The Effects of a High Fat Meal on Blood Flow Regulation during Arm Exercise

A diet high in saturated fats results in endothelial dysfunction and can lead to atherosclerosis, a precursor to cardiovascular disease. Exercise training is a potent stimulus though to mitigate the negative effects of a high saturated fat diet; however, it is unclear how high-saturated fat meal (HSFM) consumption impacts blood flow regulation during a single exercise session. PURPOSE: This study sought to examine the impact of a single HSFM on peripheral vascular function during an acute upper limb exercise bout. METHODS: Ten young healthy individuals completed two sessions of progressive handgrip exercise. Subjects either consumed a HSFM (0.84 g of fat/kg of body weight) 4 hours prior or remained fasted before the exercise bout. Progressive rhythmic handgrip exercise (6kg, 12kg, 18kg) was performed for 3 minutes per stage at rate of 1 Hz. The brachial artery (BA) diameter and blood velocity was obtained using Doppler Ultrasound (GE Logiq e) and BA blood flow was calculated with these values. RESULTS: BA blood flow and flow mediated dilation (normalized for shear rate) during the handgrip exercise significant increased from baseline in all workloads, but no differences were revealed in response to the HSFM consumption. CONCLUSION: Progressive handgrip exercise augmented BA blood flow and flow mediated dilation in both testing days; however, there was no significant differences following the HSFM consumption. This suggests that upper limb blood flow regulation during exercise is unaltered by a high fat meal in young healthy individuals.https://scholarscompass.vcu.edu/gradposters/1060/thumbnail.jp

Mitochondrial function in heart failure: The impact of ischemic and non-ischemic etiology

Background Although cardiac mitochondrial dysfunction is associated with heart failure (HF), this is a complex syndrome with two predominant etiologies, ischemic HF (iHF) and non-ischemic HF (niHF), and the exact impact of mitochondrial dysfunction in these two distinct forms of HF is unknown. Methods and results To determine the impact of HF etiology on mitochondrial function, respiration was measured in permeabilized cardiac muscle fibers from patients with iHF (n = 17), niHF (n = 18), and healthy donor hearts (HdH). Oxidative phosphorylation capacity (OXPHOS), assessed as state 3 respiration, fell progressively from HdH to niHF, to iHF (Complex I + II: 54 ± 1; 34 ± 4; 27 ± 3 pmol·s− 1·mg− 1) as did citrate synthase activity (CSA: 206 ± 18; 129 ± 6; 82 ± 6 nmol·mg− 1·min− 1). Although still significantly lower than HdH, normalization of OXPHOS by CSA negated the difference in mass specific OXPHOS between iHF and niHF. Interestingly, Complex I state 2 respiration increased progressively from HdH, to niHF, to iHF, whether or not normalized for CSA (0.6 ± 0.2; 1.1 ± 0.3; 2.3 ± 0.3; pmol·mg− 1·CSA), such that the respiratory control ratio (RCR), fell in the same manner across groups. Finally, both the total free radical levels (60 ± 6; 46 ± 4 AU) and level of mitochondrial derived superoxide (1.0 ± 0.2; 0.7 ± 0.1 AU) were greater in iHF compared to niHF, respectively. Conclusions Thus, the HF-related attenuation in OXPHOS actually appears to be independent of etiology when the lower mitochondrial content of iHF is taken into account. However, these findings provide evidence of deleterious intrinsic mitochondrial changes in iHF, compared to niHF, including greater proton leak, attenuated OXPHOS efficiency, and augmented free radical levels

Macrosystems ecology: Understanding ecological patterns and processes at continental scales

Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sources of unexpected and novel behaviors in macrosystems. We present three examples that highlight the importance of this multiscaled systems perspective for understanding the ecology of regions to continents

Microfluidic technology and simulation models in studying pharmacokinetics during pregnancy

Introduction: Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents.Methods: We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data.Results: Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%.Discussion: The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as “therapeutic orphans” due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes

Approaches for advancing scientific understanding of macrosystems

The emergence of macrosystems ecology (MSE), which focuses on regional- to continental-scale ecological patterns and processes, builds upon a history of long-term and broad-scale studies in ecology. Scientists face the difficulty of integrating the many elements that make up macrosystems, which consist of hierarchical processes at interacting spatial and temporal scales. Researchers must also identify the most relevant scales and variables to be considered, the required data resources, and the appropriate study design to provide the proper inferences. The large volumes of multi-thematic data often associated with macrosystem studies typically require validation, standardization, and assimilation. Finally, analytical approaches need to describe how cross-scale and hierarchical dynamics and interactions relate to macroscale phenomena. Here, we elaborate on some key methodological challenges of MSE research and discuss existing and novel approaches to meet them

A novel source of arterial valve cell linked to bicuspid aortic valve without rephe in mice

Abnormalities of the arterial valve leaflets, predominantly bicuspid aortic valve, are the commonest congenital malformations. Although many studies have investigated the development of the arterial valves, it has been assumed that, as with the atrioventricular valves, endocardial to mesenchymal transition (EndMT) is the predominant mechanism. We show that arterial is distinctly different from atrioventricular valve formation. Whilst the four septal valve leaflets are dominated by NCC and EndMT-derived cells, the intercalated leaflets differentiate directly from Tnnt2-Cre+/Isl1+ progenitors in the outflow wall, via a Notch-Jag dependent mechanism. Further, when this novel group of progenitors are disrupted, development of the intercalated leaflets is disrupted, resulting in leaflet dysplasia and bicuspid valves without raphe, most commonly affecting the aortic valve. This study thus overturns the dogma that heart valves are formed principally by EndMT, identifies a new source of valve interstitial cells, and provides a novel mechanism for causation of bicuspid aortic valves without raphe.British Heart Foundation RG/12/15/29935 Lorriane Eley Rachel V Richardson Lindsay Murphy Bill Chaudhry Deborah J Henderson; British Heart Foundation PG/15/46/31589 Lorriane Eley Bill Chaudhry Deborah J Henderson; Ministerio de Ciencia, Innovacion y Universidades of Spain CB16/11/00399 (Ciber Cardiovascular) Donal MacGrogan Alejandro Salguero-Jimenez Jose Luis de La Pompa; Ministerio de Ciencia, Innovacion y Universidades of Spain SAF2016-78370-R Donal MacGrogan Alejandro Salguero-Jimenez Jose Luis de La Pompa; Ministerio de Ciencia, Innovacion y Universidades of Spain RD16/0011/0021 (Red de Terapia Celular, TERCEL) Donal MacGrogan Alejandro Salguero-Jimenez Jose Luis de La Pompa; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.S

Strengthening confidence in climate change impact science

Aim: To assess confidence in conclusions about climate-driven biological change through time, and identify approaches for strengthening confidence scientific conclusions about ecological impacts of climate change. Location: Global. Methods: We outlined a framework for strengthening confidence in inferences drawn from biological climate impact studies through the systematic integration of prior expectations, long-term data and quantitative statistical procedures. We then developed a numerical confidence index (Cindex) and used it to evaluate current practices in 208 studies of marine climate impacts comprising 1735 biological time series. Results: Confidence scores for inferred climate impacts varied widely from 1 to 16 (very low to high confidence). Approximately 35% of analyses were not associated with clearly stated prior expectations and 65% of analyses did not test putative non-climate drivers of biological change. Among the highest-scoring studies, 91% tested prior expectations, 86% formulated expectations for alternative drivers but only 63% statistically tested them. Higher confidence scores observed in studies that did not detect a change or tracked multiple species suggest publication bias favouring impact studies that are consistent with climate change. The number of time series showing climate impacts was a poor predictor of average confidence scores for a given group, reinforcing that vote-counting methodology is not appropriate for determining overall confidence in inferences. Main conclusions: Climate impacts research is expected to attribute biological change to climate change with measurable confidence. Studies with long-term, high-resolution data, appropriate statistics and tests of alternative drivers earn higher Cindex scores, suggesting these should be given greater weight in impact assessments. Together with our proposed framework, the results of our Cindex analysis indicate how the science of detecting and attributing biological impacts to climate change can be strengthened through the use of evidence-based prior expectations and thorough statistical analyses, even when data are limited, maximizing the impact of the diverse and growing climate change ecology literature

Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery