bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics
Authors: Darrous Liza , Mounier Ninon , Kutalik Zoltán 
Published: January 2020

AbstractMendelian Randomisation (MR), an increasingly popular method that estimates the causal effects of risk factors on complex human traits, has seen several extensions that relax its basic assumptions. However, most of these extensions suffer from two major limitations; their under-exploitation of genome-wide markers, and sensitivity to the presence of a heritable confounder of the exposure-outcome relationship. To overcome these limitations, we propose a Latent Heritable Confounder MR (LHC-MR) method applicable to association summary statistics, which estimates bi-directional causal effects, direct heritabilities, and confounder effects while accounting for sample overlap. We demonstrate that LHC-MR out-performs several existing MR methods in a wide range of simulation settings and apply it to summary statistics of 13 complex traits. Besides several concordant results, LHC-MR unravelled new mechanisms (how being diagnosed for certain diseases might lead to improved lifestyle) and revealed new causal effects (e.g. HDL cholesterol being protective against high systolic blood pressure), hidden from standard MR methods due to a heritable confounder of opposite direction. Phenome-wide MR search suggested that the confounders indicated by LHC-MR for the birth weight-diabetes pair are likely to be obesity traits. Finally, LHC-MR results indicated that genetic correlations are predominantly driven by bi-directional causal effects and much less so by heritable confounders.
Trends in hepatitis C virus seroprevalence and associated risk factors among men who have sex with men in Montréal: results from three cross-sectional studies (2005, 2009, 2018)
Authors: Delaunay Charlotte Laniece , Cox Joseph , Klein Marina B. , Lambert Gilles , Grace Daniel , Lachowsky Nathan , Maheu-Giroux Mathieu 
Published: January 2020

AbstractIntroductionTo eliminate the hepatitis C virus (HCV) by 2030, Canada must adopt a micro-elimination approach targeting priority populations, including gay, bisexual, and other men who have sex with men (MSM). HCV prevalence and risk factors among MSM populations are context-dependent, and accurately describing these indicators at the local level is essential if we want to design appropriate, targeted prevention and treatment interventions. We aimed first to estimate and investigate temporal trends in HCV seroprevalence between 2005-2018 among Montréal MSM, and then to identify the socio-economic, behavioural, and biological factors associated with HCV exposure among this population.MethodsWe used data from three bio-behavioural cross-sectional surveys conducted among Montréal MSM in 2005 (n=1,795), 2009 (n=1,258), and 2018 (n=1,086). To ensure comparability of seroprevalence estimates across time, we standardized the 2005 and 2009 time-location samples to the 2018 respondent-driven sample. Time trends overall and stratified by HIV status, history of injection drug use (IDU), and age were examined. Modified Poisson regression analyses with generalized estimating equations were used to identify factors associated with HCV seropositivity pooling all surveys. We used multiple imputation by chained equations for all missing values.ResultsStandardized HCV seroprevalence among all MSM remained stable from 7% (95% confidence interval (CI): 3-10%) in 2005, to 8% (95%CI: 1-9%) in 2009, and 8% (95%CI: 4-11%) in 2018. This apparent stability hides diverging temporal trends in seroprevalence between age groups, with a decrease among MSM <30 years old, and an increase among MSM aged ≥45 years. History of IDU was the strongest predictor for HCV seropositivity (adjusted prevalence ratio: 8.0; 95%CI: 5.5-11.5), and no association was found between HCV seroprevalence and the sexual risk factors studied (condomless anal sex with men of serodiscordant/unknown HIV status, number of sexual partners, and group sex), nor with biological markers of syphilis.ConclusionsHCV seroprevalence remained stable among Montréal MSM between 2005-2018. Unlike other settings where HCV infection was strongly associated with sexual risk factors among MSM subgroups, IDU was the preeminent risk factor for HCV seropositivity. Understanding the intersection of IDU contexts, practices, and populations is essential to prevent HCV transmission among MSM.
A Pilot Study of an Esophageal Cooling Device During Radiofrequency Ablation for Atrial Fibrillation
Authors: Clark Brad , Alvi Nazia , Hanks Joseph , Suprenant Brad 
Published: January 2020

AbstractBackgroundEsophageal thermal injury is a risk of ablation of the posterior left atrium despite various devices utilized to date.ObjectiveEvaluate the potential of a commercially-available esophageal cooling device to provide esophageal protection during left atrial catheter ablation.MethodsIn this pilot study, we randomized 6 patients undergoing catheter ablation for atrial fibrillation. Three patients received standard of care for our site (use of a single-sensor temperature probe, with adjunct iced-water instillation for any temperature increases >1°C). Three patients received standard ablation after placement of the esophageal cooling device using a circulating water temperature of 4°C. All patients underwent transesophageal echocardiogram (TEE) and esophagogastroduodenoscopy (EGD) on the day prior to ablation followed by EGD on the day after.ResultsIn the 3 control patients, one had no evidence of esophageal mucosal damage, one had diffuse sloughing of the esophageal mucosa and multiple ulcerations, and one had a superficial ulcer with large clot. Both patients with lesions were classified as Zargar 2a. In the 3 patients treated with the cooling device, one had no evidence of esophageal mucosal damage, one had esophageal erythema (Zargar 1), and one had a solitary Zargar 2a lesion. At 3-month follow-up, 1 patient in each group had recurrence of atrial fibrillation.ConclusionsThe extent of esophageal injury was less severe with a commercially available esophageal cooling device than with reactive instillation of ice-cold water. This pilot study supports further evaluation with a larger clinical trial.
Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3
Authors: Phoo Wint Wint , Sahili Abbas El , Zhang ZhenZhen , Chen Ming Wei , Liew Chong Wai , Lescar Julien , Vasudevan Subhash G. , Luo Dahai 
Published: January 2020

AbstractFlavivirus is a genus of emerging and re-emerging arboviruses which include many significant human pathogens. Non-structural protein 3 (NS3), a multifunctional protein with N-terminal protease and C-terminal helicase, is essential in viral replication. The NS3 protease together with NS2B cofactor is an attractive antiviral target. A construct with an artificial glycine linker connecting the NS2B cofactor and NS3 protease has been used for structural, biochemical and drug-screening studies. The effect of this linker on dynamics and enzymatic activity of the protease was studied by several biochemical and NMR methods but the findings remained inconclusive. Here, we designed constructs of NS2B cofactor joined to full length DENV4 NS3 in three different manners, namelybNS2B47NS3 (bivalent),eNS2B47NS3(enzymatically cleavable) andgNS2B47NS3 (glycine-rich G4SG4 linker). We report the first crystal structures of linked and unlinked full-length NS2B-NS3 enzyme in its free state and also in complex with Bovine Pancreatic Trypsin Inhibitor (BPTI). These structures demonstrate that the NS2B-NS3 protease mainly adopts a closed conformation. BPTI binding is not essential to but favors the closed conformation by interacting with both NS2B and NS3. The artificial linker between NS2B and NS3 tends to induce the open conformation and interfere with the protease activity. This negative impact on the enzyme structure and function is restricted to the protease domain as the ATPase activities of these constructs are not affected.
Experience-dependent modulation of the visual evoked potential: testing effect sizes, retention over time, and associations with age in 415 healthy individuals
Authors: Valstad Mathias , Moberget Torgeir , Roelfs Daniël , Slapø Nora B. , Timpe Clara M.F. , Beck Dani , Richard Geneviève , Sofie Sæther Linn , Haatveit Beathe , Andre Skaug Knut , Egil Nordvik Jan , Hatlestad-Hall Christoffer , Einevoll Gaute T. , Mäki-Marttunen Tuomo , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Elvsåshagen Torbjørn 
Published: January 2020

AbstractExperience-dependent modulation of the visual evoked potential (VEP) is a promising proxy measure of synaptic plasticity in the cerebral cortex. However, existing studies are limited by small to moderate sample sizes as well as by considerable variability in how VEP modulation is quantified. In the present study, we used a large sample (n = 415) of healthy volunteers to compare different quantifications of VEP modulation with regards to effect sizes and retention of the modulation effect over time. We observed significant modulation for VEP components C1 (Cohen’sd= 0.53), P1 (d= 0.66), N1 (d= −0.27), N1b (d= −0.66), but not P2 (p = 0.1), and in one time-frequency cluster (~30 Hz and ~70 ms post-stimulus;d= −0.48), 2-4 minutes after 2 Hz prolonged visual stimulation. For components N1 (d= −0.21) and N1b (d= −0.38), as well for the time-frequency cluster (d= −0.33), this effect was retained after 54-56 minutes. Moderate to high correlations (ρ= [0.39, 0.69]) between modulation at different postintervention blocks revealed a relatively high temporal stability in the modulation effect for each VEP component. However, different VEP components also showed markedly different temporal retention patterns. Finally, P1 modulation correlated positively with age (t = 5.26), and was larger for female participants (t = 3.91), with no effects of either age or sex on N1 and N1b potentiation. These results provide strong support for VEP modulation, and especially N1b modulation, as a robust measure of synaptic plasticity, but underscore the need to differentiate between components, and to control for demographic confounders.
A ballistic pollen dispersal strategy hidden in stylar oscillation
Authors: Ito Shuto , Rajabi Hamed , Gorb Stanislav N 
Published: January 2020

AbstractAsteraceae, the most successful flowering plant family, is adapted to the vast range of ecological niches. Their adaptability is partially based on their strong ability of reproduction. The initial, yet challenging, step for plant reproduction is to transport pollen to flower-visiting pollinators. Using quantitative experiments and numerical simulations, here we show that the common floral feature of Asteraceae, a pollen-bearing style, serves as a ballistic lever for catapulting pollen grains to pollinators. This is likely to be a pollination strategy to propel pollen to blind spots of pollinators’ bodies, which are beyond the physical reach of the styles. Our results suggest that the specific morphology and length of the floret, as well as the pollen adhesion, avoid pollen waste by catapulting pollen within a certain range equal to the size of a flowerhead. The insights into the functional floral oscillation may shed light on the superficially unremarkable, but ubiquitous functional floral design of Asteraceae.
Evolution of transmissible spongiform encephalopathy and the prion protein gene (PRNP) in mammals
Authors: Buchanan Brittaney L. , Zink Robert M. 
Published: January 2020

AbstractWildlife managers are concerned with transmissible spongiform encephalopathies (TSEs) as they are currently incurable, always fatal, and have the potential to cross species boundaries. Although a wide range of mammals exhibit TSEs, it is currently unclear whether they are evolutionarily clustered or if TSE+ species are randomly distributed phylogenetically. We tested whether mammalian species with TSEs are phylogenetically underdispersed on a tree derived from 102 PRNP sequences obtained from the Orthologous Mammalian Markers database. We determined that the PRNP tree was topologically congruent with a species tree for these same 102 taxa constructed from 20 aligned gene sequences, excluding the PRNP sequence. Searches in Google Scholar were done to determine whether a species is known to have expressed a TSE. TSEs were present in a variety of orders excluding Chiroptera, Eulipotyphyla, and Lagomorpha and no marine mammals (Artiodactyla) were recorded to have a TSE. We calculated the phylogenetic signal of binary traits (D-Value) to infer if the phylogenetic distribution of TSEs are conserved or dispersed. The occurrence of TSEs in both trees is non-random (Species tree D-value = 0.291; PRNP tree D-value = 0.273), and appears to have arisen independently in the recent history of different mammalian groups. Our findings suggest that the evolution of TSEs develops in groups of species irrespective of PRNP genotype. The evolution of TSEs merits continued exploration at a more in-depth phylogenetic level, as well as the search for genetic combinations that might underlie TSE diseases.
Long-read Assays Shed New Light on the Transcriptome Complexity of a Viral Pathogen and on Virus-Host Interaction
Authors: Tombácz Dóra , Prazsák István , Maróti Zoltán , Moldován Norbert , Csabai Zsolt , Balázs Zsolt , Dénes Béla , Kalmár Tibor , Snyder Michael , Boldogkői Zsolt 
Published: January 2020

AbstractCharacterization of global transcriptomes using conventional short-read sequencing is challenging because of the insensitivity of these platforms to transcripts isoforms, multigenic RNA molecules, and transcriptional overlaps, etc. Long-read sequencing (LRS) can overcome these limitations by reading full-length transcripts. Employment of these technologies has led to the redefinition of transcriptional complexities in reported organisms. In this study, we applied LRS platforms from Pacific Biosciences and Oxford Nanopore Technologies to profile the dynamic vaccinia virus (VACV) transcriptome and assess the effect of viral infection on host gene expression. We performed cDNA and direct RNA sequencing analyses and revealed an extremely complex transcriptional landscape of this virus. In particular, VACV genes produce large numbers of transcript isoforms that vary in their start and termination sites. A significant fraction of VACV transcripts start or end within coding regions of neighboring genes. We distinguished five classes of host genes according to their temporal responses to viral infection. This study provides novel insights into the transcriptomic profile of a viral pathogen and the effect of the virus on host gene expression.Author SummaryViral transcriptomes that are determined using conventional (first- and second-generation) sequencing techniques are incomplete because these platforms are inefficient or fail to distinguish between types of transcripts and transcript isoforms. In particular, conventional sequencing techniques fail to distinguish between parallel overlapping transcripts, including alternative polycistronic transcripts, transcriptional start site (TSS) and transcriptional end site (TES) isoforms, and splice variants and RNA molecules that are produced by transcriptional read-throughs. Long-read sequencing (LRS) can provide complete sets of RNA molecules, and can therefore be used to assemble complete transcriptome atlases of organisms. Although vaccinia virus (VACV) does not produce spliced RNAs, its transcriptome contains large numbers of TSSs and TESs for individual viral genes and has a high degree of polycistronism, together leading to enormous complexity. In this study, we applied single molecule real-time and nanopore-based cDNA and direct-RNA sequencing methods to investigate transcripts of VACV and the host organism.
Heterogeneity of proteome dynamics between connective tissue phases of adult tendon
Authors: Simpson Deborah , Choi Howard , Wang Ding , Prescott Mark , Pitsillides Andrew A. , Dudhia Jayesh , Clegg Peter D. , Ping Peipei , Thorpe Chavaunne T. 
Published: January 2020

AbstractMaintenance of connective tissue integrity is fundamental to sustain function, requiring protein turnover to repair damaged tissue. However, connective tissue proteome dynamics remain largely undefined, as do differences in turnover rates of individual proteins in the collagen and glycoprotein phases of connective tissue extracellular matrix (ECM). Here, we investigate proteome dynamics in the collagen and glycoprotein phases of connective tissues by exploiting the spatially distinct fascicular (collagen-rich) and interfascicular (glycoprotein-rich) ECM phases of tendon. Using isotope labelling, mass spectrometry and bioinformatics, we calculate turnover rates of individual proteins within rat Achilles tendon and its ECM phases. Our results demonstrate complex proteome dynamics in tendon, with ~1000-fold differences in protein turnover rates, and overall faster protein turnover within the glycoprotein-rich interfascicular matrix compared to the collagen-rich fascicular matrix. These data provide insights into the complexity of proteome dynamics in tendon, likely required to maintain tissue homeostasis.
Breast cancer-secreted factors induce atrophy and reduce basal and insulin-stimulated glucose uptake by inhibiting Rac1 activation in rat myotubes
Authors: Ali Mona Sadek , Bitsch-Olsen Stine , Frank Emma , Battey Edmund , Perla Mirela , Themsen Scott Sebastian Birch , Raun Steffen Henning , Jong Steven de , Sylow Lykke 
Published: January 2020

AbstractBackgroundMetabolic disorders are prevalent in women with breast cancer, increasing mortality and cancer recurrence rates. Despite clinical implications, the cause of breast cancer-associated metabolic dysfunction remains poorly understood. Skeletal muscle is crucial for insulin-stimulated glucose uptake, thus key to whole-body glucose homeostasis. In this study, we determined the effect of breast cancer cell-conditioned media on skeletal muscle glucose uptake in response to insulin.MethodL6 myotubes overexpressing myc-tagged GLUT4 (GLUT4myc-L6) were incubated with 40% conditioned media from tumorigenic MCF7 or BT474, or non-tumorigenic control MCF10A breast cells. Mass-spectrometry-based proteomics was applied to detect molecular rewiring in response to breast cancer in the muscle. Expression of myogenesis and inflammation markers, GLUT4 translocation, [3H]-2-deoxyglucose (2DG) uptake, and intramyocellular insulin signalling were determined.ResultsBreast cancer cell-conditioned media induced proteomic changes in pathways related to sarcomere organisation, actin filament binding, and vesicle trafficking, disrupted myogenic differentiation, activated an inflammatory response via NF-κB, and induced muscle atrophy. Basal and insulin-stimulated GLUT4 translocation and 2DG uptake were reduced in myotubes treated with breast cancer cell-conditioned media compared to the control. Insulin signalling via the Rho GTPase Rac1 was blocked in breast cancer-treated myotubes, while Akt-TBC1D4 signalling was unaffected.ConclusionConditioned media from MCF7 and BT474 breast cancer cells reduced skeletal muscle glucose uptake via inhibition of GLUT4 translocation and intramyocellular insulin signalling by selectively blocking Rac1 activation and inducing inflammation. These findings indicate that the rewiring of skeletal muscle proteome, inflammation, and insulin signalling could play a role in metabolic dysfunction in patients with breast cancer.
Transcriptomic Organization of Human Posttraumatic Stress Disorder
Authors: Girgenti Matthew J. , Wang Jiawei , Ji Dingjue , Cruz Dianne ,   Traumatic Stress Brain Research Study Group,   the Million Veteran Program, Stein Murray B. , Gelernter Joel , Young Keith , Huber Bertrand R. , Williamson Douglas E. , Friedman Matthew J. , Krystal John H. , Zhao Hongyu , Duman Ronald S. 
Published: January 2020

ABSTRACTPosttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic geneELFN1as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.
Tomato wall-associated kinase SlWak1 acts in an Fls2- and Fls3-dependent manner to promote apoplastic immune responses toPseudomonas syringae
Authors: Zhang Ning , Pombo Marina A , Rosli Hernan G , Martin Gregory B. 
Published: January 2020

AbstractWall-associated kinases (Waks) are known to be important components of plant immunity against various pathogens includingPseudomonas syringaepv. tomato (Pst) although their molecular mechanisms are largely unknown. In tomato,SlWak1has been implicated in immunity because its transcript abundance increases significantly in leaves after treatment with the flagellin-derived peptides flg22 and flgII-28, which activate the receptors Fls2 and Fls3, respectively. We generated twoSlWak1tomato mutants (Δwak1) using CRISPR/Cas9 and investigated the role ofSlWak1in tomato-Pstinteractions. PTI activated in the apoplast by flg22 or flgII-28 was compromised in Δwak1 plants but PTI at the leaf surface was unaffected. The Δwak1 plants developed fewer callose deposits than wild-type plants but retained the ability to generate reactive oxygen species and activate MAPKs in response to flg22 and flgII-28. The induction ofWak1gene expression by flg22 and flgII-28 was greatly reduced in a tomato mutant lacking Fls2 and Fls3 but induction ofFls3gene expression by flgII-28 was unaffected in Δwak1 plants. AfterPstinoculation, Δwak1 plants developed disease symptoms more slowly than Δfls2.1/fls2.2/fls3 mutant plants, although both plants ultimately were similarly susceptible. SlWak1 co-immunoprecipitated with both Fls2 and Fls3 independently of flg22/flgII-28 or Bak1. These observations suggest that SlWak1 acts in a complex with Fls2/Fls3 and plays an important role at later stages of the PTI in the apoplast.