bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term Outcomes of Peripheral Artery Disease In Veterans: Analysis of the PEripheral ARtery Disease Long-term Survival Study (PEARLS)
Authors: Girotra Saket , Li Qiang , Vaughan-Sarrazin Mary , Lund Brian C. , Al-Garadi Mohammad , Beckman Joshua A. , Nathani Rohit , Hoffman Richard M. , Chan Paul S. , Banerjee Subhash , Tsai Shirling , Kumbhani Dharam J. , Minniefield-Young Nicole , Smolderen Kim G. , Arya Shipra , Nguyen Cathy , Matheny Michael E. , Gobbel Glenn T. 
Published: August 2024

AbstractBackgroundContemporary research in peripheral artery disease (PAD) remains limited due to lack of a national registry and low accuracy of diagnosis codes to identify PAD patients in electronic health records.Methods & ResultsLeveraging a novel natural language processing (NLP) system that identifies PAD with high accuracy using ankle brachial index (ABI) and toe-brachial index (TBI) values, we created a registry of 103,748 patients with new onset PAD patients in the Veterans Health Administration (VHA). Study endpoints include mortality, cardiovascular (hospitalization for acute myocardial infarction or stroke) and limb events (hospitalization for critical limb ischemia or major amputation) and were identified using VA and non-VA encounters. The mean age was 70.6 years; 97.3% were males, and 18.5% self-identified as Black race. The mean ABI value was 0.78 (SD: 0.26) and the mean TBI value was 0.51 (SD: 0.19). Nearly one-third (32.4%) patients were currently smoking and 35.4% formerly smoked. Prevalence of hypertension (86.6%), heart failure (22.7%), diabetes (54.8%), renal failure (23.6%), and chronic obstructive pulmonary disease (35.4%) was high. At 1-year, 9.4% of patients had died. The 1-year incidence of cardiovascular events was 5.6 per 100 patient-years and limb events was 4.5 per 100 patient-years.ConclusionsWe have successfully launched a registry of >100,000 patients with a new diagnosis of PAD in the VHA, the largest integrated health system in the U.S. The ncidence of death and clinical events in our cohort is high. Ongoing studies will yield important insights regarding improving care and outcomes in this high-risk group.
The microbiota affects stem cell decision making inHydra
Authors: He Jinru , Klimovich Alexander , Kock Sabine , Dahmke Linus , Franzenburg Sören , Bosch Thomas C.G. 
Published: August 2024

AbstractResearch on microbial communities colonizing animals has revealed that the microbiota, despite its typical containment to surfaces, influences virtually all organ systems of the host. In absence of a natural microbiota, the host’s development can be disturbed, but how developmental programs are affected by the microbiota is still poorly understood. Removing the microbiota fromHydra, a classic model animal in developmental biology, causes drastic developmental malformations and leads to polyps that temporarily lack the ability to bud. Recolonizing non-budding germfreeHydrawith bacteria reverses this budding inhibition. Single-cell RNA sequencing and trajectory-based differential expression analysis showed that epithelial stem cell decision making is disturbed in non-budding polyps, whereby key developmental regulators are not expressed. This process is reversible by adding back bacteria. Transcriptionally silencing of one of the genes that failed to be activated in non-budding animals, GAPR1, led to polyps that have a significantly reduced budding capacity. The results show that maintaining a species-specific microbiota may enable the animal host to maintain its developmental program.Significance StatementAnimal developmental programs work within the context of coevolved associations with microbes. Here, we provide mechanistic evidence of the involvement of the microbiota in maintaining the pattern formation program ofHydrawith the asexual formation of buds in the lower part of the body column. We demonstrate that in the absence of bacteria key regulatory factors are not expressed, causing changes in stem cell trajectories that result in loss of budding capacity. This study provides a new perspective on the role that microbiota play during animal development and evolution.One Sentence SummaryMicrobiota interfere withHydra’s asexual reproduction via modulating its stem cell differentiation programs.
Bases for the selection of alternate foot placement during straight- and turning-gait
Authors: Kreter Nicholas , Fino Peter C. 
Published: August 2024

AbstractHumans typically plan foot placement strategy multiple steps in advance when walking across complex terrain. Planning steps in advance is beneficial for both upright stability and forward progress, but one drawback is that new obstacles can make planned foot placement location unsafe between planning and execution, necessitating a rapid shift to foot placement that impacts stability and progress. This study investigates the bases for selection of alternate foot placement during both straight- and turning-gait. Thirteen healthy young adults walked along a virtually projected walkway with precision footholds oriented in either a straight line or with a single 60°, 90°, or 120° turn to the right. On a subset of trials, participants were required to rapidly avoid stepping on select footholds. We found stereotyped alternate foot placement strategies across turn angles that differed by turn strategy. Alternate foot placement for step turns supported the walker’s instantaneous kinematics but not the planned change in trajectory; whereas foot placement for disrupted spin turns supported the walker’s anticipated change in trajectory. We conclude that when humans are forced to rapidly alter previously developed motor plans for foot placement, they utilize a rapid stereotyped behavior that changes based on the demand of the turn.
AalpiRNA-18529 regulates vitellogenesis ofAedes albopictusvia theGadd45a-mediated JNK-dependent nurse cell apoptosis pathway
Authors: Yang Lu , Gao Yonghui , Chen Yulan , Ren Shuyi , Guo Yifan , Liu Peiwen , Batool Khadija , Tang Jianxia , Gu Jinbao 
Published: August 2024

AbstractAedes albopictusshows a rapid global expansion and dramatic vectorial capacity for various arboviruses. Mosquitoes display distinct sexual dimorphisms, only adult females consume blood meals to complete ovarian follicle development. Therefore, cyclic reproduction in female mosquitoes serves as a foundation for the transmission of numerous disease-causing pathogens. Aedes have an expansion of the piRNA biogenesis genes, indicated that piRNA may play multiple functional roles in mosquitoes. Although the antiviral function of piRNA pathway in mosquitoes has been extensively studied, the role of piRNAs in mosquito reproduction remain to be further understood. In the present study, we first profiled the characteristics of sex-biased piRNAs in adultAe.albopictus. Then, we identified a female biased piRNA (Aalpi18529) in adult females, that was highly expressed in ovaries at blood feeding-dependent termination, and depended on PIWI5 and ago3 mediated biogenesis. Aalpi18529 overexpression suppressed ovarian development, and reduced fertility and fecundity in adult females post-bloodmeal. Furthermore, we demonstrated that Aalpi18529 can effectively repress its direct target, growth arrest and DNA-damage-inducible protein 45a (GADD45A), and eventually regulates ovarian development via theGadd45a-mediated JNK-dependent nurse cell apoptosis pathway. Our study is the first to report an endogenous piRNA, which trigger silencing of an important protein-coding gene by posttranscriptional regulation in mosquitoes, expanding our current understanding of the important and multiple roles of piRNAs in biological processes inAe. albopictus.Author SummaryHere, we conducted high throughput piRNA sequencing and comprehensive analysis of piRNA sex-based expression profiles in adult females and males of Aedes albopictus. Based on several established universal tools for research, we demonstrate an ovary-enriched endogenous piRNA, Aalpi-18529, is involved in the regulation of the apoptosis of nurse cells during vitellogenesis via the GADD45A/phosphorylated JNK (pJNK) axis and ultimately affects ovarian development. In general, uncovering the biological functions of sex-biased piRNAs in Aedes albopictus will enhance the understanding of piRNA roles in mosquito Sexual dimorphism (SD) and will provide provide more information about the high reproductive capacity of Aedes albopictus, which is essential to find alternative control strategies.Classification:Research Reports
EEG Biomarkers of Age-Related Memory Change
Authors: Broitman Adam W. , Healey M. Karl , Kahana Michael J. 
Published: August 2024

AbstractThe current study investigates whether electroencephalographic (EEG) activity reflects age-related memory changes during encoding. We recorded scalp EEG in 151 young adults (aged 18-30) and 37 older adults (aged 60-85) as they memorized lists of words. Subjects studied the word lists either under full attention or while performing a secondary task that required them to make semantic judgments about each word. Although the secondary task reduced recall among all subjects, differences in recall performance between the age groups were smaller when participants performed a secondary task at encoding. Older adults also exhibited distinct neural subsequent memory effects, characterized by less negativity in the alpha frequencies compared to young adults. Multivariate classifiers trained on neural features successfully predicted subsequent memory at the trial level in both young and older adults, and captured the differential effects of task demands on memory performance between young and older adults. The findings indicate that neural biomarkers of successful memory vary with both cognitive aging and task demands.Public significanceThe current study investigates the EEG spectral biomarkers of memory encoding in young and older adults, and identifies key features of neural activity associated with age-related memory change. We further find that age-related memory differences are smaller when participants perform a semantic judgment task during encoding, and that multivariate classifiers trained on the EEG data predict these effects.
Evaluating the quality of prostate cancer diagnosis recording in routinely collected primary care data for observational research: A study using multiple linked English electronic health records databases
Authors: Somathilake Gayasha , Ford Elizabeth , Armes Jo , Moschoyiannis Sotiris , Collins Michelle , Francsics Patrick , Lemanska Agnieszka 
Published: August 2024

AbstractBackgroundPrimary care data in the UK are widely used for cancer research, but the reliability of recording key events such as diagnoses remains uncertain. Data linkage can mitigate these uncertainties; however, researchers may avoid linkage due to high costs, tight timelines, and sample size limitations. Hence, this study aimed to assess the quality of prostate cancer (PCa) diagnoses in primary care. We utilised Clinical Practice Research Datalink (CPRD) primary care data linked to National Cancer Registration and Analysis Service (NCRAS) and Hospital Episode Statistics (HES) in England. We compared accuracy, completeness, and timing of diagnosis recording between sources to facilitate decision-making regarding data source selection for future research.MethodsIncident PCa diagnoses (2000-2016) for males aged ≥46 years recorded in at least one study data source were examined. The accuracy of a data source was estimated by the proportion of diagnoses recorded in the specific source that was also confirmed by any linked source. Completeness was estimated by identifying the proportion of all diagnoses in linked sources with a matching diagnosis in the specific source.ResultsThe study included 51,487 PCa patients from either source. CPRD demonstrated 86.9% accuracy and 68.2% completeness against NCRAS and 75.1% accuracy and 61.1% completeness against HES. Overall, CPRD showed the highest accuracy (93%) but the lowest completeness (60.7%). Diagnosis dates in CPRD were more concordant with NCRAS (90.6% within 6 months) than with HES (61.2%). Over time, accuracy and completeness improved, especially after 2004. Discrepancies in diagnosis dates revealed a median delay of 2 weeks in CPRD than NCRAS and 1 week than HES. CPRD Aurum exhibited better quality compared to GOLD.ConclusionsWhile the accuracy of PCa diagnoses in CPRD compared to linked sources was high, completeness was low. Therefore, linking to HES or NCRAS should be considered for improved case capture, acknowledging their inherent limitations.
Lateral hypothalamus drives early-onset sleep alterations in amyotrophic lateral sclerosis
Authors: Guillot Simon J. , Lang Christina , Simonot Marie , Knehr Antje , Stuart-Lopez Geoffrey , Weydt Patrick , Dorst Johannes , Kandler Katharina , Kassubek Jan , Wassermann Laura , Rouaux Caroline , Arthaud Sebastien , Luppi Pierre-Herve , Roselli Francesco , Ludolph Albert C. , Dupuis Luc , Bolborea Matei 
Published: August 2024

AbstractLateral hypothalamic neurons producing melanin-concentrating hormone (MCH) and orexin/hypocretin are involved in sleep regulation. Both MCH and orexin neurons are altered in amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. However, sleep alterations are currently poorly characterized in ALS, and could represent either early symptoms or late consequences of disease progression. Here, we characterized sleep architecture using polysomnography in cohorts of both early ALS patients without respiratory impairment and presymptomatic carriers of mutations leading to familial ALS. We observed prominent sleep alterations, including increased wake and decreased deep sleep (non-rapid eye movement—NREM3) in both cohorts, which were replicated in two mouse models of familial ALS,Sod1G86RandFusΔNLS/+mice. Importantly, altered sleep structure in mice was fully rescued byper osadministration of a dual-orexin receptor antagonist, and partially rescued by intracerebroventricular MCH supplementation. Thus, our study shows the existence of a primary sleep alteration in ALS, driven by abnormal MCH and orexin signalling.One Sentence SummaryAmyotrophic lateral sclerosis is a tragic uncurable motor neuron disease, in this study we decribed for the first time sleep alterations in symptomatic patients and healthy gene carrier which can be reverted byper osadministartion of a dual-orexin receptor antagonist in preclinical models.
aiHumanoid Simulations Uncover Dominant-Negative Effects in HNRNPH2-Related Neurodevelopmental Disorders
Authors: Danter WR 
Published: August 2024

AbstractHNRNPH2-related neurodevelopmental disorders (NDDs) encompass a spectrum of cognitive, motor, and systemic impairments driven by mutations in the HNRNPH2 gene. While these disorders have been linked to both gain-of-function (GOF) and loss-of-function (LOF) mutations, the precise mechanisms underlying their varied phenotypic features remain unclear. In this study, we employed advanced aiHumanoid simulations to conduct a virtual longitudinal analysis of HNRNPH2 mutations, spanning from birth through young adulthood. Our findings reveal that LOF mutations, particularly severe missense, and nonsense/frameshift mutations, exert dominant-negative effects that significantly impair neurodevelopmental outcomes.Through detailed comparison of mild versus severe mutations, we observed that severe LOF mutations lead to markedly worse cognitive, motor, and systemic deficits. These effects are compounded by the interference of mutant HNRNPH2 with the function of wild-type HNRNPH2 and potentially compensatory proteins such as HNRNPH1. Notably, our simulations indicate that the upregulation of HNRNPH1 observed in knockout models fails to compensate in the presence of dominant-negative mutations, highlighting a critical pathway disruption.This study not only elucidates the mechanistic basis of dominant-negative effects in HNRNPH2-related NDDs but also suggests new therapeutic avenues, including the enhancement of compensatory mechanisms and targeted inhibition of mutant HNRNPH2. The use of aiHumanoid simulations offers a powerful tool for predicting long-term outcomes and testing potential interventions, providing a robust platform for advancing the understanding and treatment of HNRNPH2-NDDs.Our findings underscore the importance of early diagnosis and intervention, particularly for patients with severe LOF mutations, and facilitate future research focused on mitigating the dominant-negative effects of these mutations.
Plasma triacylglycerol length and saturation level mark healthy aging groups in humans
Authors: Li Weisha , Schomakers Bauke V. , Weeghel Michel van , Grevendonk Lotte , Vaz Frédéric M. , Salomons Gajja S. , Schrauwen Patrick , Hoeks Joris , Gao Arwen W. , Houtkooper Riekelt H. , Janssens Georges E. 
Published: August 2024

AbstractComplex lipids, essential components in biological processes, exhibit conserved age-related changes that alter membrane properties, cellular functions, and are implicated as biomarkers and contributors to longevity and age-related diseases. While physical activity alleviates age-related comorbidities and physical impairments, comprehensive exploration of the underlying biological mechanisms, particularly at the level of complex lipids, remains limited. However, clinical studies suggest that physical activity may counteract these age-related lipidomic changes, presenting a promising avenue for intervention. We performed lipidomic profiling of plasma from an extensively characterized cohort of young and aged individuals. Annotating 1446 unique lipid species across 24 lipid classes we found the most prominent difference in older adults was an accumulation of triacylglycerols (TGs), with lower physical activity levels associated with higher TG levels in plasma and reduced physical functionality. Remarkably, lipid species in the TG class did not accumulate uniformly. Rather, our study unveiled a negative correlation between higher physical activity levels and TGs with shorter chain length and more double bonds in this demographic. Overall, our research highlights that plasma TG length and saturation level can help mark healthy aging groups in humans. These findings deepen our understanding of how aging affects complex lipids, and the influence of physical activity on this process.
Predictingin vivoconcentrations of dietary hop phytoestrogens by physiologically based kinetic modeling
Authors: Stevanoska Maja , Beekmann Karsten , Punt Ans , Sturla Shana J. , Aichinger Georg 
Published: August 2024

AbstractHop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information onin vivoconcentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of the safety profile of hop polyphenols and highlights the need for further research into their use as an alternative to hormone therapy in menopausal women.
The role of a non-native host plant in altering the seasonal dynamics of monarch development
Authors: DuBose James G. , Hoogshagen Mackenzie , de Roode Jacobus C. 
Published: August 2024

AbstractThe development and life history of many organisms have evolved to align with annual seasonal changes, but anthropogenic ecological changes have started to disrupt phenological dynamics. To understand the implications of these changes, tractable model systems are needed to identify the causes and consequences of phenological-seasonal asynchrony. Here, we investigate the potential of a non-native and tropical host plant whose phenology has been tuned to different seasonal dynamics to influence the seasonal developmental dynamics of the migratory monarch butterflyDanaus plexippus. Consistent with predictions, we found that the non-native host plant facilitated successful monarch development later into the fall and early winter, which is typically the season North American monarchs enter reproductive diapause and migrate to over-wintering locations. Furthermore, we found evidence that this success could partly be attributed to decreased thermal constraints on development experienced by monarchs reared onA. curassavica.
Mechanistic modeling of cell viability assays within silicolineage tracing
Authors: Mutsuddy Arnab , Huggins Jonah R. , Amrit Aurore , Erdem Cemal , Calhoun Jon C. , Birtwistle Marc R. 
Published: August 2024

AbstractData from cell viability assays, which measure cumulative division and death events in a population and reflect substantial cellular heterogeneity, are widely available. However, interpreting such data with mechanistic computational models is hindered because direct model/data comparison is often muddled. We developed an algorithm that tracks simulated division and death events in mechanistically detailed single-cell lineages to enable such a model/data comparison and suggest causes of cell-cell drug response variability. Using our previously developed model of mammalian single-cell proliferation and death signaling, we simulated drug dose response experiments for four targeted anti-cancer drugs (alpelisib, neratinib, trametinib and palbociclib) and compared them to experimental data. Simulations are consistent with data for strong growth inhibition by trametinib (MEK inhibitor) and overall lack of efficacy for alpelisib (PI-3K inhibitor), but are inconsistent with data for palbociclib (CDK4/6 inhibitor) and neratinib (EGFR inhibitor). Model/data inconsistencies suggest (i) the importance of CDK4/6 for driving the cell cycle may be overestimated, and (ii) that the cellular balance between basal (tonic) and ligand-induced signaling is a critical determinant of receptor inhibitor response. Simulations show subpopulations of rapidly and slowly dividing cells in both control and drug-treated conditions. Variations in mother cells prior to drug treatment all impinging on ERK pathway activity are associated with the rapidly dividing phenotype and trametinib resistance. This work lays a foundation for the application of mechanistic modeling to large-scale cell viability assay datasets and better understanding determinants of cellular heterogeneity in drug response.