Search

The heart undergoes a dynamic maturation process following birth, in response to a wide range of stimuli, including both physiological and pathological cues. This process entails substantial re-programming of mitochondrial energy metabolism coincident with the emergence of specialized structural and contractile machinery to meet the demands of the adult heart. Many components of this program revert to a more "fetal" format during development of pathological cardiac hypertrophy and heart failure. In this review, emphasis is placed on recent progress in our understanding of the transcriptional control of cardiac maturation, encompassing the results of studies spanning from in vivo models to cardiomyocytes derived from human stem cells. The potential applications of this current state of knowledge to new translational avenues aimed at the treatment of heart failure is also addressed. [ABSTRACT FROM AUTHOR]

The article focuses on the need to address challenges in replenishing the physician-scientist pipeline, discussing historical eras that expanded it, and emphasizing the importance of early exposure to research for medical students. Topics include the impact of past programs such as the Medical Scientist Training Program (MSTP), challenges faced by the current pipeline, and proposed solutions such as tapping into MD-only medical students and implementing mentorship programs.

Use of extracorporeal membrane oxygenation (ECMO) is increasing among critically ill adults with cardiac and/or respiratory failure. Use of ECMO is associated with hemostatic alterations requiring use of anticoagulation and blood product support. There are limited guidelines to direct transfusion management in the adult patient supported with ECMO. The objective of this article is to describe (1) the role of the transfusion service in providing transfusion support and current understanding of transfusion thresholds, (2) the complexities of monitoring anticoagulation, and (3) the consideration regarding additional factor concentrates and antifibrinolytics within the context of ECMO support. The information provided should assist ECMO care teams in informing transfusion and anticoagulation practice while highlighting key areas for future research and collaboration. [ABSTRACT FROM AUTHOR]

No single event in modern history has affected education like COVID-19. This study examines the effects of COVID-19 related modifications within technology and engineering education. Using social media, a survey was distributed among groups whose focus was technology and engineering education. This survey asked how teachers addressed COVID-19 related modifications to instruction and how they felt about instructional quality and support. The results showed that teachers are working longer hours, yet instruction is suffering due to virtual/hybrid teaching, social distancing, and sanitation concerns. Hands-on and group work has been largely limited or eliminated entirely, and many lessons have had to be heavily adapted if they are possible at all. Most concerning is an apparent deficit in morale, with a substantial number of teachers contemplating leaving the classroom if the current conditions continue. COVID-19 has wreaked havoc in nearly every facet of life in 2020, but the challenges faced in education are largely undocumented within the academic literature. It is imperative that the real-time effects of COVID-19 on teaching and learning be understood so that adjustments can be made while the nation is still affected by the pandemic and future changes to instruction to address currently developing deficits are made with a full understanding of what occurred during the crisis rather than retrospectively. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has impacted technology, engineering, and design education as well as workforce development programs worldwide. The emergency transition to fully online course delivery ushered experiences from which course restructuring could utilize. Through an illustrated case study approach using student course evaluations coupled with instructor interviews, this article reports on the experiences resulting from the abrupt interruption of the Spring 2020 semester and how the restructure of an introductory engineering graphics course accommodated changing expectations. The restructured course was built upon a hybrid flipped model utilizing an online learning management system including active learning modules which provided a foundation of preparedness for transitioning to fully online course delivery. As positive as the preparedness was, there were still changes that had to occur to not only meet the needs of the emergency situation but to also establish multiple models of the course for future situations. These changes included incorporating web conferencing software to meet online when a face-to-face meeting was not possible, developing video lectures for students to watch when most accommodating for their schedule, as well as the increased use of the online learning management system. Another change from the restructuring process was the new technology expectations of students and instructors. Feedback from both students and instructors reported how flexibility, empathy, and effective communication were driving traits of positive experiences in such an unprecedented situation. Reported experiences along with elements of the course restructuring can serve as an example of how future courses are delivered for a variety of situations. [ABSTRACT FROM AUTHOR]

Engineering graphics education has long been a required component of technology and engineering education at the university level. In middle and high schools, the number of computer-aided design (CAD) programs continue to proliferate and grow. Lacking in the research related to these programs is the effect on non-cognitive factors such as self-efficacy. Self-efficacy is a predictor of success and perseverance and is an important consideration in technology and engineering education. This research investigates the psychometric properties of an instrument designed to measure the three-dimensional modeling self-efficacy among middle and high school students. This study found the Three-Dimensional Modeling Self-Efficacy Scale to be a reliable measure within this population with strong evidence of validity. Based on these findings, the scale was revised, and recommendations for future study were made. This research begins to fill a gap not only in research related to engineering graphics self-efficacy but also within a pre-college population, especially those who are historically underrepresented in engineering disciplines, in this case, female students. [ABSTRACT FROM AUTHOR]

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise. [ABSTRACT FROM AUTHOR]

Drawing and sketching require the close interaction and coordination of psychomotor and biomechanical processes with developmental, learning, and maturational processes to perform the complex and fine motor behaviors of these activities. Dysgraphia is a learning disability that directly impacts a student's ability to perform these tasks proficiently, if at all. Although dysgraphia is literally interpreted as "bad writing," it also affects a person's ability to visualize and draw lines and shapes. STEM subject matter and activities often involve drawing and sketching, and this ability to transfer mental imagery to paper and viceversa is one predictor of STEM education and career success. Given this, there may exist a population of students who are being overlooked and would benefit from a better understanding of the condition by educators and potential interventions that can be researched to engage these students within STEM disciplines. This paper will explore this learning disability as is exists in STEM education through a narrative case study involving a student currently enrolled in an engineering program. This case study is designed to understand the condition of dysgraphia and the barriers to STEM education as perceived and experienced by a student successfully mitigating these barriers through assistive technologies, self-advocacy, and teacher awareness. This paper is meant to raise awareness of the condition in our field and serve as a starting point in the literature where this topic currently represents a dearth of the academic discourse surrounding special education in STEM. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF. [ABSTRACT FROM AUTHOR]

The article profiles the works of educational community Go Baby Go related to technology, engineering, and design (TED) education. It includes information on the significance of service learning, rehabilitative technology, and do it yourself projects of Go Baby Go. It also offers information on educational curriculum of Go Baby Go including academic content, implementation of technological solutions to real-world challenges, and outdoor learning.

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy. [ABSTRACT FROM AUTHOR]

A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ~280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient's elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated. [ABSTRACT FROM AUTHOR]

The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart. [ABSTRACT FROM AUTHOR]

Highlights from the article: The path leading to a new drug becoming commercially available is long and expensive, involving an average of 13 years [1] and estimated costs from US$618 million to US$2.6 billion [1], [2], [3]. Drug repurposing, the use of an existing drug for a new indication, has emerged as a viable alternative to traditional de novo drug discovery. Drug repurposing allows investigators to bypass or streamline toxicity studies and should make these drugs more acceptable than early-phase drugs to providers, patients and families [4].

The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts. [ABSTRACT FROM AUTHOR]

Abstract: The PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators, together with estrogen related receptors (ERRs), plays a key role in regulating genes involved in myocardial fuel metabolism and cardiac function. Increasing evidence implicates dysregulation of this transcriptional regulatory circuit in the metabolic and functional disturbances that presage heart failure due to common diseases such as hypertension and diabetes. Accordingly, the PGC-1/ERR axis is a plausible candidate therapeutic target for novel therapeutics aimed at reversing the energy metabolic disturbances that contribute to heart failure. This review describes the biologic actions of the PGC-1 and ERR cascade and summarizes the evidence that dysregulation of this transcriptional regulatory circuit contributes to heart failure. Potential strategies to modulate this target pathway are reviewed. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.” [Copyright &y& Elsevier]

Abstract: Common causes of heart failure are associated with derangements in myocardial fuel utilization. Evidence is emerging that metabolic abnormalities may contribute to the development and progression of myocardial disease. The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors has been shown to regulate cardiac fuel metabolism at the gene expression level. The three PPAR family members (alpha, beta/delta and gamma) are uniquely suited to serve as transducers of developmental, physiological, and dietary cues that influence cardiac fatty acid and glucose metabolism. This review describes murine PPAR loss- and gain-of-function models that have shed light on the roles of these receptors in regulating myocardial metabolic pathways and have defined key links to disease states including the hypertensive and diabetic heart. [Copyright &y& Elsevier]

Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure. [ABSTRACT FROM AUTHOR]

The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure. [ABSTRACT FROM AUTHOR]

We are witnessing a period of renewed interest in the biology of the mitochondrion. The mitochondrion serves a critical function in the maintenance of cellular energy stores, thermogenesis, and apoptosis. Moreover, alterations in mitochondrial function contribute to several inherited and acquired human diseases and the aging process. This review summarizes our understanding of the transcriptional regulatory mechanisms involved in the biogenesis and energy metabolic function of mitochondria in higher organisms. [ABSTRACT FROM AUTHOR]

SUMMARY 1. The present review focuses on the gene regulatory mechanisms involved in the control of cardiac mitochondrial energy production in the developing heart and following the onset of pathological cardiac hypertrophy. Particular emphasis has been given to the mitochondrial fatty acid oxidation (FAO) pathway and its control by members of the nuclear receptor transcription factor superfamily. 2. During perinatal cardiac development, the heart undergoes a switch in energy substrate preference from glucose in the fetal period to fatty acids following birth. This energy metabolic switch is paralleled by changes in the expression of the enzymes and protein involved in the respective pathways. 3. The postnatal activation of the mitochondrial energy production pathway involves the induced expression of nuclear genes encoding FAO enzymes, as well as other proteins important in mitochondrial energy transduction/production pathways. Recent evidence indicates that this postnatal gene regulatory effect involves the actions of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα ) and its coactivator the PPARγ coactivator 1 (PGC-1). 4. The PGC-1 not only activates PPARα to induce FAO pathway enzymes in the postnatal heart, but it also plays a pivotal role in the control of cardiac mitochondrial number and function. Thus, PGC-1 plays a master regulatory role in the high-capacity mitochondrial energy production system in the adult mammalian heart. 5. During the development of pathological forms of cardiac hypertrophy, such as that due to pressure overload, the myocardial energy substrate preference shifts back towards the fetal pattern, with a corresponding reduction in the expression of FAO enzyme genes. This metabolic shift is due to the deactivation of the PPARα /PGC-1 complex. 6. The deactivation of PPARα and PGC-1 during the development of cardiac hypertrophy involves regulation at several levels, including a... [ABSTRACT FROM AUTHOR]

The article focuses on distinction between active learning and traditional structure of teaching. Topics discussed include providing a student-centered environment of learning through student engagement, need to structure active learning for descriptive knowledge and problem with integrating small-group design.

Demonstrates that subunit e expression is regulated, at the pretranslational level, by changes in environmental PO2. Technique of differential display to identify genes; Studies performed with primary rat cardiocytes; Hypoxia-regulated gene involved in mitochondrial ATP production; Regulatory function of subunit e within the ATP synthase complex.

Investigates the influence of cell differentiation on the hypoxia-mediated regulation of subunit e gene expression in C2C12 cells. Time course and pattern of hypoxia-mediated regulation of subunit e messenger ribonucleic acid expression in C2C12 myoblasts; Expression of subunit e and a related transcript regulated by hypoxia in cardiocytes.

BACKGROUND: Discovering determinants of cardiomyocyte maturity is critical for deeply understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration, but elucidation of endogenous developmental regulators of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. MBNL1 (muscleblind-like 1) regulates fibroblast, thymocyte, and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. METHODS: MBNL1 gain- and loss-of-function mouse models were studied at several developmental time points and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro assays to determine the mechanisms through which MBNL1 exerts its effects. RESULTS: MBNL1 is coexpressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/ calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deficiency was insufficient to promote regeneration in the adult heart because of cell cycle checkpoint activation. CONCLUSIONS: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Targeting loss of cardiomyocyte maturity and downregulation of cell cycle inhibitors through MBNL1 deletion was not sufficient to promote adult regeneration. [ABSTRACT FROM AUTHOR]

The authors examine signalling in cardiac metabolism. They discuss the control of myocardial mitochondrial function, signalling control of cardiac fatty acid metabolism and exogenous hormonal and substrate control of cardiac energy metabolism. They conclude that adequate supply of energy to the heart is ensured by the signalling pathways and that a diseased heart has a deranged control of myocardial fuel metabolism.

Many organisms have an amazing capacity to adapt to conditions of low oxygen, but the cellular mechanisms of this are poorly understood. A new study in mice has unveiled a molecular trigger that initiates a cascade of events to reprogram cellular oxygen requirements. [ABSTRACT FROM AUTHOR]

The article discusses the discovery of a messenger system between muscle and fat tissue, using a mouse model, by researcher P. Böstrom and colleagues that could help explain the systemic benefits of exercise. Topics include a brief overview of the physiological effect of exercise, results from Böstrom's team describing a proposed mechanism, called the irisin messenger system, that may help explain how the body's total energy expenditure is increased by exercising muscle via the transcriptional co-regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1 alpha (PGC-1α) and the membrane protein fibronectin type III domain containing 5 (FNDC5), and a diagram illustrating the proposed irisin messenger system.

The article offers information regarding cell biology. It features the study of E. Sahin and colleagues on the unified mechanism of cell ageing particularly the nucleus and mitochondria in mice. It adds that Proliferator-Activated Receptor-Gamma Coactivator-1 (PGC-1) gene suppression by p53 protein activation in telomere deficiency causes mitochondrial DNA damage. Moreover, impaired mitochondria leads to cell injury, while heart failure and liver dysfunction were seen in mitochondrial ageing.

During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM-specific RIP140-deficient (csNrip1-/-) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF. [ABSTRACT FROM AUTHOR]

Background: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown. Methods: Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning. Results: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P <0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non–branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites. Conclusions: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome. [ABSTRACT FROM AUTHOR]

Background: Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined. Methods: We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus–mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP–mediated inactivation of ERRα and ERRγ in cardiomyocytes. Results: We identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus–mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27–anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs. Conclusions: We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi–transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation. [ABSTRACT FROM AUTHOR]

The article offers information on the guest editors for the spotlight issue on signalling in cardiac metabolism.

The article discusses the application of unmanned aerial vehicles (UAVs) as an educational tool in the classroom. It refers to Technology, Engineering and Design (TED) courses that prepare students to understand concepts, apply skills and make informed decisions. It notes the importance of connecting science, technology, engineering and mathematics (STEM) education into students. INSET: Design Brief.

Mouse surgical models are important tools for evaluating mechanisms of human cardiac disease. The clinically relevant comorbidities of hypertension and ischaemia have not been explored in mice. We have developed a surgical approach that combines transverse aortic constriction and distal left anterior coronary ligation (MI) to produce a gradual and predictable progression of adverse left ventricular (LV) remodelling that leads to heart failure (HF). Mice received either sham, MI alone, transverse aortic constriction alone or HF surgery. Infarct size and LV remodelling were evaluated by serial 2-D echocardiograms. Transverse aortic constriction gradients were measured by the Doppler velocity-time integral ratio between constricted and proximal aortic velocities. At 4 weeks, hearts were weighed and analysed for histology and brain natriuretic peptide, a molecular marker of HF. Echocardiographic analysis of segmental wall motion scores showed similarly small apical infarct sizes in the MI and HF groups at day 1 postsurgery. MI alone showed little change in infarct size over 4 weeks (0.26 ± 0.02 to 0.27 ± 0.04, P = 0.77); however, HF mice showed infarct expansion (0.25 ± 0.06 to 0.39 ± 0.09, P < 0.05). HF mice also showed LV remodelling with increases in LV volumes (1 day = 36.5 ± 5.2 mL, 28 days = 89.1 ± 16.0 mL) versus no significant changes in the other groups. Furthermore, systolic function progressively deteriorated in the HF group only (ejection fraction, 1 day = 55.6 ± 3.6%, 28 days = 17.6 ± 4.1%, P < 0.05) with an increase of brain natriuretic peptide by 3.5-fold. This surgical model of pressure overload in the setting of a small infarction causes progressive deterioration of cardiac structural and functional properties, and provides a clinically relevant tool to study adverse LV remodelling and heart failure. [ABSTRACT FROM AUTHOR]

Melanoma is the most lethal form of skin cancer and its incidence is rapidly rising. Breakthroughs in the understanding of the basic biology of melanoma in the past decade have yielded several new treatments, and advances continue to be made on a variety of fronts. One such area involves the delineation of changes in mitochondria that occur during melanoma formation, and how these changes affect responses to therapy. In this review, we summarize recent developments on the multiple functions that mitochondria play in melanoma, and how these roles are currently being evaluated as new targets for clinical intervention. [ABSTRACT FROM AUTHOR]

Focuses on the relatively few inherited diseases causing cardiomyopathy for which an abnormal gene or defective protein has been identified. Disorders of cardiac energy metabolism; Disorders of mitochondrial oxidative phosphorylation; Familial hypertrophic cardiomyopathy; X-linked muscular dystrophies.

To determine whether glutaminolysis inhibition is sufficient to revert myofibroblasts to a quiescent phenotype and reverse tissue fibrosis, we targeted I Gls1 i (glutaminase-1), the replace with committed step in of glutaminolysis, following fibroblast activation in a murine model of pressure-overload heart failure (HF). Keywords: fibrosis; glutamine; heart failure; metabolism; myofibroblasts EN fibrosis glutamine heart failure metabolism myofibroblasts 1625 1628 4 05/23/22 20220524 NES 220524 After injury, cardiac fibroblasts (CFs) differentiate into highly specialized myofibroblasts, essential for maintaining myocardial structural integrity by contracting surrounding tissue and remodeling the extracellular matrix network.[1] It was recently reported that withdrawal of stress stimuli is sufficient for some myofibroblasts to revert to a quiescent phenotype,[2] suggesting the potential for myofibroblast reversion by targeting the molecular pathways maintaining the fibrotic phenotype. [Extracted from the article]

Abstract: The heart is an omnivore organ that requires constant energy production to match its functional demands. In the adult heart, adenosine‐5′‐triphosphate (ATP) production occurs mainly through mitochondrial fatty acid and glucose oxidation. The heart must constantly adapt its energy production in response to changes in substrate supply and work demands across diverse physiologic and pathophysiologic conditions. The cardiac myocyte maintains a high level of mitochondrial ATP production through a complex transcriptional regulatory network that is orchestrated by the members of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family. There is increasing evidence that during the development of cardiac hypertrophy and in the failing heart, the activity of this network, including PGC-1, is altered. This review summarizes our current understanding of the perturbations in the gene regulatory pathways that occur during the development of heart failure. An appreciation of the role this regulatory circuitry serves in the regulation of cardiac energy metabolism may unveil novel therapeutic targets aimed at the metabolic disturbances that presage heart failure. This article is part of a Special Issue entitled:Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. [Copyright &y& Elsevier]

Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation, and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family of transcriptional coactivators play a major role in transducing and integrating physiological signals governing metabolism, differentiation, and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease. [ABSTRACT FROM AUTHOR]

PGC-1α is a potent, inducible transcriptional coactivator that exerts control on mitochondrial biogenesis and multiple cellular energy metabolic pathways. PGC-1α levels are controlled in a highly dynamic manner reflecting regulation at both transcriptional and post-transcriptional levels. Here, we demonstrate that PGC-1α is rapidly degraded in the nucleus (t½ 0.3 h) via the ubiquitin proteasome system. An N-terminal deletion mutant of 182 residues, PGC182, as well as a lysine-less mutant form, are nuclear and rapidly degraded (t½ 0.5 h), consistent with degradation via the N terminus-dependent ubiquitin subpathway. Both PGC-1α and PGC182 degradation rates are increased in cells under low serum conditions. However, a naturally occurring N-terminal splice variant of 270 residues, NT-PGC-1α is cytoplasmic and stable (t½ >7 h), providing additional evidence that PGC-1α is degraded in the nucleus. These results strongly suggest that the nuclear N terminus-dependent ubiquitin proteasome pathway governs PGC-1α cellular degradation. In contrast, the cellular localization of NT-PCG-1α results in a longer-half-life and possible distinct temporal and potentially biological actions. [ABSTRACT FROM AUTHOR]

Estrogen-related receptors (ERRs) play critical roles in regulation of cellular energy metabolism in response to inducible coactivators such as peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERR coactivator. Bcl3 was shown to synergize with PGC-1α to coactivate ERRα. Chromatin immunoprecipitation studies demonstrated that ERRα, PGC-1α, and Bcl3 form a complex on an ERRα-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1α and ERRα, allowing for interaction with both proteins. Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1α, ERRα, and a second nuclear receptor, PPARα. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPAR with PGC-1α in a manner similar to ERRα. We propose that the cooperativity between Bcl3 and PGC-1α may serve as a point of convergence on nuclear receptor targets to direct programs orchestrating inflammatory and energy metabolism responses in heart and other tissues. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondria in the adult mammalian heart have a tremendous capacity for oxidative metabolism, and the conversion of energy by these pathways is critical for proper cardiac function. This review describes mouse models relating mitochondrial metabolism to cardiac function through gain- or loss-of-function approaches that manipulate mitochondrial energy transduction or ATP synthetic pathways. Mouse models of mitochondrial defects are relevant to genetic and acquired forms of human cardiomyopathy. Examples include inborn errors in mitochondrial metabolism or end-stage heart failure. Conversely, chronic reliance on energy production via mitochondrial fatty acid oxidation, such as occurs in the diabetic heart, likely leads to maladaptive sequelae including cellular lipotoxicity and mitochondrial dysfunction. Collectively, these model systems have allowed us to begin to dissect the relationship between mitochondrial metabolism and the development of cardiomyopathy and to define the molecular pathways regulating cardiac mitochondrial number and function. [Copyright &y& Elsevier]

This paper presents the theoretical design and analysis of a tunable Fabry–Perot resonant microcavity filter realized by movable-waveguide-based integrated optical MEMS technology in InP. Wide-bandwidth, high-reflectivity horizontal InP/air-gap distributed bragg reflector (DBR) mirrors monolithically integrated with the waveguides have been proposed. The filter can be tuned by moving one of the high-reflectivity mirrors axially with on-chip MEMS electrostatic actuation. Spectral performance of the filter is numerically simulated taking into account the diffraction effects. Finite element mechanical modeling of the parallel-plate capacitive microactuator, consisting of a micromachined suspension beam and fixed electrodes, predicts a wide wavelength tuning range (1250–1650 nm) achievable by low actuation voltage (<7 V). [Copyright &y& Elsevier]

We investigate mechanical properties of indium phosphide (InP) for optical micro-electro-mechanical systems (MEMS) applications. A material system and fabrication process for InP-based beam-type electrostatic actuators is presented. Strain gradient, intrinsic stress, Young’s modulus, and hardness are evaluated by beam profile measurements, nanoindentation, beam bending, and electrostatic testing methods. We measured an average strain gradient of δ&epsiv;0/δt=4.37×10−5 μm−1, with an average intrinsic stress of σ0=−5.4 MPa for [0 1 1] beams. The intrinsic stress results from arsenic contamination during molecular beam epitaxy and (MBE) can be minimized by careful MBE growth and through the use of stress compensating layers. Nanoindentation of (1 0 0) InP resulted in E=106.5 GPa and H=6.2 GPa, while beam bending of [0 1 1] doubly clamped beams resulted in E=80.4 GPa and σ0=−5.6 MPa. We discuss the discrepancy in Young’s modulus between the two measurements. In addition, we present a method for simultaneously measuring Young’s modulus and residual stress using beam bending. Electrostatic actuation in excess of 20 V is demonstrated without breakdown. [Copyright &y& Elsevier]

Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remodeling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies. [ABSTRACT FROM AUTHOR]

Objectives: Hemoptysis is uncommon in children, even among the critically ill, with a paucity of epidemiological data to inform clinical decision-making. We describe hemoptysis-associated ICU admissions, including those who were critically ill at hemoptysis onset or who became critically ill as a result of hemoptysis, and identify predictors of mortality.Design: Retrospective cohort study. Demographics, hemoptysis location, and management were collected. Pediatric Logistic Organ Dysfunction-2 score within 24 hours of hemoptysis described illness severity. Primary outcome was inhospital mortality.Setting: Quaternary pediatric referral center between July 1, 2010, and June 30, 2017.Patients: Medical/surgical (PICU), cardiac ICU, and term neonatal ICU admissions with hemoptysis during or within 24 hours of ICU admission.Interventions: No intervention.Measurements and Main Results: There were 326 hemoptysis-associated ICU admissions in 300 patients. Most common diagnoses were cardiac (46%), infection (15%), bronchiectasis (10%), and neoplasm (7%). Demographics, interventions, and outcomes differed by diagnostic category. Overall, 79 patients (26%) died inhospital and 109 (36%) had died during follow-up (survivor mean 2.8 ± 1.9 yr). Neoplasm, bronchiectasis, renal dysfunction, inhospital hemoptysis onset, and higher Pediatric Logistic Organ Dysfunction-2 score were independent risk factors for inhospital mortality (p < 0.02). Pharmacotherapy (32%), blood products (29%), computerized tomography angiography (26%), bronchoscopy (44%), and cardiac catheterization (36%) were common. Targeted surgical interventions were rare. Of survivors, 15% were discharged with new respiratory support. Of the deaths, 93 (85%) occurred within 12 months of admission. For patients surviving 12 months, 5-year survival was 87% (95% CI, 78-92) and mortality risk remained only for those with neoplasm (log-rank p = 0.001).Conclusions: We observed high inhospital mortality from hemoptysis-associated ICU admissions. Mortality was independently associated with hemoptysis onset location, underlying diagnosis, and severity of critical illness at event. Additional mortality was observed in the 12-month posthospital discharge. Future directions include further characterization of this vulnerable population and management recommendations for life-threatening pediatric hemoptysis incorporating underlying disease pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Older adults exposed to periods of inactivity during hospitalization, illness, or injury lose muscle mass and strength. This, in turn, predisposes poor recovery of physical function upon reambulation and represents a significant health risk for older adults. Bed rest (BR) results in altered skeletal muscle fuel metabolism and loss of oxidative capacity that have recently been linked to the muscle atrophy program. Our primary objective was to explore the effects of BR on mitochondrial energetics in muscle from older adults. A secondary objective was to examine the effect of β-hydroxy-β-methylbuturate (HMB) supplementation on mitochondrial energetics.Methods: We studied 20 older adults before and after a 10-day BR intervention, who consumed a complete oral nutritional supplement (ONS) with HMB (3.0 g/d HMB, n = 11) or without HMB (CON, n = 9). Percutaneous biopsies of the vastus lateralis were obtained to determine mitochondrial respiration and H2O2 emission in permeabilized muscle fibers along with markers of content. RNA sequencing and lipidomics analyses were also conducted.Results: We found a significant up-regulation of collagen synthesis and down-regulation of ribosome, oxidative metabolism and mitochondrial gene transcripts following BR in the CON group. Alterations to these gene transcripts were significantly blunted in the HMB group. Mitochondrial respiration and markers of content were both reduced and H2O2 emission was elevated in both groups following BR.Conclusions: In summary, 10 days of BR in older adults causes a significant deterioration in mitochondrial energetics, while transcriptomic profiling revealed that some of these negative effects may be attenuated by an ONS containing HMB. [ABSTRACT FROM AUTHOR]

The article discusses the importance of planning for data collection, expressing data in usable forms, and interpreting patterns in the data are successfully using data analysis for teaching practice and student learning. Topics discussed include analyzing pedagogical practices and make data-driven decisions; use of analysis to determine instructional efforts and communicate with students to learn or improve; and Classroom data analysis can focus on analyzing the success of a learning target.