bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy
Authors: Khetarpal Sumeet A. , Li Haobo , Vitale Tevis , Rhee James , Grauvogel Louisa , Castro Claire , Mittenbühler Melanie J. , Houstis Nicholas E. , Vargas-Castillo Ariana , Smythers Amanda L. , Liu Jing , Curtin Casie , Sprenger Hans-Georg , Blackmore Katherine A. , Kuznetsov Alexandra , Freeman Rebecca , Bogoslavski Dina , Ellinor Patrick T. , Asnani Aarti , Dumesic Phillip A. , Puigserver Pere , Roh Jason D. , Spiegelman Bruce M. , Rosenzweig Anthony 
Published: February 2024

SummaryExercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1α is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1α, but it is unclear whether cardiomyocyte PGC-1α is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1α is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1α, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1α as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1α-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1α-deficient mice during endurance training. Finally, we show that cardiomyocytePPARGC1Aexpression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1α as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.
Chronic Pod-Mod E-Cigarette Aerosol Exposure Induces Aortic Dysfunction in Hypercholesterolemic Mice: Role of Oxidative Stress and Inflammation
Authors: Farra Yasmeen M. , Matz Jacqueline , Wilker Hannah , Kim Hannah , Rivera Cristobal , Vlahos John , Ramkhelawon Bhama , Oakes Jessica M. , Bellini Chiara 
Published: February 2024

ABSTRACTObjectiveElectronic (e-)cigarettes are the most used tobacco product amongst youth, and adult smokers favor e-cigarettes over approved cessations aids. Despite the lower perceived harm of vaping compared to smoking, inhalation of e-cigarette aerosol elicits cardiovascular responses that may lead to permanent injury when repeated over time. We thus aimed to infer the long-term outcomes of vaping on the function and structure of the aorta and shed light on the underlying cellular and molecular mechanisms.Approach and ResultsWe exposed female hypercholesterolemic mice to either pod-mod e-cigarette aerosol or room air daily for 24 weeks. Chronic inhalation of e-cigarette aerosol triggered accumulation of inflam-matory signals systemically and within aortic tissues, as well as T lymphocyte accrual in the aortic wall. Reduced eNOS expression and enhanced ROS production following eNOS uncoupling and NADPH oxi-dase activation curbed nitric oxide availability in the aorta of mice exposed to e-cigarette aerosol, impairing the endothelium-dependent vasodilatation that regulates blood flow distribution. Inhalation of e-cigarette aerosol thickened and stiffened aortic tissues via collagen deposition and remodeling, hindering the storage of elastic energy and limiting the cyclic distensibility that enables the aorta to function as a pressure reservoir. These effects combined contributed to raising systolic and pulse pressure above control levels.ConclusionsChronic inhalation of aerosol from pod-mod e-cigarettes promotes oxidative stress, inflammation, and fibrosis within aortic tissues, significantly impairing passive and vasoactive aortic functions. This evidence provides new insights on the biological processes that increase the risk for adverse cardio-vascular events as a result of pod-mod e-cigarette vaping.
Population-based analysis of knee joint loading in a knee osteoarthritis cohort: the impact of PCA-derived gait kinematic variations on estimated medial knee contact forces
Authors: Di Raimondo Giacomo , Willems Miel , Killen Bryce Adrian , Havashinezhadian Sara , Turcot Katia , Vanwanseele Benedicte , Jonkers Ilse 
Published: February 2024

AbstractOsteoarthritis (OA) is a prevalent musculoskeletal condition leading to functional limitations, especially among the elderly. Current treatments focus on pain relief and functional improvement, however there is a lack of approaches which slow disease progression. A promising approach focusses on reducing knee joint loading, as excessive loading contributes to knee OA progression. This study explores kinematic variations in the knee OA population, utilizing principal component analysis (PCA) to examine gait variations (primitives) in both healthy individuals and those with knee osteoarthritis (KOA) and their implications for knee joint loading. The KOA population exhibited 14 modes of variation representing 95% of the cumulative variance, compared to 20 in the healthy population, indicating lower variability with KOA. The relation between identified gait primitives and knee loading parameters, revealed complex relationships. Surprisingly, modes with the largest kinematic variations did not consistently correspond to the highest variations in knee loading parameters revealing degrees of freedom which may have a larger role in determining joint loading. Moreover, potential gait-retraining strategies for KOA, associating specific kinematic combinations with altered knee loading were identified. The results showed a good agreement with previously applied strategies. However, this study highlights the importance of analyzing whole-body kinematics for effective gait retraining, as opposed to focusing on one single joint variation. The study’s insights contribute to understanding the intricate interplay between gait pattern variations and knee joint loading changes in healthy and KOA populations, offering practical applications for guiding interventions and estimating loading parameters.
A Stacking Framework for Polygenic Risk Prediction in Admixed Individuals
Authors: Liao Kevin , Zöllner Sebastian 
Published: February 2024

1.1AbstractPolygenic risk scores (PRS) are summaries of an individual’s personalized genetic risk for a trait or disease. However, PRS often perform poorly for phenotype prediction when the ancestry of the target population does not match the population in which GWAS effect sizes were estimated. For many populations this can be addressed by performing GWAS in the target population. However, admixed individuals (whose genomes can be traced to multiple ancestral populations) lie on an ancestry continuum and are not easily represented as a discrete population.Here, we propose slaPRS (stackinglocalancestryPRS), which incorporates multiple ancestry GWAS to alleviate the ancestry dependence of PRS in admixed samples. slaPRS uses ensemble learning (stacking) to combine local population specific PRS in regions across the genome. We compare slaPRS to single population PRS and a method that combines single population PRS globally. In simulations, slaPRS outperformed existing approaches and reduced the ancestry dependence of PRS in African Americans. In lipid traits from African British individuals (UK Biobank), slaPRS again improved on single population PRS while performing comparably to the globally combined PRS. slaPRS provides a data-driven and flexible framework to incorporate multiple population-specific GWAS and local ancestry in samples of admixed ancestry.
Socioeconomic correlates of urban mobility trends in two Australian cities during transitional periods of the COVID-19 pandemic
Authors: Kollepara Pratyush , Dey Subhrasankha , Tomko Martin , Martino Erika , Bentley Rebecca , Tizzoni Michele , Geard Nicholas , Zachreson Cameron 
Published: February 2024

AbstractDuring the COVID-19 pandemic, both government-mandated lockdowns and discretionary changes in behaviour combined to produce dramatic and abrupt changes to human mobility patterns. To understand the socioeconomic determinants of intervention compliance and discretionary behavioural responses to epidemic threats, we investigate whether changes in human mobility showed a systematic variation with socioeconomic status during two distinct periods of the COVID-19 pandemic in Australia. We analyse mobility data from two major urban centres and compare the trends during mandated stay-at-home policies and after the full relaxation of NPIs, which coincided with a large surge of COVID-19 cases. We analyse data aggregated from de-identified GPS trajectories, collated from providers of mobile phone applications and aggregated to small spatial regions. Our results demonstrate systematic decreases in mobility relative to pre-pandemic baseline with the Index of Education and Occupation, for both pandemic periods. On the other hand, the Index of Economic Resources was not correlated with mobility changes. This result contrasts with observations from other national contexts, where reductions in mobility typically increased strongly with indicators of wealth. We interpret these findings in the context of the economic policies put in place by Australian authorities to subsidise household incomes and maintain the essential workforce.
Automated Deep Learning Segmentation of Cardiac Inflammatory FDG PET
Authors: Poitrasson-Rivière Alexis , Vanderver Michael D. , Hagio Tomoe , Arida-Moody Liliana , Moody Jonathan B. , Renaud Jennifer M. , Ficaro Edward P. , Murthy Venkatesh L. 
Published: February 2024

AbstractBackgroundFluorodeoxyglucose positron emission tomography (FDG PET) with glycolytic metabolism suppression plays a pivotal role in diagnosing cardiac sarcoidosis. Reorientation of images to match perfusion datasets is critical and myocardial segmentation enables consistent image scaling and quantification. However, both are challenging and labor intensive. We developed a 3D U-Net deep learning (DL) algorithm for automated myocardial segmentation in cardiac sarcoidosis FDG PET.MethodsThe DL model was trained on 316 patients’ FDG PET scans, and left ventricular contours derived from perfusion datasets. Qualitative analysis of clinical readability was performed to compare DL segmentation with the current automated method on a 50-patient test subset. Additionally, left ventricle displacement and angulation, as well as SUVmax sampling were compared to inter-user reproducibility results.ResultsDL segmentation enhanced readability scores in over 90% of cases compared to the standard segmentation currently used in the software. DL segmentation performed similarly to a trained technologist, surpassing standard segmentation for left ventricle displacement and angulation, as well as correlation of SUVmax.ConclusionThe DL-based automated segmentation tool presents a marked improvement in the processing of cardiac sarcoidosis FDG PET, promising enhanced clinical workflow. This tool holds significant potential for accelerating clinical practice and improving consistency and quality. Further research with varied datasets is warranted to broaden its applicability.
Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
Authors: Touvier Thierry , Veneri Francesca A. , Claessens Anke , Ferri Cinzia , Mastrangelo Rosa , Sorgiati Noémie , Bianchi Francesca , Valenzano Serena , Del Carro Ubaldo , Rivellini Cristina , Duong Phu , Shy Michael E. , Kelly Jeffery W. , Svaren John , Wiseman R. Luke , D’Antonio Maurizio 
Published: February 2024

AbstractMutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing ofXbp1mRNA to generate splicedXbp1(Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models whereXbp1is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed thatXbp1is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However,Xbp1deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy inXbp1deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
The Effect of Adrenalectomy on Bleomycin-Induced Pulmonary Fibrosis in Mice
Authors: McGovern John , Perry Carrighan , Ghincea Alexander , Shao Shuai , Herzog Erica L. , Sun Huanxing 
Published: February 2024

AbstractProgressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA), and hormones such as aldosterone (ALD). The essential functions of adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that the bleomycin induced collagen over deposition in the lung was not affected by adrenalectomy. However, histologic indices of lung remodeling were ameliorated by adrenalectomy. These findings were accompanied by a decrease in bronchoalveolar lavage (BAL) cell count along with concomitant reductions in alpha smooth muscle actin (⍺SMA) and fibronectin. Surgical adrenalectomy completely abrogated AD detection in all compartments, but only reduced NA in the BAL of uninjured mice. Systemic ALD levels were reduced after adrenalectomy. Taken together, these results support the presence of pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies.
Model mimicry limits conclusions about neural tuning and can mistakenly imply unlikely priors
Authors: Wolff Michael J. , Rademaker Rosanne L. 
Published: February 2024

In a recent issue of Nature Communications, Harrison, Bays, and Rideaux1use electroencephalography (EEG) to infer population tuning properties from human visual cortex, and deliver a major update to existing knowledge about the most elemental building block of visual perception – orientation tuning. Using EEG together with simulations in an approach they refer to as “generative forward modeling”, the authors adjudicate between two competing population tuning schemes for orientation tuning in visual cortex. They claim that a redistribution of orientation tuning curves can explain their observed pattern of EEG results, and that this tuning scheme embeds a prior of natural image statistics that exhibits a previously undiscovered anisotropy between vertical and horizontal orientations. If correct, this approach could become widely used to find unique neural coding solutions to population response data (e.g., from EEG) and to yield a “true” population tuning scheme deemed generalizable to other instances. However, here we identify major flaws that invalidate the promise of this approach, which we argue should not be used at all. First, we will examine the premise of Harrison and colleagues1, to subsequently explain why “generative forward modeling” cannot circumvent model mimicry pitfalls and can deliver many possible solutions of unknowable correctness. Finally, we show a tentative alternative explanation for the data.Conflict of interestThe authors declare no conflict of interest
Cardiovascular and Locomotor Effects of Binary Mixtures of Common “Bath Salts” Constituents: Studies with Methylone, MDPV, and Caffeine in Rats
Authors: Seaman Robert W. , Galindo David G. , Stinson Benjamin T. , Sulima Agnieszka , Rice Kenner C. , Javors Martin A. , Ginsburg Brett C. , Collins Gregory T. 
Published: February 2024

ABSTRACTBackground and PurposeThe use of “Bath Salts” drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among “Bath Salts” constituents contribute to the adverse effects often reported in users.Experimental ApproachThis study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures. Dose-addition analyses were used to determine the effect levels predicted for a strictly additive interaction for each dose pair.Key ResultsMethylone, MDPV, and caffeine increased heart rate and locomotion, with methylone producing the largest increase in heart rate, MDPV producing the largest increase in locomotor activity, and caffeine being the least effective in stimulating heart rate and locomotor activity. MDPV and caffeine increased mean arterial pressure, with caffeine being more effective than MDPV. The nature of the interactions between methylone and MDPV tended toward sub-additivity for all endpoints, whereas interactions between MDPV or methylone and caffeine tended to be additive or sub-additive for cardiovascular endpoints, and additive or supra-additive for increases in locomotion. No pharmacokinetic interactions were observed between individual constituents, but methylone displayed non-linear pharmacokinetics at the largest dose evaluated.Conclusion and ImplicationsThese findings demonstrate that the composition of “Bath Salts” preparations can impact both cardiovascular and locomotor effects and suggest that such interactions among constituent drugs could contribute to the “Bath Salts” toxidrome reported by human users.What is already known“Bath Salts” preparations are associated with a sympathomimetic toxidrome in human users.What this study addsCharacterization of both pharmacokinetic and pharmacodynamic interactions between common “Bath Salts” constituents with regard to cardiovascular and locomotor effects.Clinical SignificanceThe vast majority of drug overdose deaths involve more than one substance. Though these studies focused on combinations of stimulant drugs, they provide direct evidence that the toxidrome resulting from multi-drug overdoses can be significantly different than would be expected for a single drug.
The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces
Authors: Kellner Anna V. , Hunter Rae , Do Priscilla , Eggert Joel , Jaffe Maya , Geitgey Delaney K. , Lee Miyoung , Hamilton Jamie A. G. , Ross Anthony J. , Ank Raira S. , Bender Rachel L. , Ma Rong , Porter Christopher C. , Dreaden Erik C. , Au-Yeung Byron B. , Haynes Karmella A. , Henry Curtis J. , Salaita Khalid 
Published: February 2024

AbstractObesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.