bluuebunny/crossref_metadata_2025_split huggingface dataset:
ClimateMind50+ a comprehensive short questionnaire to measure climate change knowledge, worries, preparedness, behaviours, and involvement of adults aged 50 and over
Authors: Zaninotto Paola , Wu Yu-Tzu , Prina Matthew 
Published: December 2024

AbstractThe ClimateMind50+ questionnaire is a tailored instrument to assess the knowledge, concerns, preparedness, behaviours, and involvement of individuals aged 50 and above. Older adults are particularly vulnerable to climate-related hazards such as extreme heat, flooding, and severe storms, yet their perspectives and contributions to climate resilience remain underrepresented in research. The systematic development of the ClimateMind50+ involved rigorous cognitive testing with diverse participants, ensuring clarity, accessibility, and relevance. The tool is designed for versatility in administration—face-to-face, via telephone, or self-completion—facilitating its integration across various research contexts.Cognitive testing highlighted the need for clear wording, simplified response scales, and age-appropriate framing of questions. For instance, questions on climate preparedness and sustainable practices were refined to capture lifetime actions (“ever”) rather than limited timeframes, enhancing their relevance for older respondents. Additionally, the questionnaire effectively explores older adults’ engagement in climate actions, from individual behavioural changes to advocacy and activism, challenging stereotypes of passivity in this demographic.By providing nuanced insights into the experiences of older adults and their potential contributions to climate mitigation and adaptation, the ClimateMind50+ offers a robust foundation for climate change research among older people. Its deployment can support policymaking and community initiatives aimed at reducing climate risks while promoting sustainable and healthy aging practices. This innovative tool underscores the importance of amplifying the voices of older adults in climate discourse and harnessing their capacities for fostering resilience.
Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ∼265,000 individuals
Authors: Hofmeister Robin J. , Cavinato Théo , Karimi Roya , van der Graaf Adriaan , Pajuste Fanny-Dhelia , Kronberg Jaanika , Taba Nele ,   Estonian Biobank research team, Mägi Reedik , Vaudel Marc , Rubinacci Simone , Johansson Stefan , Milani Lili , Delaneau Olivier , Kutalik Zoltán 
Published: December 2024

AbstractParent-of-origin effects (POEs) occur when the impact of a genetic variant depends on its parental origin. Traditionally linked to genomic imprinting, these effects are believed to have evolved from parental conflict over resource allocation to offspring, which results in opposing parental genetic influences. Despite their potential importance, POEs remain heavily understudied in complex traits, largely due to the lack of parental genomes.Here, we present a multi-step approach to infer the parent-of-origin of alleles without parental genomes, leveraging inter-chromosomal phasing, mitochondrial and chromosome X data, and sibling-based crossover inference. Applied to the UK Biobank (discovery cohort) and Estonian Biobank (replication cohort), this scalable approach enabled parent-of-origin inference for up to 221,062 individuals, representing the largest dataset of its kind.GWAS scans in the UK Biobank for more than 60 complex traits and over 2,400 protein levels contrasting maternal and paternal effects identified over 30 novel POEs and confirmed more than 50% of testable known associations. Notably, approximately half of our POEs exhibited a bi-polar pattern, where maternal and paternal alleles exert conflicting effects. These effects were particularly prevalent for traits related to growth (e.g., IGF-1, height, fat-free mass) and metabolism (e.g., type 2 diabetes, triglycerides, glucose). Replication in the Estonian Biobank and in 45,402 offspring from the Norwegian Mother, Father and Child Cohort Study validated over 75% of testable associations.Overall, our findings shed new light on the influence of POEs on diverse complex traits and align with the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon.
Dnmt3a-dependentde novoDNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells
Authors: Perkins Bryant , Novis Camille L. , Baessler Andrew , Sircy Linda M. , Thomas Monyca M. , Harrison-Chau Malia , Richens Andrew W. , Fuchs Bryce , Nguyen Nguyen X. , Flint Kaitlyn , Strobelt Brittany M. , Varley Katherine E. , Hale J. Scott 
Published: December 2024

ABSTRACTFollowing acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. We demonstrate that Tfh and Th1 lineages acquire distinct Dnmt3a-dependentde novoDNA methylation programs that are preserved into memory.Dnmt3adeletion impairs lineage commitment and functionality of memory Th1 and Tfh cells, resulting in aberrantRunx1upregulation that represses germinal center Tfh cell differentiation. In contrast, transient pharmacological DNA methyltransferase inhibition during priming impairs repression of Tfh-associated genes while properly silencingRunx1, and results in enhanced Tfh cell functionality in primary and secondary responses to viral infections. Together, these findings demonstrate that Dnmt3a-mediated epigenetic programing is required to enforce T helper lineage commitment and preserve Tfh and Th1-specific functions during the recall response to infection, and reveal novel strategies to improve long-lived adaptive immunity against infectious diseases.SUMMARYThis article demonstrates that Dnmt3a-dependent epigenetic programing regulates functionality and plasticity of Th1 and Tfh memory cells. Furthermore, early pharmacological inhibition of such programing enhances GC Tfh cell differentiation, suggesting novel strategies for modulating the immune response to viral infections.
The R-loop Grammar predicts R-loop formation under different topological constraints
Authors: Ferrari Margherita Maria , Poznanović Svetlana , Riehl Manda , Lusk Jacob , Hartono Stella , González Georgina , Chédin Frédéric , Vázquez Mariel , Jonoska Nataša 
Published: December 2024

AbstractR-loops are transient three-stranded nucleic acids that form during transcription when the nascent RNA hybridizes with the template DNA, freeing the DNA non-template strand. There is growing evidence that R-loops play important roles in physiological processes such as control of gene expression, and that they contribute to chromosomal instability and disease. It is known that R-loop formation is influenced by both the sequence and the topology of the DNA substrate, but many questions remain about how R-loops form and the 3-dimensional structures that they adopt. Here we represent an R-loop as a word in a formal grammar called theR-loop grammarand predict R-loop formation. We train the R-loop grammar on experimental data obtained by single-molecule R-loop footprinting and sequencing (SMRF-seq). Despite not containing explicit topological information, the R-loop grammar accurately predicts R-loop formation on plasmids with varying starting topologies and outperforms previous methods in R-loop prediction.Author summaryR-loops are prevalent triple helices that play regulatory roles in gene expression and are involved in various diseases. Our work improves the understanding of the relationship between the nucleotide sequence and DNA topology in R-loop formation. We use a mathematical approach from formal language theory to define an R-loop language and a set of rules to model R-loops as words in that language. We train the resulting R-loop grammar on experimental data of co-transcriptional R-loops formed on different DNA plasmids of varying topology. The model accurately predicts R-loop formation and outperforms prior methods. The R-loop grammar distills the effect of topology versus sequence, thus advancing our understanding of R-loop structure and formation.
Fingerprinting and chemotyping approaches reveal a wide genetic and metabolic diversity among wild hops (Humulus lupulusL.)
Authors: Ducrocq Florent , Piutti Séverine , Henychová Alena , Villerd Jean , Laflotte Alexandre , Girardeau Loïc , Grosjean Jérémy , Patzak Josef , Hehn Alain 
Published: December 2024

AbstractHop (Humulus lupulusL.) is an emblematic industrial crop in the French North East region that developed at the same time as the brewing activity. Presently, this sector, especially microbreweries, are interested in endemic wild hops, which give beer production a local signature. In this study, we investigated the genetic and metabolic diversity of thirty-six wild hops sampled in various ecological environments. These wild accessions were propagated aeroponically and cultivated under uniform conditions (the same soil and the same environmental factors). Our phytochemical approach based on UHPLC-ESI-MS/MS analysis led to the identification of three metabolic clusters based on leaf content and characterized by variations in the contents of twelve specialized metabolites that were identified (including xanthohumol, bitter acids, and their oxidized derivatives). Furthermore, molecular characterization was carried out using sixteen EST-SSR microsatellites, allowing a genetic affiliation of our wild hops with hop varieties cultivated worldwide and wild hops genotyped to date using this method. Genetic proximity was observed for both European wild and hop varieties, especially for Strisselspalt, the historical variety of our region. Finally, our findings collectively assessed the impact of the hop genotype on the chemical phenotype through multivariate regression tree (MRT) analysis. Our results highlighted the ‘WRKY 224’ allele as a key discriminator between high– and low-metabolite producers. Moreover, the model based on genetic information explained 40% of the variance in the metabolic data. However, despite this strong association, the model lacked predictive power, suggesting that its applicability may be confined to the datasets analyzed.
Characterization and whole genome sequencing ofSaccharomyces cerevisiaestrains lacking several amino acid transporters: tools for studying amino acid transport
Authors: Sonawala Unnati , Busidan Aymeric , Haak David , Pilot Guillaume 
Published: December 2024

AbstractSaccharomyces cerevisiaemutants have been used since the early 1980s as a tool to characterize genes from other organisms by functional complementation. This approach has been extremely successful in cloning and studying transporters, for instance, plant amino acid, sugar, urea, ammonium, peptide, sodium, and potassium were characterized using yeast mutants lacking these functions. Over the years, new strains lacking even more endogenous transporters have been developed, enabling the characterization of transport properties of heterologous proteins in a more precise way. Furthermore, these strains provide the added advantage of characterization of a transporter belonging to a family of proteins in isolation, and thus can be used to study the relative contribution of redundant transporters to the whole function. We focused on amino acid transport; starting with the yeast strain 22Δ8AA, developed to clone plant amino acid transporters in the early 2000s. We recently deleted two additional amino acid permeases, Gnp1 and Agp1, creating 22Δ10α. In the present work, five additional permeases (Bap3, Tat1, Tat2, Agp3, Bap2) were deleted from 22Δ10α genome in up to a combination of three at a time. Unexpectedly, the amino acid transport properties of the new strains were not very different from the parent, suggesting that these amino acid permeases play a minor role in amino acid uptake in our conditions. The inability to grow on a few amino acids as the sole nitrogen sources did not correlate with lower uptake activity, questioning the well-accepted relationship between lack of growth and loss of transport properties. Finally, in order to verify the mutations and the integrity of 22Δ10α genome, we performed whole-genome sequencing of 22Δ10α using long-read PacBio sequencing technology. We successfully assembled 22Δ10α’s genomede novo, identified all expected mutations and precisely characterized the nature of the deletions of the ten amino acid transporters. The sequencing data and genome will serve as a resource to researchers interested in using these strains as a tool for amino acid transport study.
Association between the use of levodopa/carbidopa and the disease outcomes included in the National Alzheimer’s Coordinating Center Uniform Data Set
Authors: Sárkány Zsuzsa , Damásio Joana , Macedo-Ribeiro Sandra , Martins Pedro M. 
Published: December 2024

AbstractINTRODUCTIONThis retrospective study investigates whether exposition to levodopa/carbidopa (LA/CA) medication is associated with modified Alzheimer’s disease (AD) trajectories.METHODSMultivariate analysis used cerebrospinal fluid (CSF) biomarker information included in the National Alzheimer’s Coordinating Center Uniform Data Set for subjects with normal cognition (NC), mild cognitive impairment (MCI) and dementia (DE). Survival analyses examined the progression to MCI/DE and death events.RESULTSLA/CA use is associated with lower levels of CSF amyloid beta, phosphorylated tau (P-tau) and total Tau. After adjusting for age, sex and APOE ε4 allele presence, that effect was quantified by negative coefficients of the fitted linear mixed models − P values <0.01 in all cases except for P-tau in the MCI subgroup (P=0.02). No similar effects were identified for other antiparkinsonian drugs. Exposition to LA/CA decreased the progression from MCI to DE (P=0.03).DISCUSSIONThe identified effects of LA/CA exposition on AD biomarkers and progression deserve further investigation in controlled clinical trials.
Genome-wide Association Study of Complex Lipid Species: Results from the Population-based Rhineland Study
Authors: Landstra Elvire N. , Imtiaz Mohammed A. , Talevi Valentina , Eichelmann Fabian , Schulze Matthias B. , Aziz N. Ahmad , Breteler Monique M.B. 
Published: December 2024

AbstractThe human lipidome comprises numerous complex lipids, dysregulation of which can contribute to the pathogenesis of a wide range of diseases. Despite the high heritability of parts of the lipidome, the genetic architecture of many circulating lipid species and their structure remains mostly unknown. Thus, we performed genome-wide association studies on 970 lipid species and 267 fatty acid composite measures using samples from the population-based Rhineland Study (n=6,096). We validated our findings using corresponding data from two other independent cohorts, including FinnGen (n=7,266) and EPIC-Potsdam (n=1,188). Out of 217 lead genomic loci, we found 135 to be novel, such asFDFT1. Using mendelian randomization and individual-level gene expression data, we identified five possible causal associations between candidate genes and corresponding lipid species, includingFDFT1-diacylglycerol (16:0/18:0). Our findings provide new insights into the intricate genetic underpinnings of lipid metabolism, which may facilitate risk stratification and discovery of new therapeutic targets.
A 2-year calorie restriction intervention reduces glycomic biological age biomarkers
Authors: Pribić Tea , Das Jayanta K , Đerek Lovorka , Belsky Daniel W. , Orenduff Melissa , Huffman Kim M , Kraus William E , Deriš Helena , Šimunović Jelena , Štambuk Tamara , Hodžić Azra Frkatović , Kraus Virginia B , Das Sai Krupa , Racette Susan B. , Banskota Nirad , Ferruci Luigi , Pieper Carl , Lewis Nathan E , Lauc Gordan , Krishnan Sridevi 
Published: December 2024

AbstractBackground/ObjectiveIn a subset of participants from the CALERIE™ Phase 2 study we evaluated the effects of 2y of ∼25% Calorie Restriction (CR) diet on IgG N-glycosylation (GlycAge), plasma and complement C3 N-glycome as markers of aging and inflammaging.MethodsPlasma samples from 26 participants in the CR group who completed the CALERIE2 trial and were deemed adherent to the intervention (∼>10 % CR at 12 mo) were obtained from the NIA AgingResearchBiobank. Glycomic investigations using UPLC or LC-MS analyses were conducted on samples from baseline (BL), mid-intervention (12 mo) and post-intervention (24 mo), and changes resulting from the 2y CR intervention were examined. In addition, anthropometric, clinical, metabolic, DNA methylation (epigenetic) and skeletal muscle transcriptomic data were analyzed to identify aging-related changes that occurred in tandem with the N-glycome changes.ResultsFollowing the 2y CR intervention, IgG galactosylation was higher at 24mo compared to BL (p = 0.051), digalactosylation and GlycAge (the IgG-based surrogate for biological age) were not different between BL and 12mo or BL and 24mo, but increased between 12mo and 24mo (p = 0.016, 0.027 respectively). GlycAge was also positively associated with TNF-α and ICAM-1 (p=0.030, p=0.017 respectively). Plasma highly branched glycans were decreased by the 2y intervention (BL vs 24 mo: p=0.013), but both plasma and IgG bisecting GlcNAcs were increased (BL vs 24mo: p<0.001, p = 0.01 respectively). Furthermore, total complement C3 protein concentrations were reduced (BL vs 24mo: p <0.001), as were Man9 glycoforms (BL vs 24mo: p<0.001), and Man10 (which is glucosylated) C3 glycoforms (BL vs 24mo: p = 0.046).Conclusions24-mos of CR was associated with several favorable, anti-aging, anti- inflammatory changes in the glycome: increased galactosylation, reduced branching glycans, and reduced GlycAge. These promising CR effects were accompanied by an increase in bisecting GlcNAc, a known pro-inflammatory biomarker. These intriguing findings linking CR, clinical, and glycomic changes may be anti-aging and inflammatory, and merit additional investigation.
Real-World Evidence on Dose-Reduction and Treatment Outcomes in Small Cell Lung Cancer; A Bayesian mixed effects and Competitive Risk Approach
Authors: Marzano Luca , Dan Asaf , Darwich Adam S. , De Petris Luigi , Tendler Salomon , Lewensohn Rolf , Raghothama Jayanth , Meijer Sebastiaan 
Published: December 2024

ABSTRACTBackgroundSmall cell lung cancer (SCLC) is a challenging disease to treat due to rapid progression, development of chemo-resistance, and discrepancies in outcomes between real-world data and clinical trials. Previous studies lack comprehensive analyses of intermediate events and the treatment process, such as treatment decisions, progression of disease, and the occurrence of adverse events (AEs) over time. The aim of this study was to apply advanced statistical methods on a longitudinal SCLC data set in order to identify factors of importance for the risk of AEs and for survival.MethodsInformation was collected on the treatment pathways of 421 SCLC patients treated at the Karolinska University Hospital between 2016-2022 (Stockholm, Sweden). Analysis focused on the impact of dose-adjustment on adverse events (AEs), including neutropenia, by estimating odds ratios (OR) using Bayesian mixed-effects modelling. Covariate’s effects on ECOG performance status (PS) deterioration and early discontinuation of chemotherapy with cause-specific hazard ratios (csHR) were explored using competitive risk models. This approach was applied to cohorts of patients receiving first line platinum etoposide, and second line platinum etoposide or platinum irinotecan.ResultsAt the end of the first line treatment, most patients exhibited tumour regression (n=167). Patients with neutropenia had longer overall survival (HR: 0.70 [0.53, 0.92]). Higher etoposide dose levels were associated with subsequent occurrences of AEs (OR: 5.97 [1.41, 30.5]) and neutropenia (OR: 3.55 [1.03, 13.3]). Dose adjustment did not affect overall survival as long as the patient completed the four-dose regimen treatment. For the second-line, fewer patients completed four treatment cycles and the most common reason of early discontinuation was tumour progression (n=72). Male patients experienced fewer AEs and better first line treatment response compared to females (csHR: 0.51 [0.25, 0.90]). High-risk patients (here defined as ECOG PS 2-3, or age over 75 years) with early discontinuation of therapy had survival outcomes similar to those who did not receive therapy.ConclusionsOur results indicate that SCLC therapies may benefit from more individualized dosing strategies. These strategies would aim to balance improved survival with reduced risk of AEs, particularly neutropenia. It would also be beneficial to assess the risk-benefit of treating specific subgroups, including patients receiving second line therapy. Real-world data are crucial for studying therapy response and risk-benefit of treating patient groups that are underrepresented in clinical trials.
Evolution in response to prophage activation attenuates the virulence of culturableSerratia symbioticarelatives of aphid endosymbionts
Authors: VanDieren Anthony J. , Barrick Jeffrey E. 
Published: December 2024

ABSTRACTSerratia symbioticabacteria exhibit a range of relationships with aphids. They may be co-obligate mutualists, commensals, or even pathogens depending on the strain, aphid host species, and environment.Serratia symbioticaCWBI-2.3T(CWBI), a culturable member of this group, is transmitted to embryos transovarially when it is injected into pea aphids (Acyrthosiphon pisum), the same route used byS. symbioticastrains that are vertically inherited endosymbionts. Yet, aphids colonized with CWBI die before they give birth to infected offspring. We evolved laboratory populations of CWBI through 15-30 serial passages at two different temperatures in rich media. These conditions mimic aspects of the nutritional environment in aphid hosts that lead to the evolution of reduced endosymbiont genomes. Unexpectedly, allS. symbioticapopulations propagated at one temperature appeared to evolve slower growth after only a few days due to reactivation of a lytic prophage from the CWBI genome. Though these populations continued to reach saturating cell densities slower than cultures of the ancestor throughout the experiment, most bacteria in them had mutations affecting lipopolysaccharide biosynthesis and were resistant to the phage. Some evolved strains exhibited less virulence when injected into aphids, and we observed instances of gene inactivation and loss mediated by insertion elements. Our results illustrate how transposons and prophages can dominate laboratory evolution of newly cultured bacteria, particularly those that are host-associated in nature and have genomes rife with selfish DNA elements. They also suggest that bacteria-phage coevolution can catalyze evolutionary paths that contribute to converting pathogens into stably inherited endosymbionts.IMPORTANCELaboratory experiments can be used to explore evolutionary innovations in how microbes associate with animal hosts.Serratia symbioticabacteria exhibit a variety of interactions with aphids. Some strains are obligate endosymbionts. Others have facultative associations with benefits or costs depending on the environmental context.S. symbioticaCWBI-2.3T(CWBI) resembles aphid endosymbionts in how it can be transovarially transmitted to aphid embryos. However, adults injected with CWBI do not survive long enough to give birth to infected offspring. We evolved this aphid protosymbiont in rich media to see if this would attenuate its virulence and recapitulate genome reduction observed in endosymbionts. We observed large deletions and gene inactivation, but reactivation of a prophage from the CWBI genome and then evolution of phage resistance dominated. Some evolved strains became less virulent to aphids, suggesting that evolution driven by selfish DNA elements can contribute to the emergence of new endosymbionts from pathogen ancestors.