bluuebunny/crossref_metadata_2025_split huggingface dataset:
Women’s Sociocultural Representations of HIV Pre-Exposure Prophylaxis and Intimate Partner Violence in Heterosexual Relationships: A Qualitative Story Method
Authors: Willie Tiara C. , Sharpless Laurel , Knight Deja , Shah Aashna , Antar Amina , Watts Z. Thomasina , Alexander Kamila A. , Kershaw Trace 
Published: February 2025

ABSTRACTObjectiveThe current study sought to assess women’s understanding of pre-exposure prophylaxis interest and initiation in heterosexually-active relationships with and without histories of intimate partner violence.Design2017-18 prospective cohort study with an embedded, story completion exercise in the 90-day follow-up such that participants were randomized to receive one of two versions of a story stem based on whether they experienced intimate partner violence.SettingConnecticut.Participants132 heterosexually-active, cisgender adult women residing in the state of Connecticut.Primary outcomes measuresOur primary outcome included identifying principal narratives that describes women’s conceptualizations of pre-exposure prophylaxis interest and initiation in heterosexually-active relationships.ResultsUsing both story mapping and thematic analysis techniques, four principal narratives were identified across the stories: 1) theInformed and Empowered PrEP User, 2) theClandestine PrEP User, 3) theHesitant PrEP Contemplator, and 4) theDisenfranchised PrEP Non-User. These novel narratives provide insights on how social, clinical, and interpersonal factors are underpinning heterosexually-active, cisgender adult women’s ability to display interest and initiate pre-exposure prophylaxis in their relationships.ConclusionsIf our findings are replicated in studies in different settings, it will provide substantial support for future prevention interventions adopting empowerment-centered approaches to refocus women’s needs in the context of PrEP initiation and healthy relationships.
Bayesian multistate modelling of prefrailty and frailty: a microsimulation study with weight management interventions for prevention in Asian settings
Authors: Zhang Xinyu , Jin Shihui , Song Haolong , Yeo Johnathan , Dickens Borame L 
Published: February 2025

BackgroundPre-frailty and frailty prevalence is increasing in the Western Pacific, resulting in substantial morbidity and mortality in older populations. Modelling frameworks are required to estimate the prevalence of frailty and potential impacts of ongoing population level nutritional interventions.MethodsUsing a microsimulation sociodemographic model of 3,353,032 individuals from 1990 to 2050, and data from the Singapore Longitudinal Ageing Study 2 of 3,270 participants, we developed a Bayesian multistate model of robust, pre-frailty and frailty stages with estimated transition probabilities by age, race, and gender for each body-mass index (BMI) category. We then explored four scenarios where nutritional and physical activity interventions are applied that modify the annual distribution of underweight, normal weight, overweight, obese I and obese II individuals.FindingsBetween 2011 and 2050, the overall prevalence of pre-frailty and frailty increased from 44.2% to 50.5%, and from 3.2% to 11.8% respectively. Reductions of 9,529 pre-frail (95% CI: 7,303-11,673) and 6,960 frail individuals (6,094-7,886) were estimated when underweights shifted to normal weights, 11,598 (8,270-15,184) and 57,131 (39,258-82,696) when obese II moved to obese I, and 21,091 (16,179-25,846) and 63,891 (45,372-90,072) when both groups shifted respectively. Total healthcare utilization decreases by 6.9% (5.5%-8.3%) with the latter intervention.InterpretationFrailty prevalence is projected to substantially increase by 2050 where large-scale weight management interventions could be utilised to avert cases of both pre-frailty and frailty in older individuals.
Exploring Microbiota-Associated Metabolites in Twins Discordant for Type 1 Diabetes
Authors: Flammer Elizabeth R. , Christopher Michael W. , Powers Esabella R. , Broncucia Hali , Steck Andrea K. , Gitelman Stephen E. , Garrett Timothy J. , Ismail Heba M. 
Published: February 2025

AbstractObjectiveIdentify microbial and microbiota-associated metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to gain insight into potential environmental factors that may influence T1D.Research Design and MethodsSerum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). Statistical analyses identified significant metabolites (p < 0.1) within three groups: All twins (combined group), MZ twins, and DZ twins.ResultsThirteen metabolites were identified as significant. 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in T1D individuals across all groups. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups.ConclusionsMetabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed.Article HighlightsWhy did we undertake this study? We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors.What is the specific question(s) we wanted to answer? We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D.What did we find? Thirteen metabolites were identified as significantly different.What are the implications of our findings? Our results show the dysregulation of several microbial metabolites in twin pairs, suggesting that the gut microbiome plays a role in the pathogenesis of T1D.
Evaluating risks and benefits of Newer Diabetes medications when Used in Routine care (ENDURe)
Authors: Colacci Michael , Hurst Mack , Fritz Jamie Lee , Olar Patricia , Ray Prachi , Verma Amol , Razak Fahad , Mamdani Muhammad , Quinn Kieran L. , Rosella Laura , Fralick Michael 
Published: February 2025

AbstractIntroductionSodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 analogues (GLP1a) improve clinical outcomes (e.g., myocardial infarction, stroke, death from CV causes) for adults with type 2 diabetes mellitus. The majority of available data from clinical trials and observational studies are from outpatients. Data on their effectiveness among hospitalized patients, however, are lacking.MethodsWe conducted a multicentre, retrospective, cohort study of adults aged 65 years and older with type 2 diabetes mellitus hospitalized between 2017 and 2023 in Ontario. We compared adults newly prescribed an SGLT2i or GLP1a in hospital to adults newly prescribed a DPP4i in hospital. In a sensitivity analysis, new use of sulfonylurea was the comparator. Our primary outcome was the 1-year risk of a composite of all-cause mortality, hospitalization with myocardial infarction, stroke, heart failure, or renal failure. Secondary outcomes included components of the composite, short-term (i.e., 30 day) risk of hypoglycemia, and the 1-year risk of DKA.ResultsWe identified 6,713 older adults with diabetes who were newly prescribed one of the following medications during an inpatient hospitalization: SGLT2i (N=1520), GLP1 (N=90), DPP4i (N=3726), sulfonylurea (N=1377). Because new use of GLP1 was rare in hospital, we updated our exposure group to SGLT2i alone. Adults who received an SGLT2i were typically younger, and more likely to have heart failure or coronary artery disease compared to adults who received a DPP4i or sulfonylurea. Among adults who received an SGLT2i, at 1-year the primary outcome occurred in 26% compared to 31% who newly received a DPP4i (adjusted hazard ratio [HR] 0.82 95% Confidence Interval [CI] 0.69,0.97). In our sensitivity analysis using sulfonylurea as the comparator group, the hazard ratio for the primary outcome was 0.97 (95% CI 0.80, 1.18). We did not identify an increased risk of DKA or hypoglycemia for SGLT2i compared to DPP4i, though patients receiving an SGLT2i did have a lower rate of 30-day readmission (HR 0.73, 95%CI 0.58-0.92).ConclusionAmong older adults with type 2 diabetes mellitus, newly prescribing an SGLT2i or GLP1 during a hospitalization was uncommon. New use of an SGLT2i was associated with improved outcomes compared to DPP4i but this finding was not robust when new use of a sulfonylurea was the comparator. Future larger studies are needed to provide more definitive results.
Arginine metabolism has a pivotal function for the encystation ofGiardia duodenalis
Authors: Klotz Christian , Leisering Ricarda , Hagen Kari D , Starcevich Hannah N , Ewald Christoph , Türken Samuel , Marquardt Malte , Schramm Saskia , Ehret Kasemo Totta , Marek Stefanie , Seeber Frank , Ignatius Ralf , Dawson Scott , Aebischer Toni 
Published: February 2025

AbstractArginine metabolism plays a key role in the energy metabolism of the intestinal parasiteGiardia duodenalis, an amitochondrial protozoan that infects humans and animals and causes significant morbidity. An arginine deiminase (ADI) has been implicated in virulence, but it is currently unknown if ADI allele variants from the different geneticG. duodenalissubgroups (assemblages) differ in function. Here, the hypothesis was tested that sequence variation detected betweenG. duodenalisADI alleles from the twoG. duodenalisassemblage types found in humans affects functional parameters of the enzyme with potential consequences in life cycle progression.The ADI enzyme affinity for arginine was drastically reduced in sub-assemblage AII isolates, a human specific assemblage, in comparison to zoonotic sub-assemblage AI and B isolates. We identified the two amino acid residues responsible for the lower substrate affinity of ADIAIIvariant. Using genetic approaches to generate ADI knockout mutants, biochemical approaches to unravel substrate affinity as well as cellular approaches to determine efficiency of life cycle progression, we show that ADI is essential for efficient encystation of the parasite and that the lower substrate affinity in ADIAIIcorrelates with lower encystation efficiency. We further demonstrate that arginine is essential for efficient encystation, and by generating ADI knock-out parasites we present evidence that ADI is the functional correlate for this arginine dependence.Thus, our data describe ADI as a quantitative trait that affects life cycle progression ofG. duodenaliswith putative clinical and epidemiological relevance.Author summaryIn the human pathogenic parasiteGiardia duodenalis, arginine deiminase (ADI) mediates the first step in the arginine dehydrolase pathway (ADH), metabolizing arginine to provide chemical energy in form of ATP. The bacterial-derived ADH pathway had been inherited by horizontal gene transfer, and ADI has been proposed as a virulence factor. We show here by biochemical and genetic approaches with ADI knock-out mutants that arginine and its metabolizing enzyme ADI are essential for efficient life cycle progression (encystation) to form infectious cysts. Furthermore, we show a drastically impaired arginine substrate affinity for the human-specificG. duodenalisgenotype AII in comparison to the zoonotic genotypes AI and B and identified the molecular entities responsible for this altered substrate affinity. This lower substrate affinity also correlated with lower cyst formation in the AII genotype.
Emergence of cooperation promoted by higher-order strategy updates
Authors: Wang Dini , Yi Peng , Hong Yiguang , Chen Jie , Yan Gang 
Published: February 2025

AbstractCooperation is fundamental to human societies, and the interaction structure among individuals profoundly shapes its emergence and evolution. In real-world scenarios, cooperation prevails in multi-group (higher-order) populations, beyond just dyadic behaviors. Despite recent studies on group dilemmas in higher-order networks, the exploration of cooperation driven by higher-order strategy updates remains limited due to the intricacy and indivisibility of group-wise interactions. Here we investigate four categories of higher-order mechanisms for strategy updates in public goods games and establish their mathematical conditions for the emergence of cooperation. Such conditions uncover the impact of both higher-order strategy updates and network properties on evolutionary outcomes, notably highlighting the enhancement of cooperation by overlaps between groups. Interestingly, we discover that the group-mutual comparison update – selecting a high-fitness group and then imitating a random individual within this group – can prominently promote cooperation. Our analyses further unveil that, compared to pairwise interactions, higher-order strategy updates generally improve cooperation in most higher-order networks. These findings underscore the pivotal role of higher-order strategy updates in fostering collective cooperation in complex social systems.Author summaryHuman societies often organize and cooperate within social groups, where relatives, friends, neighbors, and colleagues influence behavior at both group and individual levels. Individuals may exhibit biased or neutral attitudes when selecting a neighboring group and a peer within it for imitation or comparison, a process termed as higher-order strategy update. These selection preferences originate from four personality types: aggressive, open-minded, myopic, and passive. This work demonstrates that the open-minded type – indiscriminately imitating a peer within a well-functioning group – significantly promotes cooperation. The mathematical framework proposed in this study deepens the understanding of how decision-making within higher-order structures affects the emergence and spread of cooperative behaviors.
The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats
Authors: Paterson Alex , Loh Su-Yi , Gholami Shadi Kadijeh , Rogers Mark F , Murugan Dharmani Devi , Sau-Kuen Lam , Mustafa Mohammad Rais , Ott Benjamin P , Balaratnam Prusha , Mecawi Andre S , Murphy David , Hindmarch Charles C. T. 
Published: February 2025

AbstractBackgroundHypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.MethodsSHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis.ResultsIn total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate.ConclusionsT status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome
Species tree branch length estimation despite incomplete lineage sorting, duplication, and loss
Authors: Tabatabaee Yasamin , Zhang Chao , Arasti Shayesteh , Mirarab Siavash 
Published: February 2025

AbstractPhylogenetic branch lengths are essential for many analyses, such as estimating divergence times, analyzing rate changes, and studying adaptation. However, true gene tree heterogeneity due to incomplete lineage sorting (ILS), gene duplication and loss (GDL), and horizontal gene transfer (HGT) can complicate the estimation of species tree branch lengths. While several tools exist for estimating the topology of a species tree addressing various causes of gene tree discordance, much less attention has been paid to branch length estimation on multi-locus datasets. For single-copy gene trees, some methods are available that summarize gene tree branch lengths onto a species tree, including coalescent-based methods that account for heterogeneity due to ILS. However, no such branch length estimation method exists for multi-copy gene family trees that have evolved with gene duplication and loss. To address this gap, we introduce the CASTLES-Pro algorithm for estimating species tree branch lengths while accounting for both GDL and ILS. CASTLES-Pro improves on the existing coalescent-based branch length estimation method CASTLES by increasing its accuracy for single-copy gene trees and extends it to handle multi-copy ones. Our simulation studies show that CASTLES-Pro is generally more accurate than alternatives, eliminating the systematic bias toward overestimating terminal branch lengths often observed when using concatenation. Moreover, while not theoretically designed for HGT, we show that CASTLES-Pro maintains relatively high accuracy under high rates of random HGT.Code availabilityCASTLES-Pro is implemented inside the software package ASTER, available athttps://github.com/chaoszhang/ASTER.Data availabilityThe datasets and scripts used in this study are available athttps://github.com/ytabatabaee/CASTLES-Pro-paper.
Epigenetic and Transcriptomic Alterations Precede Amyloidosis in the Hippocampus of the Alzheimer’s DiseaseAppNL-G-FKnock in Mouse Model
Authors: Okhovat Mariam , Layman Cora , Davis Brett A. , Pederson Alexandra , O’Niel Abigail , Holden Sarah , Kessler Kat , Acharya Sonia , Wheeler Kandace J. , Nevonen Kimberly A. , Herrera Jarod , Ward Samantha , Vigh-Conrad Katinka , Adey Andrew , Raber Jacob , Carbone Lucia 
Published: February 2025

ABSTRACTDetecting and understanding the early stages of Alzheimer’s disease (AD) is essential for uncovering initial mechanisms of neuropathology and devising effective interventions. In this study, we leveraged the humanizedAppNL-G-Fmouse which exhibits early-onset amyloid pathology with a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type andAppNL-G-Fmice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus ofAppNL-G-Fmice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways associated with brain function, including neuron development and synaptic processes, highlighting a connection between blood methylation patterns and brain activity. This finding suggests the potential use of blood DNA methylation as a biomarker for the early detection of amyloidosis. Notably, we identified five candidate biomarker genes, includingRbfox1andCamta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential blood biomarkers.
RAB23 Modulates Signaling Protein Ciliary Homeostasis through Promoting RAB18-mediated Inward BBSome Transition Zone Passage
Authors: Sun Sheng-Nan , Sun Wen-Jian , Wei Yan , Fan Zhen-Chuan 
Published: February 2025

AbstractAs an intraflagellar transport (IFT) cargo adaptor, the BBSome targets the basal body region located just below the transition zone (TZ) before proceeding to cross the TZ for ciliary entry. This process of TZ crossing crucially governs BBSome presence and quantity available for signaling protein coupling within cilia, influencing the dynamic behavior of signaling proteins in cilia by controlling their ciliary removal. Our previous study revealed that the GTPase RAB18 binds to its BBSome effector in the basal bodies right below the TZ and recruits the BBSome to cross the TZ for ciliary entry by lateral transport between the plasma and ciliary membranes. However, the mechanism by which RAB18 is activated to accomplish this function has remained elusive. This study uncovers that, under physiological conditions,ChlamydomonasRAB23 in its GDP-bound state (RAB23-GDP) predominantly localizes to the same basal body region as RAB18-GDP and activates RAB18-GDP as a RAB18-specific guanine nucleotide exchange factor. RAB18-GDP attaches to the membrane and binds to the BBSome. This interaction occurs independently of anterograde IFT association, allowing the BBSome to diffuse through the TZ and enter cilia. Subsequently, RAB23-GDP facilitates its own ciliary entry by binding to the RAB18-GTP/BBSome entity as a BBSome cargo. Our findings establish a model where the BBSome enters cilia through the RAB23-RAB18 module-mediated inward BBSome TZ diffusion pathway. According to this model, hedgehog signaling defects caused byrab23mutations could induce Carpenter syndrome in humans, providing a mechanistic understanding behind the inward BBSome TZ passage required for proper ciliary signaling.Significance statementCertain ciliary signaling proteins are removed from cilia through the outward BBSome transition zone (TZ) diffusion pathway. The inward BBSome TZ crossing is orchestrated by RAB18. The current study unveils that RAB23 in its GDP-bound state (RAB23-GDP) and RAB18-GDP predominantly localize to the same basal body region located just below the TZ. RAB23-GDP activates RAB18-GDP as a RAB18-specific guanine nucleotide exchange factor. RAB18-GTP subsequently recruits the BBSome as its effector to cross the TZ for ciliary entry. Following this, RAB23-GDP enters cilia as a BBSome cargo. The regulatory interplay between RAB23 and RAB18, with RAB23 promoting inward BBSome TZ crossing via RAB18, establishes a molecular mechanism for the BBSome-dependent retrieval of signaling proteins from cilia.