bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the prevalence of discrepancies between study registrations and publications: A systematic review and meta-analyses
Authors:   TARG Meta-Research Group & Collaborators, Thibault Robert T , Clark Robbie , Pedder Hugo , van den Akker Olmo , Westwood Samuel , Thompson Jacqueline , Munafo Marcus 
Published: July 2021

AbstractObjectivesProspectively registering study plans in a permanent time-stamped and publicly accessible document is becoming more common across disciplines and aims to reduce risk of bias and make risk of bias transparent. Selective reporting persists, however, when researchers deviate from their registered plans without disclosure. This systematic review aimed to estimate the prevalence of undisclosed discrepancies between prospectively registered study plans and their associated publication. We further aimed to identify the research disciplines where these discrepancies have been observed, whether interventions to reduce discrepancies have been conducted, and gaps in the literature.DesignSystematic review and meta-analyses.Data sourcesScopus and Web of Knowledge, published up to 15 December 2019.Eligibility criteriaArticles that included quantitative data about discrepancies between registrations or study protocols and their associated publications.Data extraction and synthesisEach included article was independently coded by two reviewers using a coding form designed for this review (osf.io/728ys). We used random-effects meta-analyses to synthesize the results.ResultsWe reviewed k = 89 articles, which included k = 70 that reported on primary outcome discrepancies from n = 6314 studies and, k = 22 that reported on secondary outcome discrepancies from n = 1436 studies. Meta-analyses indicated that between 29% to 37% (95% confidence interval) of studies contained at least one primary outcome discrepancy and between 50% to 75% (95% confidence interval) contained at least one secondary outcome discrepancy. Almost all articles assessed clinical literature, and there was considerable heterogeneity. We identified only one article that attempted to correct discrepancies.ConclusionsMany articles did not include information on whether discrepancies were disclosed, which version of a registration they compared publications to, and whether the registration was prospective. Thus, our estimates represent discrepancies broadly, rather than our target ofundiscloseddiscrepancies betweenprospectivelyregistered study plans and their associated publications. Discrepancies are common and reduce the trustworthiness of medical research. Interventions to reduce discrepancies could prove valuable.Registrationosf.io/ktmdg. Protocol amendments are listed in Supplementary Material A.
Modeling the emergence of vaccine-resistant variants with Gaussian convolution COVID-19: Could the wrong strategy ruin vaccine efficiency?
Authors: Bongiorno Christian , Cagnol John 
Published: July 2021

AbstractThe SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic, has been shown to mutate. In the absence of a vaccine, natural selection will favor variants with higher transmissibility rates. However, when a substantial portion of the population is vaccinated, natural selection will shift towards favoring variants that can resist the vaccine. These variants can therefore become dominant and even cancel out the benefit of the vaccine. This paper develops a compartmental model which simulates this phenomenon and shows how various vaccination strategies can lead to the emergence of vaccine-resistant variants.
Quantitative susceptibility mapping improves the detection of calcified carotid vessels by multi-contrast MRI using computed tomography angiography as the reference standard
Authors: Nguyen Thanh D. , Wen Yan , Du Jingwen , Spincemaille Pascal , Wang Yi , Qi Yang , Kamel Hooman , Gupta Ajay 
Published: July 2021

AbstractThe objective of this study was to evaluate initial feasibility and improvement in the detection of calcified carotid arteries by including quantitative susceptibility mapping (QSM) in the carotid vessel wall multi-contrast MRI (mcMRI) protocol using CTA as the reference standard. In a pilot cohort of ten patients with significant carotid artery stenosis, calcified vessel detection by mcMRI achieved 64.7% sensitivity and 100% specificity. Adding QSM to mcMRI improved sensitivity to 100% while not affecting specificity.
Mapping psychological distress, depression and anxiety measures to adolescent AQoL-6D utility using data from a sample of young people presenting to primary mental health services
Authors: Hamilton Matthew P , Gao Caroline , Filia Kate M , Menssink Jana M , Sharmin Sonia , Telford Nic , Herrman Helen , Hickie Ian B , Mihalopoulos Cathrine , Rickwood Debra J , McGorry Patrick D , Cotton Sue M 
Published: July 2021

AbstractBackgroundHealth utility data are rarely routinely collected in mental helath services. Mapping models that predict health utility from other outcome measures are typically derived from cross-sectional data but often used to predict longitudinal change.ObjectiveWe aimed to develop models to map six psychological measures to adolescent Assessment of Quality of Life – Six Dimensions (AQOL-6D) health utility for youth mental health service clients and assess the ability of mapping models to predict longitudinal change.MethodsWe recruited 1107 young people attending Australian primary mental health services, collecting data at two time points, three months apart. Five linear and three generalised linear models were explored to identify the best mapping model. Ten-fold cross-validation usingR2, root mean square error (RMSE) and mean absolute error (MAE) were used to compare models and assess predictive ability of six candidate measures of psychological distress, depression and anxiety. Linear / generalised linear mixed effect models were used to construct longitudinal predictive models for AQoL-6D change.ResultsA depression measure (Patient Health Questionnaire-9) was the strongest independent predictor of health utility. Linear regression models with complementary log-log transformation of utility score were the best performing models. Between-person associations were slightly larger than within-person associations for most of the predictors.ConclusionsAdolescent AQoL-6D utility can be derived from a range of psychological distress, depression and anxiety measures. Mapping models estimated from cross-sectional data can approximate longitudinal change but may slightly bias health utility predictions.DataReplication code and model catalogues are available at:https://doi.org/10.7910/DVN/DKDIB0.
Reconstruction of nitrogenase predecessors suggests origin from maturase-like proteins
Authors: Garcia Amanda K. , Kolaczkowski Bryan , Kaçar Betül 
Published: July 2021

ABSTRACTThe evolution of biological nitrogen fixation, uniquely catalyzed by nitrogenase enzymes, has been one of the most consequential biogeochemical innovations over life’s history. Though understanding the early evolution of nitrogen fixation has been a longstanding goal from molecular, biogeochemical, and planetary perspectives, its origins remain enigmatic. In this study, we reconstructed the evolutionary histories of nitrogenases, as well as homologous maturase proteins that participate in the assembly of the nitrogenase active-site cofactor but are not able to fix nitrogen. We combined phylogenetic and ancestral sequence inference with an analysis of predicted functionally divergent sites between nitrogenases and maturases to infer the nitrogen-fixing capabilities of their shared ancestors. Our results provide phylogenetic constraints to the emergence of nitrogen fixation and are consistent with a model wherein nitrogenases emerged from maturase-like predecessors. Though the precise functional role of such a predecessor protein remains speculative, our results highlight evolutionary contingency as a significant factor shaping the evolution of a biogeochemically essential enzyme.SIGNIFICANCE STATEMENTThe origin of nitrogenase-catalyzed nitrogen fixation was a transformative event in life’s history, garnering long-term study from molecular, biogeochemical, and planetary perspectives. Reconstruction of ancestral nitrogenases suggests that the protein sequence space capable of yielding a nitrogen-fixing enzyme in the past was likely more constrained than previously thought. Specifically, here we show that nitrogenases likely evolved from ancestors that resemble maturases, homologs that today participate in nitrogenase cofactor assembly, contrary to the commonly accepted view that maturases evolved from a nitrogenase ancestor. We further submit that the molecular architecture that may have been required for nitrogenase origins was unlikely to have been shaped by the same environmental drivers often implicated in the evolution of nitrogen fixation. If this decoupling is found to be a recurring pattern in metabolic origins, then the presented results would undercut the common, systems-focused rationale of using ancient environmental conditions to explain the timing of critical and singular biogeochemical innovations in life’s past.
Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles
Authors: Glaberman Scott , Bulls Stephanie E. , Vazquez Juan Manuel , Chiari Ylenia , Lynch Vincent J. 
Published: July 2021

AbstractThere are many costs associated with increased body size and longevity in animals, including the accumulation of genotoxic and cytotoxic damage that comes with having more cells and living longer. Yet, some species have overcome these barriers and have evolved remarkably large body sizes and long lifespans, sometimes within a narrow window of evolutionary time. Here, we demonstrate through phylogenetic comparative analysis that multiple turtle lineages, including Galapagos giant tortoises, concurrently evolved large bodies, long lifespans, and reduced cancer risk. We also show through comparative genomic analysis that Galapagos giant tortoises have gene duplications related to longevity and tumor suppression. To examine the molecular basis underlying increased body size and lifespan in turtles, we treated cell lines from multiple species, including Galapagos giant tortoises, with drugs that induce different types of cytotoxic stress. Our results indicate that turtle cells, in general, are resistant to oxidative stress related to aging, while Galapagos giant tortoise cells, specifically, are sensitive to endoplasmic reticulum stress, which may give this species an ability to mitigate the effects of cellular stress associated with increased body size and longevity.
Causes of variability in estimates of mutational variance from mutation accumulation experiments
Authors: Conradsen Cara , Blows Mark W. , McGuigan Katrina 
Published: July 2021

ABSTRACTCharacteristics of the new phenotypic variation introduced via mutation have broad implications in evolutionary and medical genetics. Standardised estimates of this mutational variance,VM, span two orders of magnitude, but the causes of this remain poorly resolved. We investigated estimate heterogeneity using two approaches. First, meta-analyses of ~150 estimates from 37 mutation accumulation (MA) studies did not support a difference among taxa (which differ in mutation rate) in standardisedVM, but provided equivocal support for standardisedVMto vary with trait type (life history versus morphology, predicted to differ in mutation rate). Notably, several experimental factors were confounded with taxon and trait, and further empirical data are required to resolve their influences. Second, we analysed morphological data from an experiment inDrosophila serratato determine the potential for unintentional heterogeneity among environments in which phenotypes were measured (i.e., among laboratories or time points) or transient segregation of mutations within MA lines to affect standardisedVM. Approximating the size of an average MA experiment, variability among repeated estimates of (accumulated) mutational variance was comparable to variation among published estimates of standardisedVMfor morphological traits. This heterogeneity was (partially) attributable to unintended environmental variation or within line segregation of mutations only for wing size, not wing shape traits. We conclude that sampling error contributed substantial variation within this experiment, and infer that it will also contribute substantially to differences among published estimates. We suggest a logistically permissive approach to improve the precision of estimates, and consequently our understanding of the dynamics of mutational variance of quantitative traits.
Combinations of Peptides Synergistically Activate the Regenerative Capacity of Skin Cells In Vitro
Authors: Flagler Michael J. , Tamura Makio , Laughlin Tim , Hartman Scott , Ashe Julie , Adams Rachel , Kozak Kim , Cresswell Kellen , Mullins Lisa , Jarrold Bradley B. , Isfort Robert J. , Sherrill Joseph D. 
Published: July 2021

ABSTRACTOBJECTIVETo explore synergistic effects related to skin regeneration, peptides with distinct biological mechanisms of action were evaluated in combination in different skin cell lines in the presence or absence of niacinamide (Nam). Furthermore, the synergistic responses of peptide combinations on global gene expression were compared to the changes that occur with fractional laser resurfacing treatment, a gold standard approach for skin rejuvenation, to further define optimal peptide combinations.METHODSMicroarray profiling was used to characterize the biological responses of peptide combinations (+/− Nam) relative to the individual components in epidermal keratinocyte and dermal fibroblast cell lines. Cellular functional assays were utilized to confirm the synergistic effects of peptide combinations. Bioinformatics approaches were used to link the synergistic effects of peptide combinations on gene expression to the transcriptomics of the skin rejuvenation response from fractional laser treatment.RESULTSMicroarray analysis of skin cells treated with peptide combinations revealed synergistic changes in gene expression compared to individual peptide controls. Bioinformatic analysis of synergy genes in keratinocytes revealed activation of NRF2-mediated oxidative stress responses by a combination of Ac-PPYL, Pal-KTTKS, and Nam. Additional analysis revealed direct downstream transcriptional targets of NRF2/ARE exhibiting synergistic regulation by this combination of materials, which was corroborated by a cellular reporter assay. NRF2-mediated oxidative stress response pathways were also found to be activated in the transcriptomics of the early skin rejuvenation response to fractional laser treatment, suggesting the importance of this biology in the early stages of tissue repair. Additionally, a second combination of peptides (pal-KT and Ac-PPYL) was found to synergistically restore cellular ATP levels that had been depleted due to the presence of ROS, indicating an additional mechanism whereby peptide synergies may accelerate skin repair.CONCLUSIONThrough combinatorial synergy studies, we have identified additional in vitro skin repair mechanisms beyond the previously described functions of individual peptides and correlated these to the transcriptomics of the skin rejuvenation response of fractional laser treatment. These findings suggest that specific peptides can act together, via complementary and synergistic mechanisms, to holistically enhance the regenerative capacity of in vitro skin cells.
Pharmacokinetic Effects of Combined Exposure to Nicotine and THC via E-Cigarettes in Pregnant Rats
Authors: Breit K. R. , Rodriguez C. G. , Hussain S. , Thomas K. , Zeigler M. , Gerasimidis I. , Thomas J. D. 
Published: July 2021

ABSTRACTNicotine and cannabis are two of the most commonly consumed licit and illicit drugs during pregnancy, often consumed together via e-cigarettes. Vaping is assumed to be a safer alternative than traditional routes of consumption, yet the potential consequences of prenatal e-cigarette exposure are largely unknown, particularly when these two drugs are co-consumed. In a novel co-exposure model, pregnant Sprague-Dawley rats received nicotine (36 mg/mL), THC (100 mg/mL), the combination, or the vehicle via e-cigarettes daily from gestational days 5-20, mimicking the first and second human trimesters. Maternal blood samples were collected throughout pregnancy to measure drug and metabolite levels, and core body temperatures before and after exposure were also measured. Pregnant dams exposed to combined nicotine and THC had lower plasma nicotine and cotinine levels than those exposed to nicotine alone; similarly, the combined exposure group also had lower plasma THC and THC metabolite (THC-OH and THC-COOH) levels than those exposed to THC alone. Prenatal nicotine exposure gradually decreased basal core body temperatures each day, with chronic exposure, whereas exposure to THC alone decreased temperatures during the individual sessions. Despite these physiological effects, no changes were observed in food or water intake, weight gain, or basic litter outcomes. These data suggest that combined exposure to nicotine and THC elicits both separate and interactive physiological effects of nicotine and THC on pregnant dams. These data and use of this model can help improve education for pregnant mothers about prenatal e-cigarette use and has important implications for public policy.HIGHLIGHTSRepeated prenatal nicotine exposure via e-cigarettes gradually decreased temperaturesPrenatal THC exposure via e-cigarettes decreased temperatures during intoxicationCombined prenatal exposure via e-cigarettes altered plasma drug and metabolite levelsThis co-exposure model elicits separate and interactive effects of nicotine and THC
The EGF-motif containing protein SPE-36 is a secreted protein required for sperm function at fertilization inC. elegans
Authors: Krauchunas Amber R. , Marcello Matthew R. , Looper A’Maya , Mei Xue , Putiri Emily , Singaravelu Gunasekaran , Ahmed Iqra I. , Singson Andrew 
Published: July 2021

AbstractThe growing number of genes specifically required for fertilization suggests that there is a significant amount of molecular complexity at the sperm-egg interface. Thus, we have adopted a model of a “fertilization synapse” where specialized zones of interaction and multi-protein complexes mediate gamete interaction and fusion. The fertilization synapse is likely to be composed of bothtransandcisprotein-protein interactions at the surface of each gamete. Mutations in theCaenorhabditis elegans spe-36gene result in a sperm-specific fertility defect. Surprisingly,spe-36encodes a secreted EGF-motif containing protein that functions cell autonomously. Despite the fact that morphology and migratory behavior ofspe-36sperm are indistinguishable from wild-type sperm,spe-36sperm make close contact with oocytes but fail to fertilize them. The genetic requirement for a secreted sperm-derived protein for fertilization is novel and represents a paradigm-shifting discovery in the molecular understanding of fertilization.
Identification of Acute Respiratory Distress Syndrome subphenotypes denovo using routine clinical data: a retrospective analysis of ARDS clinical trials
Authors: Duggal Abhijit , Kast Rachel , Van Ark Emily , Bulgarelli Lucas , Siuba Matthew T. , Osborn Jeff , Rey Diego , Zampieri Fernando G , Cavalcanti Alexandre B , Maia Israel S , Paisani Denise M , Laranjeira Ligia N , Neto Ary Serpa , Octávio Deliberato Rodrigo 
Published: July 2021

ABSTRACTRationaleThe acute respiratory distress syndrome (ARDS) is a heterogenous condition, and identification of subphenotypes may help in better risk stratification.ObjectivesIdentify ARDS subphenotypes using new simpler methodology and readily available clinical variables.DesignRetrospective Cohort Study of ARDS trials.SettingData from the U.S. ARDSNet trials and from the international ART trial.Participants3763 patients from ARDSNet datasets and 1010 patients from the ART dataset.Primary and secondary outcome measuresThe primary outcome was 60-day or 28-day mortality, depending on what was reported in the original trial. K-means cluster analysis was performed to identify subgroups. For feature selection, sets. Sets of candidate variables were tested to assess their ability to produce different probabilities for mortality in each cluster. Clusters were compared to biomarker data, allowing identification of subphenotypes.ResultsData from 4,773 patients was analyzed. Two subphenotypes (A and B) resulted in optimal separation in the final model, which included nine routinely collected clinical variables, namely: heart rate, mean arterial pressure, respiratory rate, bilirubin, bicarbonate, creatinine, PaO2, arterial pH, and FiO2. Participants in subphenotype B showed increased levels of pro-inflammatory markers, had consistently higher mortality, lower number of ventilator-free days at day 28, and longer duration of ventilation compared to patients in the subphenotype A.ConclusionsRoutinely available clinical data can successfully identify two distinct subphenotypes in adult ARDS patients. This work may facilitate implementation of precision therapy in ARDS clinical trials.ARTICLE SUMMARYStrengths and limitations of this studyLargest cohort of patients used to identify subphenotypes of ARDS patients.Subphenotypes were validated in the population of a large international ARDS randomized controlled trial.Subphenotypes were identified by using only routinely collected clinical data.Our use of data exclusively from randomized controlled trials does not prove generalizability to unselected ARDS populations.The clinical utility of the subphenotypes have to be validated in a prospective study.
Short-term diet intervention alters the small non-coding RNA (sncRNA) landscape of human sperm
Authors: Vaz Candida , Kermack Alexandra J , Burton Mark , Tan Pei Fang , Huan Jason , Yoo Tessa P X , Donnelly Kerry , Wellstead Susan J , Fisk Helena L , Houghton Franchesca D , Lewis Sheena , Chong Yap Seng , Gluckman Peter D , Cheong Ying , Macklon Nicholas S , Calder Philip C , Dutta Anindya , Godfrey Keith M , Kumar Pankaj , Lillycrop Karen A , Karnani Neerja 
Published: July 2021

AbstractOffspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing the effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of paternal effects, though less is known about the existence of similar mechanisms in human sperm. Here, we first characterised the baseline sncRNA landscape of human sperm, and then studied the effects of a 6-week diet intervention on their expression profile. Baseline profiling identified 5’tRFs, miRNAs and piRNAs to be the most abundant sncRNA subtypes, primarily expressed from regulatory elements like UTRs, CpG-rich regions and promoters. Expression of a subset of these sncRNAs varied with age, BMI and sperm quality of the donor. Diet intervention enriched in vitamin D and omega-3 fatty acids showed a marked increase of these nutrients in circulation and altered the sperm sncRNA expression. These included 3 tRFs, 15 miRNAs and 112 piRNAs, with gene targets involved in fatty acid metabolism, vitamin D response (LXR/RXR activation, TGF-beta and Wnt signaling), and transposable elements. These findings provide evidence that human sperms are sensitive to alterations in exposures such as diet, and sncRNAs capture the epigenetic imprint of this change. Hence changes to paternal nutrition during preconception may improve sperm quality and offspring health outcomes. To benefit future research, we developed iDad_DB, an open access database of baseline and diet-altered sncRNA in human male germline.