Search

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

Abstract The earliest named stromatolite Cryptozoon Hall, 1884 (Late Cambrian, ca. 490 Ma, eastern New York State), was recently re-interpreted as an interlayered microbial mat and non-spiculate (keratosan) sponge deposit. This “classic stromatolite” is prominent in a fundamental debate concerning the significance or even existence of non-spiculate sponges in carbonate rocks from the Neoproterozoic (Tonian) onwards. Cryptozoon has three types of microbially-induced carbonate layers: clotted-pelletoidal micrite with microbial filaments, clotted-pelletoidal micrite with vesicular structure, and dense microcrystalline laminae. A fourth, stratiform to patchy fabric comprises suspect sponges. Using contextual fabric analysis, elemental mapping, cathodoluminescence, fluid inclusions, electron backscatter diffraction, U–Pb dating, and burial history, the sponge interpretation is denied. Neither a distinct sponge body outline nor a canal system is identifiable. Instead, the suspect fabric is secondary in origin, and best explained as a product of Carboniferous (Mississippian) deep burial alteration associated with basement reactivation. Key petrographic observations include heterogenous recrystallization via aggrading Ostwald ripening with interfingering reaction fronts typical for partially miscible fluids, a granoblastic calcite texture (incipient metamorphism), and subsequent hypidioblastic white mica (arguably Carboniferous/Permian, Alleghenian orogeny). Topotype Cryptozoon is a stromatolite altered to sub-greenschist metacarbonate. The published Tonian to Phanerozoic record of interpreted non-spiculate sponges requires reassessment.

The personal, social, and academic challenges during the transition from high school to college contribute to lower retention rates and lower GPAs. These challenges are even more pronounced for historically underserved populations. In light of the COVID-19 pandemic, students face new challenges and a lack of access to the typical resources and events to assist with their transition. In response to these challenges, an online summer support program was developed that focused on building academic self-efficacy, fostering a sense of belonging and connection to faculty and peers, and connecting students to campus resources. Survey results showed greater connection and self-efficacy for participants, and a one-way between-subjects ANCOVA indicated significantly higher first-term GPAs for those who participated (over 0.3 points higher on a 4-point scale). Initial qualitative interviews indicated overall positive student perceptions of their participation and the program's benefit.

Abstract/Introduction: Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1–4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population5–9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such asFGF21, ADIPOQ, GCGandIL6showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liverPCSK9) as well as genes encoding enzymes producing metabolites (adiposePNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource asGene-DerivedCorrelationsAcrossTissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

BACKGROUND: The contemporary burden and characteristics of coronary atherosclerosis, assessed using coronary computed tomography angiography (CCTA), is unknown among asymptomatic adults with diabetes and prediabetes in the United States. The pooled cohort equations and coronary artery calcium (CAC) score stratify atherosclerotic cardiovascular disease risk, but their association with CCTA findings across glycemic categories is not well established. METHODS: Asymptomatic adults without atherosclerotic cardiovascular disease enrolled in the Miami Heart Study were included. Participants underwent CAC and CCTA testing and were classified into glycemic categories. Prevalence of coronary atherosclerosis (any plaque, noncalcified plaque, plaque with ≥1 high-risk feature, maximal stenosis ≥50%) assessed by CCTA was described across glycemic categories and further stratified by pooled cohort equations-estimated atherosclerotic cardiovascular disease risk and CAC score. Adjusted logistic regression was used to evaluate the associations between glycemic categories and coronary outcomes. RESULTS: Among 2352 participants (49.5% women), the prevalence of euglycemia, prediabetes, and diabetes was 63%, 30%, and 7%, respectively. Coronary plaque was more commonly present across worsening glycemic categories (euglycemia, 43%; prediabetes, 58%; diabetes, 69%), and similar pattern was observed for other coronary outcomes. In adjusted analyses, compared with euglycemia, prediabetes and diabetes were each associated with higher odds of any coronary plaque (OR, 1.30 [95% CI, 1.05-1.60] and 1.75 [1.17-2.61], respectively), noncalcified plaque (OR, 1.47 [1.19-1.81] and 1.99 [1.38-2.87], respectively), and plaque with ≥1 high-risk feature (OR, 1.65 [1.14-2.39] and 2.53 [1.48-4.33], respectively). Diabetes was associated with stenosis ≥50% (OR, 3.01 [1.79-5.08]; reference=euglycemia). Among participants with diabetes and estimated atherosclerotic cardiovascular disease risk

Background: Limited data exist on the long-term impact of beta-blocker therapy after percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF). Objectives: The aim of the study was to evaluate the effects of early beta-blocker initiation vs no initiation following PCI in patients with stable CAD and preserved LVEF. Methods: This retrospective cohort study employed target trial emulation and incident user design, utilizing the TriNetx database (2009-2024). Early beta-blocker initiation (within days 1 and 7) was compared with no initiation using 1:1 greedy propensity score matching. The outcomes included all-cause mortality, hospitalization for myocardial infarction, heart failure, atrial fibrillation/flutter, stroke, and safety endpoints. Hospitalization for bone fracture and acute appendicitis served as falsification endpoints. In the intention-to-treat analysis, outcomes were analyzed over 5 years using Cox-proportional hazards. Results: Out of 11,681 matched patients per group, beta-blocker therapy was associated with increased all-cause mortality (HR: 1.11 [95% CI: 1.09-1.18]). No significant differences were found in hospitalization for myocardial infarction (HR: 1.03 [95% CI: 0.97-1.09]), stroke (HR: 0.98 [95% CI: 0.91-1.05]), heart failure (HR: 0.99 [95% CI: 0.95-1.03]), and atrial fibrillation/flutter (HR: 0.97 [95% CI: 0.93-1.01]). Hospitalization for hypotension was higher with beta-blockers (HR: 1.10 [95% CI: 1.06-1.14]). Hospitalization for bone fracture (HR: 1.02 [95% CI: 0.85-1.22]) and acute appendicitis (HR: 1.17 [95% CI: 0.95-1.45]) showed no significant associations. Several sensitivity analyses showed consistent results. Conclusions: Early beta-blocker initiation after PCI for stable CAD with preserved LVEF was associated with higher mortality, with no impact on cardiovascular events.

Background This study examined the longitudinal associations of psychosocial stress subgroups with cardiovascular disease (CVD) events and whether social support, neighborhood cohesion, and physical activity modified these associations in MESA (Multi‐Ethnic Study of Atherosclerosis). Methods and Results Data from 6349 adults (aged: 62.2 ± 10.2 years; 52.9% women) from the MESA study with no prior CVD in 2000 to 2002 (baseline) were used in this analysis. Latent class analysis was used to specify distinct psychosocial stress subgroups based on self‐reported stressors stemming from respondents' neighborhood and social environment. Adjudicated CVD events (fatal and nonfatal events) were ascertained annually through the year 2019. Cox proportional hazards models were used to examine the associations between subgroup membership and CVD events. Five distinct psychosocial stress subgroups were identified via latent class analysis and were labeled “moderate neighborhood noise” (12.1%), “excessive neighborhood noise” (6.4%), “multiple high stressors” (6.3%), “high discrimination” (21.4%), and “optimal” (53.8%). By 2019, 1121 participants had experienced a CVD event. Membership in the high discrimination (hazard ratio [HR], 1.29 [95% CI, 1.10–1.51]) subgroup was associated with higher risk of a CVD event when adjusted for sociodemographic characteristics and cardiovascular health metrics. Neither social support, neighborhood cohesion, nor physical activity modified this association (P>0.05). Conclusions Distinct subgroups of individuals with high self‐reported psychological distress—particularly related to discrimination and chronic stress are associated with high incident cardiovascular events.

The late seventh-century introduction of silver coinage marked a transformation in the economy of north-west Europe, yet the source(s) of the silver bullion behind this change remains uncertain. Here, the authors use combined lead isotope and trace element analysis of 49 coins from England, Frisia and Francia to provide new insights into north-European silver sources during the 'long eighth century' (c. AD 660-820). The results indicate an early reliance on recycled Byzantine silver plate, followed by a shift c. AD 750 to newly mined metal from Francia. This change indicates the strong role of the Carolingian state in the control of metal sources and economic structures across the North Sea zone. Keywords: North-west Europe, Middle Ages, Byzantine period, silver mining, lead isotope analysis, coinage, Introduction The adoption of silver currency in north-west Europe from c. AD 660/70 marked a profound transformation in the early medieval economy. The replacement of gold with large silver coinages [...]