Opposing effects of genetic variation in MTCH2 for obesity versus heart failure.

Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant allele frequencies in cardiomyopathy cases versus controls identified the MTCH2 gene as having unusual variation. MTCH2 encodes an outer mitochondrial membrane protein, and prior genome-wide studies associated MTCH2 variants with body mass index, consistent with its role in metabolism. We identified the referent allele of rs1064608 (p.Pro290) as being overrepresented in cardiomyopathy cases compared to controls, and linkage disequilibrium analysis associated this variant with the MTCH2 cis eQTL rs10838738 and lower MTCH2 expression. To evaluate MTCH2, we knocked down Mtch in Drosophila heart tubes which produced a dilated and poorly functioning heart tube, reduced adiposity and shortened life span. Cardiac Mtch mutants generated more lactate at baseline, and they displayed impaired oxygen consumption in the presence of glucose but not palmitate. Treatment of cardiac Mtch mutants with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, reduced lactate and rescued lifespan. Deletion of MTCH2 in human cells similarly impaired oxygen consumption in the presence of glucose but not fatty acids. These data support a model in which MTCH2 reduction may be favorable when fatty acids are the major fuel source, favoring lean body mass. However, in settings like heart failure, where the heart shifts toward using more glucose, reduction of MTCH2 is maladaptive.

Xenohormesis: sensing the chemical cues of other species.

Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable.

mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function.

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

[Catheter ablation of ventricular tachycardia : What have we achieved?] / Katheterablation ventrikulärer Tachyarrhythmien : Was haben wir erreicht?

The role of catheter ablation in patients with ventricular tachycardia (VT) has evolved over the last two decades into an established treatment option. In patients with idiopathic VT catheter ablation is the gold standard treatment option with high effectiveness and low risk of complications. Due to the high risk of side effects the use of antiarrhythmic drugs is only indicated in exceptional cases. In patients with structural heart diseases, such as ischemic and dilated cardiomyopathy, VT is the most frequent cause of death. Furthermore, recurrent shocks from implantable cardioverter defibrillators (ICD) are one of the main reasons for the high morbidity and mortality; however, in these patients a complex myocardial substrate is present and consequently there is a relevant risk of recurrence after VT ablation. A periprocedural mortality of approximately 3% must be considered in these often severely ill patients. Nevertheless, there is no reasonable alternative to catheter ablation, particularly in patients who continue to have VT episodes even under therapy with amiodarone. Questions with respect to the optimal procedural technique for VT ablation, the endpoint and optimal timing of ablation need to be clarified in clinical trials.

Screening and profiling assays for HDACs and sirtuins.

Epigenetic factors are enzymes or proteins that confer, remove or recognize covalent modifications to chromatin DNA or proteins. They can be divided into three broad groups, commonly referred to as the 'writers', 'erasers' and 'readers'. The HDACs and sirtuins, which remove acetyl groups from the ɛ-amino of protein lysine residues, fall into the 'eraser' category. Due to their important effects on gene expression and involvement in various disease states, these enzymes have been the subjects of many assay development efforts in recent years. Commonly used techniques include mass spectrometry, antibody-based methods and protease-coupled assays with fluorogenic peptide substrates. Recent advances include the development of synthetic substrates for the assay of various newly discovered non-acetyl deacylation activities among the sirtuins.

Circulating Branched Chain Amino Acids and Cardiometabolic Disease.

Branched chain amino acids (BCAAs) are essential for protein homeostasis, energy balance, and signaling pathways. Changes in BCAA homeostasis have emerged as pivotal contributors in the pathophysiology of several cardiometabolic diseases, including type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, and heart failure. In this review, we provide a detailed overview of BCAA metabolism, focus on molecular mechanisms linking disrupted BCAA homeostasis with cardiometabolic disease, summarize the evidence from observational and interventional studies investigating associations between circulating BCAAs and cardiometabolic disease, and offer valuable insights into the potential for BCAA manipulation as a novel therapeutic strategy for cardiometabolic disease.

Metabolic liability for weight gain in early adulthood.

While weight gain is associated with a host of chronic illnesses, efforts in obesity have relied on single "snapshots" of body mass index (BMI) to guide genetic and molecular discovery. Here, we study >2,000 young adults with metabolomics and proteomics to identify a metabolic liability to weight gain in early adulthood. Using longitudinal regression and penalized regression, we identify a metabolic signature for weight liability, associated with a 2.6% (2.0%-3.2%, p = 7.5 × 10-19) gain in BMI over ≈20 years per SD higher score, after comprehensive adjustment. Identified molecules specified mechanisms of weight gain, including hunger and appetite regulation, energy expenditure, gut microbial metabolism, and host interaction with external exposure. Integration of longitudinal and concurrent measures in regression with Mendelian randomization highlights the complexity of metabolic regulation of weight gain, suggesting caution in interpretation of epidemiologic or genetic effect estimates traditionally used in metabolic research.

Gender-specific differences in carotid intima-media thickness and its progression over three years: a multicenter European study.

BACKGROUND AND AIMS: This multicentre European study evaluated, in a young-to-middle-aged healthy population without carotid atherosclerosis, the gender-related differences in carotid intima-media thickness (IMT) and its short-term (3-year) progression, and whether these differences are related to different vascular ageing rate, cardiovascular risk profile or different susceptibility to family predisposition to cardiovascular diseases (CVD). METHODS AND RESULTS: 366 men and 422 women (age between 30 and 60 years) underwent B-mode carotid ultrasound at baseline and after 3-year follow-up period. IMT in 3 carotid segments was higher in men than in women (p < 0.0001 for all segments). When evaluated according to age decade, differences between men and women disappeared in the 6th decade, as in this decade a 3-year IMT progression rate accelerated in women (p < 0.05 as compared to the 4th and 5th age decade). Age was a major determinant of baseline all-segment IMT in women; in men all-segment IMT was influenced by age and LDL-cholesterol. IMT progression did not correlate with established cardiovascular risk factors, their short-term changes or family predisposition to CVD. Yet, a 3-year IMT progression in common carotid artery (CCA) was higher in men (p = 0.01) and women (p < 0.01) in whom relative Framingham risk increased during the corresponding period. CONCLUSION: This study provides reference values on IMT and its short-term progression in healthy young-to-middle-aged population, and demonstrates gender-related differences in the susceptibility of carotid wall to ageing and LDL-cholesterol. Increase in Framingham risk accelerated a short-term CCA IMT progression rate in both genders, whereas family predisposition to CVD did not influence carotid IMT.

Taking small steps towards targets - perspectives for clinical practice in diabetes, cardiometabolic disorders and beyond.

Big changes are hard. When trying to achieve guideline targets in diabetes and cardiometabolic disorders, patients can lack commitment or suffer despondency. It is much easier to make small changes in lifestyle or treatment, which are less noticeable and easier to manage long-term. Obesity is central to the cardiometabolic disorders, and even small weight losses of 2-5% can improve the cardiometabolic risk profile and substantially reduce the risk of developing type 2 diabetes. Likewise, small increases in physical activity, such as 15-30 min of brisk walking per day, can cut the risk of heart disease by 10%. Lifestyle or treatment changes that lead to small improvements in metabolic parameters also impact patient outcome - for example, a 5 mmHg decrease in blood pressure can translate into significant reductions in the rates of myocardial infarction and cardiovascular mortality. Benefits of small changes can also be seen in health economic outcome models. Implementing change at an individual versus a population level has different implications for overall benefit and patient motivation. Even very small steps taken in trying to reach guideline targets should represent a positive achievement for patients. Patient engagement is essential - only when patients commit themselves to change can benefits be maintained, and physicians should recognise their influence. Small changes in individual parameters can result in significant beneficial effects; however, a major impact can occur when small changes are made together in multiple parameters. More research is required to elucidate the full impact of small changes on patient outcome.

Ferric derisomaltose therapy and heart failure: implications and molecular insights.

Iron is essential to the production of myocardial energy and proteins critical for cardiovascular function. Nearly 50% of patients with heart failure with reduced ejection fraction (HFrEF) meet current criteria for iron deficiency, and there has been considerable interest in intravenous repletion of iron stores as a therapeutic strategy to improve HFrEF outcomes. However, the data on intravenous iron therapy in HFrEF have been mixed.

Optimized protocol for quantification of mitochondrial non-heme and heme iron content in mouse tissues and cultured cells.

Impaired mitochondrial iron metabolism is associated with aging and a variety of diseases, and there is a growing need to accurately quantify mitochondrial iron levels. This protocol provides an optimized method for evaluating non-heme and heme iron in mitochondrial and cytosolic fractions of tissues and cultured cells. Our protocol consists of three steps: sample fractionation, non-heme iron measurement, and heme iron measurement. For complete details on the use and execution of this protocol, please refer to Sato et al. (2022).1.

Factors associated with stress impacting academic success among post-secondary students: A systematic review.

Objective: To synthesize peer-reviewed primary research exploring factors associated with perceived stress impacting post-secondary students' academic success. Methods: A systematic review identified research conducted in North America, Europe, and Australia in the last ten years across 12 databases. Results: Of the 6,214 references screened, 14 English articles published between 2011 and 2018 were deemed relevant. Subsequent analysis characterized articles by study design, location, population, factors with a statistically significant relationship with both perceived stress and academic success, and future research directions. Findings reveal a complex relationship among overlapping factors associated with perceived stress on academic success at both the intrapersonal (eg, academic, demographic, psychological, attitudinal, and behavioral characteristics) and interpersonal levels (eg, social capital). Conclusions: Further research should measure the association of the identified factors to inform areas where resources could be targeted within post-secondary institutions to prevent stress from unduly impacting students' educational outcomes.

Longitudinal trajectories of branched chain amino acids through young adulthood and diabetes in later life.

BACKGROUNDElevated circulating branched chain amino acids (BCAAs), measured at a single time point in middle life, are strongly associated with an increased risk of developing type 2 diabetes mellitus (DM). However, the longitudinal patterns of change in BCAAs through young adulthood and their association with DM in later life are unknown.METHODSWe serially measured BCAAs over 28 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of apparently healthy Black and White young adults at baseline. Trajectories of circulating BCAA concentrations from years 2-30 (for prevalent DM) or years 2-20 (for incident DM) were determined by latent class modeling.RESULTSAmong 3,081 apparently healthy young adults, trajectory analysis from years 2-30 revealed 3 distinct BCAA trajectory groups: low-stable (n = 1,427), moderate-stable (n = 1,384), and high-increasing (n = 270) groups. Male sex, higher body mass index, and higher atherogenic lipid fractions were more common in the moderate-stable and high-increasing groups. Higher risk of prevalent DM was associated with the moderate-stable (OR = 2.59, 95% CI: 1.90-3.55) and high-increasing (OR = 6.03, 95% CI: 3.86-9.43) BCAA trajectory groups in adjusted models. A separate trajectory group analysis from years 2-20 for incident DM after year 20 showed that moderate-stable and high-increasing trajectory groups were also significantly associated with higher risk of incident DM, after adjustment for clinical variables and glucose levels.CONCLUSIONBCAA levels track over a 28-year span in most young adults, but serial clinical metabolomic measurements identify subpopulations with rising levels associated with high risk of DM in later life.FUNDINGThis research was supported by the NIH, under grants R01 HL146844 (JTW) and T32 HL069771 (MRC). The CARDIA study is conducted and supported by the NIH National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I).

Role of interferon {alpha} (IFN{alpha})-inducible Schlafen-5 in regulation of anchorage-independent growth and invasion of malignant melanoma cells.

IFNα exerts potent inhibitory activities against malignant melanoma cells in vitro and in vivo, but the mechanisms by which it generates its antitumor effects remain unknown. We examined the effects of interferon α (IFNα) on the expression of human members of the Schlafen (SLFN) family of genes, a group of cell cycle regulators that mediate growth-inhibitory responses. Using quantitative RT-real time PCR, we found detectable basal expression of all the different human SLFN genes examined (SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14), in malignant melanoma cells and primary normal human melanocytes, but SLFN5 basal expression was suppressed in all analyzed melanoma cell lines. Treatment of melanoma cells with IFNα resulted in induction of expression of SLFN5 in malignant cells, suggesting a potential involvement of this gene in the antitumor effects of IFNα. Importantly, stable knockdown of SLFN5 in malignant melanoma cells resulted in increased anchorage-independent growth, as evidenced by enhanced colony formation in soft agar assays. Moreover, SLFN5 knockdown also resulted in increased invasion in three-dimensional collagen, suggesting a dual role for SLFN5 in the regulation of invasion and anchorage-independent growth of melanoma cells. Altogether, our findings suggest an important role for the SLFN family of proteins in the generation of the anti-melanoma effects of IFNα and for the first time directly implicate a member of the human SLFN family in the regulation of cell invasion.

Exploration of Factors Affecting Post-Secondary Students' Stress and Academic Success: Application of the Socio-Ecological Model for Health Promotion.

OVERVIEW: There has been an increase in the frequency and severity of stress experienced by Canadian post-secondary students, which has adverse implications on their academic success. This work applied the socio-ecological model for health promotion to explore the contextual factors that influence this relationship at the individual, interpersonal, institutional, community, and public policy levels. METHODS: Using a qualitative, phenomenological approach, we conducted 38 semi-structured interviews with undergraduate students and on-campus staff who provide services to this population at a post-secondary institution in Southwestern Ontario, Canada. Thematic analysis inductively identified overarching themes among participants' perspectives. RESULTS: Several positive and negative factors were identified at each socio-ecological model level, demonstrating the complex interplay of demographic, psychological, emotional, social, physical, and academic factors impacting students' academic stress. CONCLUSIONS: A lack of communication and knowledge seems to underlie many factors, highlighting the need to strengthen communication strategies to promote awareness, accessibility, and availability of services and programs on campus. Results also pointed to focusing on proactive, resilience-focused, upstream mental health promotion efforts at post-secondary institutions to reduce stress and improve academic success. This knowledge can help Canadian campuses better address students' needs.

Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of ATP-binding cassette B8.

Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts; however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP-binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding thus provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.

Epitaxy, exfoliation, and strain-induced magnetism in rippled Heusler membranes.

Single-crystalline membranes of functional materials enable the tuning of properties via extreme strain states; however, conventional routes for producing membranes require the use of sacrificial layers and chemical etchants, which can both damage the membrane and limit the ability to make them ultrathin. Here we demonstrate the epitaxial growth of the cubic Heusler compound GdPtSb on graphene-terminated Al2O3 substrates. Despite the presence of the graphene interlayer, the Heusler films have epitaxial registry to the underlying sapphire, as revealed by x-ray diffraction, reflection high energy electron diffraction, and transmission electron microscopy. The weak Van der Waals interactions of graphene enable mechanical exfoliation to yield free-standing GdPtSb membranes, which form ripples when transferred to a flexible polymer handle. Whereas unstrained GdPtSb is antiferromagnetic, measurements on rippled membranes show a spontaneous magnetic moment at room temperature, with a saturation magnetization of 5.2 bohr magneton per Gd. First-principles calculations show that the coupling to homogeneous strain is too small to induce ferromagnetism, suggesting a dominant role for strain gradients. Our membranes provide a novel platform for tuning the magnetic properties of intermetallic compounds via strain (piezomagnetism and magnetostriction) and strain gradients (flexomagnetism).

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

Tropopause detected by radar.

The tropopause has been detected by ultrasensitive, narrow-beam, microwave (10.7-centimeter) and ultrahigh-frequency (71.5-cm) radars. Its reflectivity is consistent with that expected theoretically for a refractively turbulent medium. Indications are that the layer is also mechanically turbulent, and that electromagnetic scatter techniques may be used to detect high-altitude clear-air turbulence.

Impact of insulin sensitivity treatment with pioglitazone on endothelial function in non-diabetic patients with arterial hypertension.

OBJECTIVE: The thiazolidindione (TDZ) pioglitazone reduces insulin resistance and blood pressure in non-diabetic patients with arterial hypertension as previously reported [Füllert et al. 2002]. The question is still not answered whether it is a direct effect on the endothelial wall or it is related with improvement of insulin sensitivity. The present investigation is the first placebo controlled study which examines the effect of TDZ induced changes of insulin sensitivity (SI) on endothelial function and blood pressure in in non-diabetic patients with high blood pressure. MATERIAL AND METHODS: Insulin sensitivity indices (SI indices) were obtained by analyzing fasting glucose and insulin concentration with homeostasis model assessment (HOMA), the glucose and insulin profiles after 75 g dextrose oral glucose tolerance tests (OGTT, Matsuda-Index) and euglycemic hyperinsulinemic clamp (m-value) in a double-blind placebo-controlled study in 60 patients with arterial hypertension before and after 4 months treatment with Pioglitazone 45 mg (PIO45). Flow-mediated dilatation of brachial artery (FMD) after reperfusion was used to determine endothelial function. Blood pressure in the morning of every visit (casual blood pressure, RRc) and 24-h ambulatory blood pressure (24RR) were measured. RESULTS: Antihypertensive treatments were equally distributed in the placebo and PIO45 group. All SI indices were closely related to with alanine-aminotransferase activities (ALAT): HOMA r = 0.1041, p < 0.05, Matsuda-Index r = 0.4242, p < 0.01, M value r = 0.1944, p < 0.01. There were no relationships of SI indices with FMD, RRc and 24RR in the study population with treated arterial hypertension. FMD was closely related to the nocturnal systolic and diastolic 24hRR (systolic r = 0.0943, p < 0.05, diastolic r = 0.0947, p < 0.05). SI indices improved after 4-month therapy with PIO45 when compared with controls: HOMA 65% (p < 0.01), Matsuda-Index 60% (p < 0.01) and M value 17.7% (p = 0.008). FMD did not change after PIO45. Casual diastolic blood pressure (p = 0.016) and systolic blood pressure were lower (p = 0.053) under PIO45. No significant changes of 24-h blood pressure were found after treatment with TDZ. CONCLUSION: 4-month treatment with PIO45 improves SI, liver function and lowers casual blood pressure (RRc. No effects on 24-h ambulatory blood pressure and on endothelial function after PIO45 therapy were observed. The higher insulin sensitivity was not related to lower blood pressure. Thus, PIO45 appears to have a direct effect on the arterial system which cannot be explained by changes of endothelial function or improved SI in non-diabetic patients with treated high blood pressure.