bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-organ and Multi-omics Aging Clocks Digitize Human Biological Age
Authors: Wen Junhao 
Published: February 2025

AbstractMulti-organ biological aging clocks derived from clinical phenotypes and neuroimaging have emerged as valuable tools for studying human aging and disease1,2,3,4. Plasma proteomics provides an additional molecular dimension to enrich these clocks5. Building on previous work1,3, I developed 11 multi-organ proteome-based biological age gaps (ProtBAGs) using 2448 plasma proteins from 43,498 participants in the UK Biobank. I highlighted key methodological and clinical considerations for developing and using ProtBAG, including age bias correction6, and investigated the impact of training data sample size, protein organ specificity, and the underlying pathologies of the training data on model generalizability and clinical interpretability. I then integrated the 11 ProtBAGs with our previously developed 9 multi-organ phenotype-based biological age gaps (PhenoBAG1) to investigate their genetic underpinnings, causal associations with 525 disease endpoints (DE) from FinnGen and PGC, and their clinical potential in predicting 14 disease categories and mortality. Genetic analyses revealed overlap between ProtBAGs and PhenoBAGs via shared loci, genetic correlations, and colocalization signals. A three-layer causal network linked ProtBAG, PhenoBAG, and DE, exemplified by the pathway of obesity→renal PhenoBAG→renal ProtBAG to holistically understand human aging and disease. Combining features across multiple organs improved predictions for disease categories and mortality. These findings provide a framework for integrating multi-organ and multi-omics biological aging clocks in biomedicine. All results are publicly disseminated athttps://labs-laboratory.com/medicine/.
Changing Physician Performance: A Systematic Review and Meta-Analysis (75 years 1950-2024) of the Effect of Continuing Medical Education Strategies, Continuous Professional Development and knowledge Translation
Authors: Abbasi Ebrahim 
Published: February 2025

ABSTRACTIntroductionMedical education has always been considered an essential component for improving the knowledg and performance of physicians and medical assistants. However, this education must be carried out continuously t update the knowledge of physicians and improve their performance. Various strategies are used to achieve this goal, the most important of which are CME, CPD, and CBME strategies. This study aimed to investigate the effect of using these strategies on improving the performance of physicians in the world using a systematic review method.MethodsThis study was conducted using a systematic review method on the effect of educational strategies o improving the performance of physicians in the world. Accordingly, all relevant articles published between 195 and 2024 were extracted and reviewed through a search in the scientific databases PubMed/Medline, Web of Science, ProQuest, and Scopus. The quality of the articles was assessed using the CONSORT checklist an Newcastle-Ottawa Scale.Resultstwenty articles conducted between 1993 and 2024 were included in the systematic review process. According to the findings, providing continuing education based on CME, CPD, CBME, and knowledge translatio strategies positively affected the knowledge, skills, and performance of physicians and medical assistants i providing health services. This can be used to train medical students and practicing physicians on an ongoing basis.ConclusionMedical education using CME, CPD, and CBME strategies can improve physicians’ knowledge and performance, and subsequently increase job satisfaction, self-efficacy, communication skills, medical knowledge, performance, and skill. However, individual, structural, and content limitations that can prevent success in learnin and training programs should be considered and addressed.
Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington’s disease flies are causally linked
Authors: Ast Anne , Roth Leonard , Brusendorf Lydia , Schindler Franziska , Ammar Orchid Wael Mostapha , Berberich Simon , Edel Juliane , Bonsor Megan , Georgii Elisabeth , Hänig Christian , Langnick Claudia , Ivanov Andranik , Beule Dieter , Piraud Marie , Kunz Severine , Popp Oliver , Mertins Philipp , Petzoldt Astrid G. , Wanker Erich E. 
Published: February 2025

ABSTRACTAmyloidogenic mutant huntingtin exon-1 (mHTTex1) protein aggregates with pathogenic polyglutamine (polyQ) tracts are the potential root cause of Huntington’s disease (HD). Here, we assessed the gain-of-function toxicity of mHTTex1 aggregation in neurons of HD transgenic flies. We show that the rate of mHTTex1 aggregation in neurons and early mortality of HD transgenic flies are correlated. We observed sequestration of key synaptic proteins into amyloid-like mHTTex1 aggregates and a concomitant decrease of their transcript levels, suggesting that progressive mHTTex1 aggregate stress in neurons leads to an impairment of synaptic function. Machine learning-based data analysis revealed that the abundance of synaptic proteins such as the vesicular monoamine transporter Vmat in the brain is predictive of fly survival. RNAi knockdown of Vmat-encoding transcripts in neurons with pathogenic amyloid-like HTTex1Q97 aggregates further shortened the lifespan of HD flies, supporting the hypothesis that mHTTex1 aggregation drives impairment of synaptic processes and pathogenesis of HD.
The molecular properties of the bHLH TCF4 protein as an intrinsically disordered hub transcription factor
Authors: Nikola Sozańska , Klepka Barbara P. , Anna Niedźwiecka , Lilia Żukowa , Michał Dadlez , Beata Greb-Markiewicz , Andrzej Ożyhar , Aneta Tarczewska 
Published: February 2025

1.AbstractBackgroundTranscription factor 4 (TCF4) is a member of the basic helix-loop-helix (bHLH) family of transcription factors and guides proper embryogenesis, particularly neurogenesis, myogenesis, heart development and hematopoiesis. bHLH proteins exhibit variations in length, expression patterns and the presence of defined motifs. The interaction of TCF4 with DNA is dependent on the presence of a conserved bHLH domain, particularly the presence of a basic (b) motif. Most mutations in theTcf4gene are either associated with the development of serious nervous system disorders, such as Pitt-Hopkins syndrome or schizophrenia, or are lethal. Although TCF4 is essential for the proper development and function of the human body, apart from the isolated bHLH domain, there is a lack of fundamental knowledge about the structure of TCF4.MethodsRecombinant full-length TCF4 was expressed inE. colicells and purified using chromatographic techniques. To determine the conformation of the polypeptide chain of TCF4, we performedin vitroanalysis using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We then determined the dissociation constant (KD) of the TCF4:DNA complex using independent methods, including fluorescence polarization (FP), electrophoretic mobility shift assay (EMSA), and fluorescence correlation spectroscopy (FCS). Finally, we compared the properties of TCF4 in itsapoandholoform in relation to the changes of the conformation of the polypeptide chain (HDX-MS), hydrodynamic properties (e.g., sedimentation-velocity analytical ultracentrifugation; SV-AUC), and stability (thermal shift, circular dichroism; CD).ResultsIn this study, we demonstrate the molecular characteristics of full-length TCF4, the dimer of which is one of the largest intrinsically disordered proteins (IDPs) described to date. According to our findings, the structure of TCF4 is extensively disordered. Only the bHLH domain, which comprises 10% of the polypeptide chain, exhibits a stable fold. Strikingly, Ephrussi-box (E-box) binding via the bHLH domain has no significant effect on the disordered nature of TCF4, but it does influence the stability of TCF4.ConclusionsWe suggest that bHLH plays the role of an anchor localizing TCF4 to specific gene sequences. The dual nature of the TCF4 structure, as well as the fact that the intrinsically disordered regions (IDRs) represents most of the protein sequence, suggests that TCF4 may act as a hub transcription factor regulating the expression of specific genes through the interaction of IDRs with gene-specific partners.
Tier-based standards for FAIR sequence data and metadata sharing in microbiome research
Authors: Kim Lina , Lavrinienko Anton , Sebechlebska Zuzana , Stoltenberg Sven , Bokulich Nicholas A. 
Published: February 2025

AbstractMicrobiome research is a growing, data-driven field within the life sciences. While policies exist for sharing microbiome sequence data and using standardized metadata schemes, compliance among researchers varies. To promote open research data best practices in the microbiome research community, we (1) propose two tiered badge systems to evaluate data/metadata sharing compliance, and (2) showcase an automated evaluation tool to determine adherence to data reporting standards in publications with amplicon and metagenome sequence data. In a systematic evaluation of publications (n ∼ 3000) spanning human gut microbiome research, we found that nearly half of publications do not meet minimum standards for sequence data availability. Moreover, poor standardization of metadata creates a high barrier to harmonization and cross-study comparison. Using this badge system and evaluation tool, our proof-of-concept work exposes (i) the ineffectiveness of sequence data availability statements, and (ii) the lack of consistent metadata standards for annotating microbial data. In this Perspective, we highlight the need for improved practices and infrastructure that reduce barriers to data submission and maximize reproducibility in microbiome research. We anticipate our tiered badge framework will promote dialogue regarding data sharing practices and facilitate microbiome data reuse, supporting best practices that make microbiome data FAIR.
Dissection of retrosplenial cortex inputs: ubiquitous drive from anterior thalamus
Authors: Margetts-Smith Gabriella , Andrianova Lilya , Kohli Shivali , Randall Andrew D , Aggleton John P , Witton Jonathan , Craig Michael T 
Published: February 2025

AbstractThe retrosplenial cortex (RSC) is a highly interconnected brain region involved in spatial navigation and associative learning. It forms extensive, reciprocal connections with sensory, hippocampal, parahippocampal, prefrontal, and thalamic areas. RSC comprises granular (gRSC) and dysgranular (dRSC) subdivisions with distinct connectivity and functions. Despite its emerging role in behaviour and its implication in memory-related disorders such as Alzheimer’s disease, the nature of its synaptic inputs remains poorly understood.Here, we combined viral anatomical tracing, optogenetic stimulation, and patch-clamp electrophysiology to investigate inputs from the anterior cingulate cortex (ACC), dorsal subiculum (dSub), and anterior thalamic nuclei (ATN) to gRSC and dRSC. Strikingly, all recorded RSC pyramidal neurons received ATN input, regardless of subdivision or cortical layer. Activation of ATN inputs evoked significantly larger post-synaptic responses than those from dSub or ACC, though both regions maintained substantial connectivity with RSC. While dSub projections appeared denser in gRSC, synaptic responses were larger in dRSC, albeit with lower input probability. Notably, NMDA receptor-mediated components of RSC excitatory inputs were weaker than expected, potentially explaining the reported inability to induce long-term potentiation in RSC inex vivoneurophysiology experiments.This is the first study to characterise the synaptic properties of retrosplenial afferents. Our findings highlight the dominant influence of ATN inputs and raise important questions about how RSC’s long-range connectivity supports its roles in memory and spatial navigation.
Cascades of effectiveness of new-generation insecticide-treated nets against malaria, from entomological trials to real-life conditions
Authors: Champagne Clara , Lemant Jeanne , Assenga Alphonce , Kibondo Ummi A. , Lekundayo Ruth G. , Mbuba Emmanuel , Moore Jason , Muganga Joseph B. , Ntabaliba Watson S. , Odufuwa Olukayode G. , Swai Johnson Kyeba , Alexa Maria , Goers Roland , Golumbeanu Monica , Chitnis Nakul , Ross Amanda , Moore Sarah , Pothin Emilie 
Published: February 2025

AbstractAs insecticide resistance spreads in Africa, new-generation insecticide-treated nets (ITNs) are increasingly being deployed to protect vulnerable populations against malaria. While these nets provide greater entomological efficacy against resistant mosquitoes, their effectiveness against malaria transmission also depends on other factors, such as durability, access, usage, and activity patterns of hosts and vectors. Here, we quantify the impact of two new-generation ITNs, namely Interceptor®G2 (chlorfenapyr-pyrethroid) and Olyset®Plus (piperonyl butoxide-pyrethroid), in a cascade from entomological efficacy to population-level effectiveness. We use a mathematical model that we parameterize with entomological data and validate against results from randomized controlled trials. We found that, beyond entomological factors, operational factors including functional survival, ITN use and in-bed exposure critically impact ITN effectiveness overall and per ITN types. Our results obtained for Tanzania can be extended to other contexts in a dashboard (https://aimswisstph.shinyapps.io/ITNcascadesdashboard) allowing users to explore product selection based on setting-specific factors that influence ITN effectiveness.
Appraising Cardiovascular 10-yr Risk Prediction Scores: A Rapid Systematic Review
Authors: Adhikari Chiranjivi , Shah Komal , Shukla Aakansha , Karmacharya Biraj Man , Mavalankar Dileep 
Published: February 2025

AbstractGlobally, the burden of cardiovascular disease is on the rise. Despite WHO’s and the UN’s frantic efforts, it appears less probable that the 25 by 25 aim will be met. Early identification of at-risk cases using a risk scoring system can aid in achieving these goals, however for primary and secondary prevention, suitability of these scoring systems, for the countries with medium to low resources, including Asians, with respect to accuracies is a challenge as majority of them are developed from non-Asian cohorts. In light of methodological considerations, risk attribution, and policy consequences, we included and described, restricting our search but sytematically, with five widely used global tools for CVD risk 10-year prediction—FRS, WHO CVD, QRISK, ASCVD, and SCORE—and their updated versions, altogether 11, published during 1970-2023. In general, the results of consolidated risk ratings and summarization showed that these algorithms can differentiate CVD 10-yr risk by 63-86% accurately, considering both for internal and external validity. Further, we discuss their methodological perspectives, ad hoc use, and suggest prospects.RegistrationOpen Science Framework (https://osf.io/72v48)HighlightsGlobally and optimally used cardiovascular disease (CVD) risk scoring algorithms have diverse accuracies, generalizability, and levels of evidence based on study designs, analyses, and given gold standards.Although validated fair to excellent, still the performance of these tools can be increased from 12 to 37%, both for internal and external accuracy, which can have a positive impact on cost and public health.Lifestyle and related changes due to gene-environment interaction, these algorithms are liable to change, so we need to update, validate, and fit them accordingly.Implementational, methodological, technological, and cost-related issues need to be addressed for a country or a state-specific algorithm to be up taken, updated, or validated.
Reconstructing the silent circulation of West Nile Virus in a Caribbean island during 15 years using sentinel serological data
Authors: Hamouche Celia , Pradel Jennifer , Pagès Nonito , Chevalier Véronique , Lecollinet Sylvie , Bastard Jonathan , Durand Benoit 
Published: February 2025

AbstractThe dynamics of zoonotic infectious diseases with silent circulation may be imperfectly understood and monitored using passive (or reactive) epidemiological surveillance data only, highlighting the interest of quantitative methods like modelling. West Nile virus (WNV) is a widespread mosquito-borne virus transmitted from birds to “dead-end” hosts including humans and horses, in whom it can be fatal. It was first detected in Guadeloupe archipelago, Caribbean, in 2002, although no WNV clinical case in humans nor horses had been reported before 2024. Undetected infections represent a risk as WNV can be transmittedviablood and organ donations. In Guadeloupe, epidemiological surveillance started in 2002 in sentinel chickens and horses and in 2015 in mosquitoes, to detect WNV and to improve knowledge on its epidemiology and dynamics. In order to reconstruct the WNV force of infection (FOI), we built a model assessing different hypotheses regarding its dynamics using serological results in respectively 1,022 and 3,649 blood samples collected from 256 horses and 317 chickens between 2002 and 2018. We fitted the model to the serological data using Markov Chains Monte Carlo. We found that WNV FOI in Guadeloupe Island presented both within-year (seasonal) and between-years fluctuations. We identified three main episodes of WNV circulation on the island between 2002 and 2017. During years with circulation, the FOI was predicted to be highest around the months of October-November, although transmission could occur all year long. We estimated a very low weekly seroreversion rate, which is consistent with a lifelong persistence of WNV IgG antibodies in many infected individuals. To conclude, combining longitudinal serological data to a mathematical model allowed reconstructing the recurrent and silent circulation of WNV in this Caribbean island, which could improve surveillance design for better virus detection.
Validating data from Multiplex Assays of Variant Effect (MAVEs): A CanVIG-UK National Survey of NHS Clinical Scientists
Authors: Allen Sophie , Garrett Alice , Rowlands Charlie F. , Durkie Miranda , Burghel George J. , Robinson Rachel , Callaway Alison , Field Joanne , Frugtniet Bethan , Palmer-Smith Sheila , Grant Jonathan , Pagan Judith , McDevitt Trudi , Snape Katie , Hanson Helen , McVeigh Terri , Adams David J. , Findlay Gregory M. , Villani Rehan M. , Spurdle Amanda B. , Turnbull Clare ,   CanVIG-UK
Published: February 2025

AbstractAdvances in technology have made possible Multiplex Assays of Variant Effect (MAVEs), systematically generating functional data for many thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to clinical adoption of new MAVEs.We delivered a survey during the November 2024 Cancer Variant Interpretation Group (CanVIG-UK) meeting comprising NHS clinical scientists and clinical geneticists, and received 46 responses from individuals regularly performing variant classification for diagnostic reporting.Only 35% reported they would accept clinical validation of the MAVE provided by its authors: 20% reported they would attempt clinical validation themselves whilst 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring such central bodies on a scale 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median=5), VCEPs (median=5) and ClinGen SVI Functional Working Group (median=4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood to alter validation scores provided by a trusted central body). These findings, from a comparatively homogenous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.
Variable pharmacokinetics of coagulation factor VIII in the perioperative setting complicates personalisation of treatment in patients with haemophilia A
Authors: Janssen Alexander , van Moort Iris , Bennis Frank C. , Cnossen Marjon H. , Mathôt Ron A.A. 
Published: February 2025

AbstractPharmacokinetic (PK)-guided dosing of factor concentrates in patients with haemophilia A is generally recommended for the optimisation of prophylactic treatment. PK-guided dosing can also be useful in the perioperative setting, where guidelines advise to keep factor VIII (FVIII) activity levels within tight target ranges to prevent bleeding. Previous studies suggest changes in FVIII PK following medical procedures as well as potential time-dependent effects, meaning that population PK models specific to the perioperative setting are required. In this study, we use data from haemophilia A patients collected during the prophylactic and perioperative setting to identify covariates that explain changes in FVIII PK. Additionally, we use machine learning methods to find potential time-dependent effects on FVIII clearance. Perioperative FVIII clearance was generally lower compared to the prophylactic setting. Covariates related to the complexity of the medical procedures were correlated to larger decreases in clearance. Importantly, subjects undergoing more complex procedures also depicted potentially relevant time-dependent effects on clearance. These effects could be highly variable between subjects. Directly using PK parameters obtained from the prophylactic setting resulted in relatively high mean absolute percentage error (MAPE) at 26.3%, while the perioperative model including time-dependent effects depicted markedly reduced error (10.3%). The presence of high variability between subjects and potential time-dependent effects complicates the selection of optimal dosing regimens before the start of medical procedures. Our method can be used to optimise treatment in real-time, but close monitoring of FVIII levels will likely remain necessary.