bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracing the evolution and genomic dynamics of mating-type loci inCryptococcuspathogens and closely related species
Authors: Coelho Marco A. , David-Palma Márcia , Marincowitz Seonju , Aylward Janneke , Pham Nam Q. , Yurkov Andrey M. , Wingfield Brenda D. , Wingfield Michael J. , Sun Sheng , Heitman Joseph 
Published: February 2025

AbstractSexual reproduction in basidiomycete fungi is governed byMATloci (P/RandHD), which exhibit remarkable evolutionary plasticity, characterized by expansions, rearrangements, and gene losses often associated with mating system transitions. The sister generaCryptococcusandKwoniellaprovide a powerful framework for studyingMATloci evolution owing to their diverse reproductive strategies and distinct architectures, spanning bipolar and tetrapolar systems with either linked or unlinkedMATloci. Building on recent large-scale comparative genomic analyses, we generated additional chromosome-level assemblies uncovering distinct evolutionary trajectories shapingMATloci organization. Contrasting with the small-scale expansions and gene acquisitions observed inKwoniella, our analyses revealed independent expansions of theP/Rlocus in tetrapolarCryptococcus, possibly driven by pheromone gene duplications. Notably, these expansions coincided with an enrichment of AT-rich codons and a pronounced GC-content reduction, likely associated with recombination suppression and relaxed codon usage selection. Diverse modes ofMATlocus linkage were also identified, including three previously unrecognized transitions: one resulting in a pseudobipolar arrangement and two leading to bipolarity. All the three transitions involved translocations. In the pseudobipolar configuration, theP/RandHDloci remained on the same chromosome but genetically unlinked, whereas the bipolar transitions additionally featured rearrangements that fused the two loci into a nonrecombining region. Mating assays confirmed a sexual cycle inC. decagattii, demonstrating its ability to undergo mating and sporulation. Progeny analysis inK. mangrovensisrevealed substantial ploidy variation and aneuploidy, likely stemming from haploid-diploid mating, yet evidence of recombination and loss of heterozygosity indicates that meiotic exchange occurs despite irregular chromosome segregation. Our findings underscore the importance of continued diversity sampling and provides further evidence for convergent evolution of fusedMATloci in basidiomycetes, offering new insights into the genetic and chromosomal changes driving reproductive transitions.
Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation
Authors: McMillan Sean N. , Pitts Jaime R. T. , Barua Bipasha , Winkelmann Donald A. , Scarff Charlotte A. 
Published: February 2025

AbstractMost sudden cardiac deaths in young people arise from hypertrophic cardiomyopathy, a genetic disease of the heart muscle, with many causative mutations found in the molecular motor beta-cardiac myosin that drives contraction. Therapeutic intervention has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to target disease progression. Mavacamten is the first example to gain FDA approval but its molecular mode of action remains unclear, limiting our understanding of its functional effects in disease. To better understand this, we solved the cryoEM structures of beta-cardiac heavy meromyosin in three ADP.Pi-bound states, the primed motor domain in the presence and absence of mavacamten, and the sequestered autoinhibited interacting-heads motif (IHM) in complex with mavacamten, to 2.9 Å, 3.4 Å and 3.7 Å global resolution respectively. Together with quantitative crosslinking mass spectrometric analysis, these structures reveal how mavacamten inhibits myosin. Mavacamten stabilises ADP.Pi binding, stalling the motor domain in a primed state, reducing motor dynamics required for actin-binding cleft closure, and slowing progression through the force generation cycle. Within the two-headed myosin molecule, these effects are propagated and lead to stabilisation of the IHM, through increased contacts at the motor-motor interface. Critically, while mavacamten treatment can thus rescue cardiac muscle relaxation in diastole, it can also reduce contractile output in systole in the heart.
Decay of the CTCF paralog BORIS in neognathous birds
Authors: Palitzsch Katja , Wiehe Thomas , Heger Peter 
Published: February 2025

AbstractBORIS (brother of the regulator of imprinted sites), the paralog of the genome organizer CTCF, originated at least 318 million years ago (Mya), in the ancestor of amniotes (mammals, reptiles, and birds). Based on results from chicken (Gallus gallus), the gene was thought to be absent from birds. Using comparative genomics of 59 bird species, we show that birds possess BORIS, but frequently experience severe degradation of the gene, as observed inGallus gallus. The degradation events are restricted to neognathous birds, specific for the BORIS coding sequence, and occur multiple times independently on different branches. They comprise a wide range of molecular decay, from individual point mutations to the inactivation and/or loss of particular zinc fingers, to the almost complete disintegration of the gene. The decay is accompanied by relaxed evolutionary constraints on BORIS codons across neognathous birds and coincides with the accumulation of species-specific repetitive elements in degenerate loci. BORIS represents a case of a presently ongoing, convergent, and specific gene loss within a lineage. As possible explanation, we propose a link between the loss of BORIS and a shift in sperm and/or genital morphology during the evolution of Neognathae.Significance StatementThe gene BORIS was believed to be absent from birds. However, genome analysis of 59 bird species reveals its presence, though it often underwent severe degradation in neognathous birds. These independent degradation events affect the BORIS coding sequence and range from point mutations to near complete gene disintegration. This decay correlates with relaxed evolutionary constraints and species-specific accumulation of repetitive elements. A potential link between BORIS loss and changes in sperm or genital morphology during neognathous bird evolution is suggested.
Dual Antiplatelet Therapy (DAPT) in Patients with NSTEMI Undergoing CABG
Authors: Bansal Agam , Reed Grant W. , Wang Tom , Tamis-Holland Jacqueline , Jaber Wael A. , Kapadia Samir R. , Menon Venu 
Published: February 2025

ABSTRACTBackgroundDual antiplatelet therapy (DAPT), combining acetylsalicylic acid (aspirin) and a P2Y12 inhibitor, is recommended for patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing coronary artery bypass grafting (CABG). However, real-world adoption and effectiveness of DAPT in this context has not been adequately evaluated.MethodsWe conducted a retrospective propensity-matched cohort analysis using data from the TriNetX research network, which includes electronic health records from over 70 healthcare organizations across the United States. The study included patients aged >18 years diagnosed with NSTEMI who underwent CABG within one month of presentation from January 2015 to January 2024. Outcomes for patients on DAPT were compared with those on aspirin monotherapy using standardized mean differences, risk ratios, and Cox proportional hazard models for survival analysis.ResultsFrom a cohort of 21,092 NSTEMI patients eligible for DAPT post-CABG, 55.28% received DAPT predominantly consisting of aspirin and clopidogrel. After propensity score matching, DAPT was associated with significantly reduced all-cause mortality at 1-year (8.1% vs 5.5%, OR: 1.52) and 5-year (14.4% vs 10.6%, OR: 1.41) follow-ups compared to aspirin monotherapy. There were no significant differences in rates of major bleeding, ischemic strokes, or repeat revascularization between the two groups.ConclusionThe underutilization of DAPT in real-world settings, despite guideline recommendations, reflects a potential gap between clinical practice and evidence-based guidelines. Our findings support the effectiveness of DAPT in reducing mortality without increasing major bleeding risks, underscoring the need for more widespread adoption and potentially more robust clinical trials to confirm these observational findings.
Structural basis of neurofibromin tetramerization and dimer-tetramer equilibrium
Authors: Si Shutian , Tüting Christian , Lohse Swanhild , Landfester Katharina , Lieberwirth Ingo , Kastritis Panagiotis L. , Harder Anja 
Published: February 2025

AbstractHuman neurofibromin (NF1) is a tumor suppressor multidomain protein known to regulate cellular functions as a dimer. Using cryo-EM, we discovered that neurofibromin can form more highly organized structures and describe tetramerization and a dynamic dimer-to-tetramer equilibrium with extensive interlocked interfaces as well as structural flexibility. The new tetramer structure generates and modifies interaction surfaces and controls protein functions such as microtubule recruitment, thereby providing novel insights into cellular functions.
A simple method for mapping the location of cross-β forming regions within protein domains of low sequence complexity
Authors: Gu Jinge , Zhou Xiaoming , Sutherland Lillian , Liszczak Glen , McKnight Steven L. 
Published: February 2025

AbstractProtein domains of low sequence complexity are unable to fold into stable, three-dimensional structures. In test tube studies, these unusual polypeptide regions can self-associate in a manner causing phase separation from aqueous solution. This form of protein:protein interaction has been implicated in numerous examples of dynamic morphological organization within eukaryotic cells. In several cases, the basis for low complexity domain (LCD) self-association and phase separation has been traced to the formation of labile cross-β structures. The primary energetic force favoring formation of these transient and reversible structures is enabled by polypeptide backbone interactions. Short, contiguous networks of peptide backbone amino groups and carbonyl oxygens are zippered together intermolecularly by hydrogen bonding as described by Linus Pauling seven decades ago. Here we describe a simple, molecular biological method useful for the identification of localized, self-associating regions within larger protein domains of low sequence complexity.SignificanceThis study describes a molecular biological method for analyzing protein domains of low sequence complexity in search of segments that mediate self-association and consequent phase separation bothin vitroandin vivo. Small regions allowing for self-association correspond to sequences that specify the formation of labile cross-β structural order. When juxtaposed to the C-terminus of GFP, cross-β prone regions suppress fluorescence. A tiled scan of overlapping fragments of the low complexity domain (LCD) of the TDP-43 RNA binding protein pinpointed an evolutionarily conserved sequence of twenty amino acids essential for self-association, phase separation and the formation of nuclear speckles. The screening method described herein should be useful for the analysis of any LCD believed to function via homotypic self-association.
Global Reporting Patterns of Suspected Adverse Drug Reactions and Their Relationship with a Country’s Socioeconomic Status- Insights from VigiBase Data- Study Protocol
Authors: Dhakal Nisha , Sartori Daniele , Holmström Anna-Riia 
Published: February 2025

AbstractIntroductionPharmacovigilance is vital for detecting Adverse Drug Reactions (ADRs), with Individual Case Safety Reports (ICSRs) serving as the primary source, despite growing interest in other data sources like electronic health records and social media. However, ICSR reporting rates remain low in low- and middle-income countries due to weak pharmacovigilance systems. Furthermore, the impact of socioeconomic factors such as health, education, and income on reporting rates has not been studied on a global scale previously.AimsTo compare global ICSR reporting patterns and quantify potential differences in their characteristics across pre-defined socioeconomic strata.MethodsIn this observational descriptive quantitative study, numbers of ICSRs will be obtained from VigiBase for members of the World Health Organization Programme for International Drug Monitoring, from 01/01/2010 to 31/12/2022. Yearly total population data and Inequality-adjusted Human Development Index (IHDI) values will be obtained from the United Nations Development Programme (UNDP) for all countries, for the same interval. Yearly ICSR reporting rates for each country will be calculated by dividing the total ICSRs submitted to VigiBase each year, and median reporting rates computed across the study period. Similarly, the median IHDI and its dimensional indices (Health, Education, and Income) will be calculated for each country. Countries will be categorized into four human development groups based on the UNDP classification: low, medium, high, and very high. To assess the relationship between IHDI (and its dimensions) and reporting rates, a linear regression model will be applied, with adjustments made as needed based on the data characteristics. VigiPoint will also be used to compare the relative frequency of covariates between reports of low, medium, and high IHDI, against those submitted to VigiBase by very high IHDI countries. VigiPoint identifies key features for review using shrunk log odds ratios, highlighting the overrepresented characteristics of ICSRs. We will present descriptive and statistical analyses in tables and scatter plots will be used to examine the relationship between ICSR reporting rates and IHDI (and its dimensions), using the calculated median values for IHDI (and its dimensions). Trendlines will highlight temporal changes in population, IHDI, and dimensional indices.DiscussionThe findings will offer insights into how socioeconomic factors affect reporting practices and may guide targeted interventions to enhance global drug safety monitoring.
Neighborhood level factors and use of cigarettes, cannabis and e-cigarettes: a population-based study among Canadian adults
Authors: Fraser Wood Truman , Dummer Trevor JB , Peters Cheryl E , Murphy Rachel A 
Published: February 2025

AbstractDespite public health efforts, use of legal substances such as cigarettes, cannabis and e-cigarettes are common in Canada. Most policies focus on individual level factors, which do not account for possible influences of the environments to which people belong (i.e. neighborhoods). This study aimed to identify neighborhood-level risk factors for use of cigarettes, cannabis and e-cigarettes in the Canadian Partnership for Tomorrow’s Health cohort. Participants completed questionnaires on demographics and health behaviors including recent (30-d) use of cigarettes, cannabis and e-cigarettes. Geospatial neighborhood-level measures: deprivation, gentrification, household security, labor force participation, immigration and visible minority proportion were linked via postal codes. Regression models were built to understand associations between substance use and neighborhood factors. Neighborhood material deprivation, social deprivation, and household insecurity were positively associated with odds of using cigarettes, cannabis, and e-cigarettes. Odds of using these substances was higher for participants living in gentrified neighborhoods. Lower odds of cigarette, cannabis, and e-cigarette use were found for participants living in neighborhoods with a high proportion of recent immigrants and/or visible minorities. Evidence from this study suggests interventions aimed at reducing or preventing substance use should be multidimensional, encompassing strategies directed at both individuals and neighborhoods.
Additive interactions between genetic susceptibility and physical activity account for nearly one third of excess T2D risk
Authors: Zhou Xuan , Carrasquilla Germán D. , Christiansen Malene R. , Smit Roelof A.J. , Ängquist Lars , Hansen Torben , Loos Ruth J.F. , Grarup Niels , Linneberg Allan , Kilpeläinen Tuomas O. , Merino Jordi 
Published: February 2025

AbstractRegular physical activity is a well-established protective factor against type 2 diabetes (T2D), yet large variability exists in its metabolic benefits. Genetic factors could partially explain this variability, but studies examining gene-by-physical activity interactions in incident T2D are limited. Here, we used data from 10,627 participants from two population-based cohorts in the United States (All of UsResearch Program) and Denmark (Inter99) to investigate how genetic risk and physical activity jointly influence T2D risk. Genetic risk was characterized using a polygenic score for T2D. Physical activity was measured using wearable devices inAll of Usand self-reported questionnaires in Inter99. InAll of Us, T2D incidence rates per 1,000 person-years were 2.1 (95% CI: 0.3, 3.9) for individuals with high physical activity and low genetic risk and 18.3 (95% CI: 13.4, 23.3) for those with low physical activity and high genetic risk (multivariable-adjusted hazard ratio of 6.9 (95% CI: 3.3, 14.4)). The interaction between physical activity and genetic risk deviated from additivity, with a relative excess risk due to interaction of 0.40 (95% CI: 0.11, 0.69; p = 0.003), accounting for 27% (95% CI: 5, 50) of excess T2D risk. These results were replicated in Inter99, where 44% (95% CI: 22, 67) of excess T2D risk was attributed to the interaction. These findings provide consistent evidence of interactions between genetic risk and physical activity on T2D risk, indicating that increasing physical activity among those with high genetic risk may represent an effective strategy for precision T2D prevention.
Determinants of hand hygiene behaviours in internally displaced persons camps in flood-affected areas of South Sudan: a mixed-methods formative research study
Authors: Bak Chol , Hotopf India , Wol Zack , Majorin Fiona 
Published: February 2025

AbstractIn addition to longstanding conflicts, South Sudan has experienced devastating flooding in recent years, resulting in an ongoing humanitarian crisis. In early 2024, it was estimated that there were two million internally displaced persons (IDPs) in South Sudan, with camp residents amongst those most vulnerable to infectious disease outbreaks. Our aim was to understand determinants of hand hygiene behaviours and explore existing hygiene programs in IDP camps in flood-affected areas of South Sudan. A mixed method approach was used to collect data in four IDP camps in Bentiu county, Unity State, in May to June 2023. Methods included: key informant interviews (n=5) with water, sanitation, and hygiene (WASH) implementing organizations, tours of WASH infrastructure in camps, focus group discussions (n=12) with camp residents disaggregated by age, gender, and disability status. Lastly, 50 camp residents were asked to participate in a brief survey and to demonstrate their handwashing behaviour in their current situation and in a hypothetical scenario if less water was available. We found that camp residents mostly washed hands with water only, with some using soap when available. Women were perceived as more likely to wash their hands. Residents commonly washed their hands after visiting the toilet, and before and after eating. Drivers of handwashing included visibly dirty appearance, smell, or a desire to feel fresh and clean. The main barriers to handwashing included a lack of soap, water, buckets, and other handwashing materials. Flooding affects handwashing behaviours in multiple ways, such as increased pressure on limited facilities due to IDP influxes and submerged water points. Handwashing using potentially contaminated flood water was also reported. Extreme weather events such as floods are predicted to increase in frequency and intensity with climate change - thus finding ways to sustainably improve handwashing in these changing contexts is essential.
Incorporating continuous mammographic density into the BOADICEA breast cancer risk prediction model
Authors: Ficorella Lorenzo , Eriksson Mikael , Czene Kamila , Leslie Goska , Yang Xin , Carver Tim , Stokes Adam E. , Easton Douglas F. , Hall Per , Antoniou Antonis C. 
Published: February 2025

AbstractBackgroundBOADICEA (v7) predicts future breast cancer (BC) risk using data on cancer family history, genetic markers, questionnaire-based risk factors and mammographic density (MD) measured using the 4-category BI-RADS classification. However, BI-RADS requires manual reading, which is impractical on a large scale and may cause information loss.MethodsWe extended BOADICEA to incorporate continuous MD measurements, calculated using the automated Volpara and STRATUS software. We used data from the KARMA cohort (60,276 participants; 1,167 incident BC). Associations between MD measurements and BC risk were estimated in a randomly selected training subset (two-thirds of the dataset). Percent MD residuals were calculated after regressing on age at mammography and BMI. Hazard ratios (HRs) were estimated using a Cox proportional hazards model, adjusting for family history and BOADICEA risk factors, and were incorporated into BOADICEA. The remaining one-third of the cohort was used to assess the performance of the extended BOADICEA (v 7.2) in predicting 5-year risks.ResultsThe BC HRs per SD of residual STRATUS density were estimated to be 1.48 (95%CI: 1.33-1.64) and 1.41 (95%CI: 1.27-1.56) for pre- and post-menopausal women, respectively. The corresponding estimates for Volpara density were 1.27 (95%CI: 1.15-1.40) and 1.38 (95%CI: 1.25-1.54). The extended BOADICEA showed improved discrimination in the testing dataset over using BIRADS, with a 1-4% increase in AUC across different combinations of risk factors. Based on 5-year BC risk with MD as the sole input, approximately 11% of the women were reclassified into lower risk categories and 18% into higher risk categories using the extended model.ConclusionIncorporating continuous MD measurements into BOADICEA enhances breast cancer risk stratification and facilitates the use of automated MD measures for risk prediction.
Recurrent evolution of cryptic triploids in cultivated enset increases yield
Authors: Dussert Yann , Borrell James S. , Stocks Jonathan , Hunt Harriet V. , White Oliver W. , Wilkin Paul , Buggs Richard , Büchi Lucie , Demissew Sebsebe , Woldeyes Feleke , Leitch Ilia J. , Abebe Wendawek M. , Nichols Richard A. 
Published: February 2025

ABSTRACTEnset is a staple crop for over 20 million people in southwestern Ethiopia. We generated a new chromosome-level genome assembly, and sequenced 65 wild and 658 cultivated individuals. We unexpectedly find that 214 cultivated individuals are triploid, from multiple origins. Landrace names consistently differentiate diploids from the triploids, which have higher pseudostem volumes and are disproportionately planted. Scientifically directed breeding of triploids could improve food security in sub-saharan Africa.