80150989), and POLI (rs2276182). A polygenic risk score for LTL was associated with the second principal component (PC2) of gene expression (Beta=0.17, p=1.0×10−3). The aspect of PC2 associated with longer LTL was also associated with being female (p=0.005), never smokers (p=0.04), and earlier tumour stage (p=0.002). PC2 was strongly associated with cell proliferation score (p=3.6×10−30) and genomic features related to genome stability, including copy number changes (p=1.6×10−5) and telomerase activity (p=1.3×10−5) in the multivariate regression analyses.ConclusionsThis study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.
Post-COVID syndrome prevalence and risk factors in children and adolescents: A population-based serological study
Authors: Dumont Roxane , Richard Viviane , Lorthe Elsa , Loizeau Andrea , Pennacchio Francesco , Zaballa María-Eugenia , Baysson Hélène , Nehme Mayssam , Perrin Anne , L’Huillier Arnaud G. , Kaiser Laurent , Barbe Rémy P. , Posfay-Barbe Klara M. , Stringhini Silvia , Guessous Idris 
Published: August 2022

AbstractObjectivesPost-COVID syndrome remain poorly studied in children and adolescents. In this study, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status.Study designWe used data from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), which included children (aged 6 months to 17 years) selected from random samples drawn from state registries or who had a household member participating in a COVID-19 seroprevalence study conducted by our group. Children were tested for anti-SARS-CoV-2 N antibodies. Parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID syndrome.ResultsFrom December 1st, 2021 to February 16th, 2022, 1034 children were included, among whom 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). After stratification by age group, the prevalence was higher among adolescents aged 12-17 years (ΔaPrev=8.3%, 95%CI: 3.5;13.5) than among younger children (0.0%, 95%CI: −5.2;5.2 among 6-11 years old and 4.2%; 95%CI: −4.4;13.3 among 0-5 years old). The most frequently declared persistent symptoms among seropositives were smell loss, trouble concentrating and abdominal pain. Older age, having a chronic condition and lower socioeconomic conditions were identified as risk factors.ConclusionA significant proportion of seropositive children, particularly adolescents, experienced persistent symptoms. While there is a need for further investigation, growing evidence of pediatric post-COVID syndrome urges early screening and primary care management.
Adherence to methotrexate and associated factors considering social desirability in patients with rheumatoid arthritis: a multicenter cross-sectional study
Authors: Yajima Nobuyuki , Kawaguchi Takashi , Takahashi Ryo , Nishiwaki Hiroki , Toyoshima Yoichi , Oh Koei , Odai Tsuyoshi , Kanai Takayuki , Morisky Donald E. , Yamaguchi Takuhiro , Kasama Tsuyoshi 
Published: August 2022

AbstractBackgroundAssessing medication adherence in rheumatoid arthritis (RA) is clinically significant as low adherence is associated with high disease activity. Self-reported medication adherence surveys have been shown to have problems with overestimation of adherence due to social desirability bias. However, no MTX adherence studies adjusted for social desirability have been conducted to date. This study aimed to evaluate adherence to MTX and perform an investigatory search for factors associated with MTX adherence including social desirability.MethodsThis cross-sectional multicenter study was conducted among adult RA patients consuming oral MTX for ≥3 months. We examined the distribution of MTX adherence, according to the eight-item Morisky Medication Adherence Scale (MMAS-8). Social desirability was using the Social Desirability Scale (SDS). Furthermore, an exploratory factor analysis involving social desirability was examined to identify factors associated with MTX adherence using linear regression analysis. To deal with missing values, we used multiple imputations with chained equations methods.ResultsA total of 165 RA patients were enrolled. The median age was 64 years, and 86.1% were women. Based on the MMAS-8, low, medium, and high adherences were noted in 12.1%, 60.0%, and 27.9% of participants, respectively. High social desirability (coefficient, 0.14; 95% confidence interval [CI], 0.05–0.23; p<0.05) and high age (coefficient per 10 years, 0.16; 95% CI, 0.01–0.03; p<0.05) were associated with high MTX adherence, whereas full-time work was negatively associated with high MTX adherence (coefficient, -0.50; 95% CI, -0.95–-0.05; p<0.05).ConclusionsA large proportion of patients with RA do not take MTX as prescribed. High social desirability, high educational level, and non-full-time work may be associated with high MTX adherence. Physicians should confirm MTX adherence before switching or adding disease-modifying anti-rheumatic drugs in cases of uncontrolled disease activity.
The necessity of pyloric drainage in esophagectomies: protocol of a meta-analysis and a systematic review of randomized controlled trials
Authors: Csontos Armand , Németh Dávid , Szakó Lajos , Berke Gergő , Lili Sindler Dóra , Hegyi Péter , Papp András 
Published: August 2022

AbstractBackgroundEsophageal carcinoma is the 8th most common malignant tumour in the world with more than 600 000 cases (3.1% of all), while being the 6th most common reason of tumour mortality, causing more than 500 000 deaths (5.5% of all) annually. The 1, 3 and 5 year-prevalence are 2.4%, 1.6% and 1.3% respectively. The question of this meta-analysis is whether pyloric drainage is preferable over the lack of pyloric drainage during elective esophagectomies in patients suffering from esophageal cancer, regarding mortality, anastomosis leakage, respiratory morbidity, vomiting, gastric emptying time.MethodsWe plan to identify randomized controlled trials to investigate the question by performing extensive search in multiple databases. Based on of predefined criteria, two independent authors will perform the steps of selection, after which appropriate statistical analysis will be performed to identify potential significant differences. Cochrane Risk of Bias Tool 2, and GRADE approach will be used to estimate the risk of bias and quality of results.Dissemination plansWe plan to distribute our results in peer-reviewed journal.
Cost-effectiveness of testing for Mycoplasma genitalium among men who have sex with men in Australia
Authors: Ong Jason J. , Lim Aaron G. , Bradshaw Catriona S. , Taylor-Robinson David , Unemo Magnus , Horner Patrick J. , Vickerman Peter , Zhang Lei 
Published: August 2022

ABSTRACTObjectivesMycoplasma genitalium (MG) disproportionately affects men who have sex with men (MSM). We determined the cost-effectiveness of testing strategies for MG using a healthcare provider perspective.MethodsWe used inputs from a dynamic transmission model of MG among MSM living in Australia in a decision tree model to evaluate the impact of four testing scenarios on MG incidence: 1) no one tested; 2) symptomatic MSM; 3) symptomatic and high-risk asymptomatic MSM; 4) all MSM. We calculated the incremental cost-effectiveness ratios (ICERs) using a willingness to pay threshold of $30,000 AUD per QALY gained. We explored the impact of adding an AMR tax (i.e. additional cost per antibiotic consumed) to identify the threshold whereby any testing for MG is no longer cost-effective.ResultsTesting only symptomatic MSM is the most cost-effective (ICER $3,677 per QALY gained) approach. Offering testing to all men is dominated (i.e. not recommended because of higher costs and lower QALYs gained compared to other strategies). When the AMR tax was above $150, any testing for MG was no longer cost-effective.ConclusionTesting only symptomatic MSM is the most cost-effective option even when the potential costs associated with AMR are accounted for (up to $150 additional cost per antibiotic consumed). For pathogens like MG where there are anticipated future costs related to AMR, we recommend models to test the impact of incorporating these costs as they can change the conclusions of cost-effectiveness studies.KEY MESSAGESWhat is already known on this topic - Mycoplasma genitalium (MG) is a sexually transmitted pathogen with rising antimicrobial resistance.What this study adds - This economic evaluation found that testing only symptomatic men who have sex with men (MSM) is the most cost-effective option. When the costs per antibiotic consumed is greater than $150, any testing for MG is no longer cost-effective.How this study might affect research, practice or policy - Among testing strategies for MSM, testing for MG should be restricted to symptomatic men only.
Experimental evaluation of environmental DNA detection of a rare fish in turbid water
Authors: Holmes Ann E. , Baerwald Melinda R. , Rodzen Jeff , Schreier Brian M. , Mahardja Brian , Finger Amanda J. 
Published: August 2022

AbstractEnvironmental DNA (eDNA) approaches enable sensitive detection of rare aquatic species. However, water conditions like turbidity can limit sensitivity, resulting in false negative detections. The dynamics of eDNA detection in turbid conditions are poorly understood, but can be better characterized through experimental work. In this study, 1-L field-collected water samples were spiked with tank-sourced eDNA from a rare, endangered estuarine fish at concentrations similar to eDNA samples collected from the natural environment. Samples using non-turbid water (5 NTU), turbid water (50 NTU), and prefiltered turbid water were filtered using four filter types (pore size range 0.45 μm-10 μm). Detection success using a species-specific Taqman qPCR assay was assessed as both eDNA copy number and detection/non-detection. Glass fiber filters (nominal pore size 1.6 μm) yielded the highest number of eDNA copies and detections in non-turbid water and the highest detection rate in turbid water when used without a prefilter. Detection was a more robust metric for evaluating species presence across turbidity conditions compared with eDNA copy number. Prefiltration improved detection rates for the other filters tested (polycarbonate and cartridge filters). Filter material and design appear to interact differently with the prefiltration step, and may be more important considerations than pore size for eDNA capture in turbid water. Interactions between eDNA particles, suspended particulate matter, and filters are important to consider for eDNA methods optimization and interpretation of rare species detections in turbid water.
Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon
Authors: Garcia-Pardo Javier , Bartolomé-Nafría Andrea , Chaves-Sanjuan Antonio , Gil-Garcia Marcos , Visentin Cristina , Bolognesi Martino , Ricagno Stefano , Ventura Salvador 
Published: August 2022

ABSTRACThnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing, with missense mutations causing limb-girdle muscular dystrophy-3 (LGMDD3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids, with the RNA binding domains building a solenoidal coat around them. The amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMDD3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs.
Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51
Authors: Mousa Muhammad G. , Vuppaladhadiam Lahari , Kelly Meredith O. , Pietka Terri , Ek Shelby , Shen Karen C. , Meyer Gretchen A. , Finck Brian N. , Brookheart Rita T. 
Published: August 2022

SUMMARYThe mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGF-β signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-β signaling and suggests this protease could be a target for therapeutic intervention in muscle.
Genomic epidemiology of the cholera outbreak in Yemen reveals the spread of a multi-drug resistance plasmid between diverse lineages of Vibrio cholerae
Authors: Lassalle Florent , Al-Shalali Salah , Al-Hakimi Mukhtar , Njamkepo Elisabeth , Bashir Ismail Mahat , Dorman Matthew J. , Rauzier Jean , Blackwell Grace A. , Taylor-Brown Alyce , Beale Mathew A. , Al-Somainy Ali Abdullah , Al-Mahbashi Anas , Almoayed Khaled , Aldawla Mohammed , Al-Harazi Abdulelah , Quilici Marie-Laure , Weill François-Xavier , Dhabaan Ghulam , Thomson Nicholas R. 
Published: August 2022

AbstractThe humanitarian crisis in Yemen led in 2016 to the biggest cholera outbreak documented in modern history, with more than 2.5 million suspected cases to date. In late 2018, epidemiological surveillance showed that V. cholerae isolated from cholera patients had turned multi-drug resistant (MDR). We generated genomes from 260 isolates sampled in Yemen between 2018 and 2019 to identify a possible shift in circulating genotypes. 84% of V. cholerae isolates were serogroup O1 belonging to the seventh pandemic El Tor (7PET) lineage, sublineage T13 – same as in 2016 and 2017 – while the remaining 16% of strains were non-toxigenic and belonged to divergent V. cholerae lineages, likely reflecting sporadic gut colonisation by endemic strains. Phylogenomic analysis reveals a succession of T13 clones, with 2019 dominated by a clone that carried an IncC-type plasmid harbouring an MDR pseudo-compound transposon (PCT). Identical copies of these mobile elements were found independently in several unrelated lineages, suggesting exchange and recombination between endemic and epidemic strains. Treatment of severe cholera patients with macrolides in Yemen from 2016 to early 2019 coincides with the emergence of the plasmid-carrying T13 clone. The unprecedented success of this genotype where an SXT-family integrative and conjugative element (SXT/ICE) and an IncC plasmid coinhabit show the stability of this MDR plasmid in the 7PET background, which may durably reduce options for epidemic cholera case management. We advocate a heightened genomic epidemiology surveillance of cholera to help control the spread of this highly-transmissible, MDR clone.
Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
Authors: DeBlasi Janine M. , Falzone Aimee , Caldwell Samantha , Prieto-Farigua Nicolas , Prigge Justin R. , Schmidt Edward E. , Chio Iok In Christine , Karreth Florian A. , DeNicola Gina M. 
Published: August 2022

ABSTRACTMutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic Nrf2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or Lkb1. When combined with KrasG12D/+, constitutive Nrf2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by Nrf2 deletion. Finally, NRF2 overexpression in KEAP1 mutant NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, our results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.SignificanceThis study reports murine lung cancer models harboring mutations in the Keap1/Nrf2 pathway and highlights the context-dependent and diverse roles of Nrf2 during lung tumor initiation and progression.
Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening
Authors: Sasi Vishnu M. , Ullrich Sven , Ton Jennifer , Fry Sarah E. , Johansen-Leete Jason , Payne Richard J. , Nitsche Christoph , Jackson Colin J. 
Published: August 2022

AbstractThe main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mpro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mpro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold, and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.Graphical Abstract
MND1 enables repair of two-ended DNA double-strand breaks
Authors: Koob Lisa , Friskes Anoek , van Bergen Louise , Feringa Femke M. , van den Broek Bram , Koeleman Emma S. , Schubert Michael , Blomen Vincent A. , Brummelkamp Thijn R. , Krenning Lenno , Medema René H. 
Published: August 2022

SummaryFaithful and timely repair of DNA double-strand breaks (DSBs) is fundamental for the maintenance of genomic integrity. Here, we demonstrate that the meiotic recombination co-factor MND1 facilitates the repair of DSBs in somatic cells. We show that MND1 localizes to DSBs, where it stimulates DNA repair through homologous recombination (HR). Importantly, MND1 is not involved in the response to replication-associated DSBs, implying that it is dispensable for HR-mediated repair of one-ended DSBs. Instead, we find that MND1 specifically plays a role in the response to two-ended DSBs that are induced by IR or various chemotherapeutic drugs, specifically in G2. MND1 localization to DSBs is dependent on resection of the DNA ends, and seemingly occurs through direct binding of MND1 to RAD51-coated ssDNA. Importantly, the lack of MND1-driven HR repair directly potentiates the toxicity of IR-induced damage, which could open new possibilities for therapeutic intervention, specifically in HR-proficient tumors.
Energy transfer in ubiquitous rhodopsin pumps with xanthophyll antennas
Authors: Chazan Ariel , Das Ishita , Fujiwara Takayoshi , Murakoshi Shunya , Shihoya Wataru , Rozenberg Andrey , Molina-Márquez Ana , Larom Shirley , Pushkarev Alina , Malakar Partha , Ruhman Sanford , Hasegawa Masumi , Tsukamoto Yuya , Ishizuka Tomohiro , Konno Masae , Nagata Takashi , Inoue Keiichi , Mizuno Yosuke , Katayama Kota , Abe-Yoshizumi Rei , Kandori Hideki , León Rosa M. , Yoshizawa Susumu , Sheves Mordechai , Nureki Osamu , Béjà Oded 
Published: August 2022

AbstractEnergy transfer from light-harvesting ketocarotenoids to light-driven proton pumps xanthorhodopsins has been previously demonstrated in two unique cases: an extreme halophilic bacterium1 and a terrestrial cyanobacterium2. Attempts to find carotenoids that bind and transfer energy to rhodopsin proton pumps from the abundant marine and freshwater photoheterotrophs have thus far failed3–5. Here, using functional metagenomics combined with chromophore extraction from the environment, we detected light energy transfer from the widespread hydroxylated carotenoids zeaxanthin and lutein to the retinal moiety of xanthorhodopsins and proteorhodopsins. The light-harvesting carotenoids transfer up to 42% of the harvested energy in the violet/blue-light range to the green-light absorbing retinal chromophore. Our data suggest that these antennas have a significant impact on rhodopsin phototrophy in the world’s lakes, seas and oceans.