Inherent Metabolic Adaptations in Adult Spiny Mouse ( Acomys ) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction.

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( Acomys ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in Acomys compared to the non-regenerative Mus musculus . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus , underscoring the unique metabolic phenotype of Acomys hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys . In conclusion, our study identifies unique metabolic characteristics of Acomys cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes Acomys as a valuable model for studying cardiac ischemic resilience in adult mammals.

Social media literacy: A conceptual framework.

Concerns over the harmful effects of social media have directed public attention to media literacy as a potential remedy. Current conceptions of media literacy are frequently based on mass media, focusing on the analysis of common content and evaluation of the content using common values. This article initiates a new conceptual framework of social media literacy (SoMeLit). Moving away from the mass media-based assumptions of extant approaches, SoMeLit centers on the user's self in social media that is in dynamic causation with their choices of messages and networks. The foci of analysis in SoMeLit, therefore, are one's selections and values that influence and are influenced by the construction of one's reality on social media; and the evolving characteristics of social media platforms that set the boundaries of one's social media reality construction. Implications of the new components and dimensions of SoMeLit for future research, education, and action are discussed.

Learning Post-Stroke Gait Training Strategies by Modeling Patient-Therapist Interaction.

For safe and effective robot-aided gait training, it is essential to incorporate the knowledge and expertise of physical therapists. Toward this goal, we directly learn from physical therapists' demonstrations of manual gait assistance in stroke rehabilitation. Lower-limb kinematics of patients and assistive force applied by therapists to the patient's leg are measured using a wearable sensing system which includes a custom-made force sensing array. The collected data is then used to characterize a therapist's strategies in response to unique gait behaviors found within a patient's gait. Preliminary analysis shows that knee extension and weight-shifting are the most important features that shape a therapist's assistance strategies. These key features are then integrated into a virtual impedance model to predict the therapist's assistive torque. This model benefits from a goal-directed attractor and representative features that allow intuitive characterization and estimation of a therapist's assistance strategies. The resulting model is able to accurately capture high-level therapist behaviors over the course of a full training session (r2=0.92, RMSE=0.23Nm) while still explaining some of the more nuanced behaviors contained in individual strides (r2=0.53, RMSE=0.61Nm). This work provides a new approach to control wearable robotics in the sense of directly encoding the decision-making process of physical therapists into a safe human-robot interaction framework for gait rehabilitation.

Using infographics to reduce the negative effects of jargon on intentions to vaccinate against COVID-19.

Guided by feelings-as-information theory, this experiment (N = 643), based in the United States, tested whether the use of jargon and infographics within messages designed to explain the COVID-19 mRNA vaccines affected behavioral intentions to vaccinate. The results revealed that the presence of jargon was associated with a difficult processing experience, message resistance, decreased perceptions of message credibility, and reduced intentions to get the COVID-19 vaccine. That said, when an infographic was integrated into the jargon message, these negative relationships went away and the presence of jargon no longer indirectly impacted intention to vaccinate. This experiment demonstrates that in contexts where jargon use exists, the use of an infographic can counteract some of the negative effects of a difficult processing experience.

Quantitative analysis of mitochondrial ATP synthesis.

We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.

Testing three explanations for stigmatization of people of Asian descent during COVID-19: maladaptive coping, biased media use, or racial prejudice?

OBJECTIVE: To investigate factors associated with the stigmatization of people of Asian descent during COVID-19 in the United States and factors that can mitigate or prevent stigmatization. DESIGN: A national sample survey of adults (N = 842) was conducted online between May 11 and May 19, 2020. Outcome variables were two dimensions of stigmatization, responsibility and persons as risk. Hierarchical regression analyses were performed. RESULTS: Racial prejudice, maladaptive coping, and biased media use each explained stigmatization. Racial prejudice, comprising stereotypical beliefs and emotion toward Asian Americans, was a stronger predictor of stigmatization than maladaptive coping or biased media use. Fear concerning the ongoing COVID-19 situation and the use of social media and partisan cable TV also predicted stigmatization. Low self-efficacy in dealing with COVID-19, when associated with high estimated harm of COVID-19, increased stigmatization. High perceived institutional efficacy in the handling of COVID-19 increased stigmatization when linked to high estimated harm of COVID-19. On the other hand, high perceived collective efficacy in coping with COVID-19 was associated with low stigmatization. More indirect contacts with Asians via the media predicted less stigmatization. CONCLUSIONS: Efforts to reduce stigmatization should address racial stereotypes and emotions, maladaptive coping, and biased media use by providing education and resources to the public. Fostering collective efficacy and media-based contacts with Asian Americans can facilitate these efforts.

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts.

Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.

Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.

Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION.

Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications, and other chromatin features at pathology-associated genes. The extent to which genome-wide chromatin reorganization also contributes to the resultant changes in gene expression remains unknown. We examined the roles of two chromatin structural proteins, Ctcf (CCCTC-binding factor) and Hmgb2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling. Our data demonstrate a reciprocal relationship between Hmgb2 and Ctcf in controlling aspects of chromatin structure and gene expression. Both proteins regulate each others' expression as well as transcription in cardiac myocytes; however, only Hmgb2 does so in a manner that involves global reprogramming of chromatin accessibility. We demonstrate that the actions of Hmgb2 on local chromatin accessibility are conserved across genomic loci, whereas the effects on transcription are loci-dependent and emerge in concert with histone modification and other chromatin features. Finally, although both proteins share gene targets, Hmgb2 and Ctcf, neither binds these genes simultaneously nor do they physically colocalize in myocyte nuclei. Our study uncovers a previously unknown relationship between these two ubiquitous chromatin proteins and provides a mechanistic explanation for how Hmgb2 regulates gene expression and cellular phenotype. Furthermore, we provide direct evidence for structural remodeling of chromatin on a genome-wide scale in the setting of cardiac disease.

Structure and Reactivity of X-ray Amorphous Uranyl Peroxide, U2O7.

Recent accidents resulting in worker injury and radioactive contamination occurred due to pressurization of uranium yellowcake drums produced in the western U.S.A. The drums contained an X-ray amorphous reactive form of uranium oxide that may have contributed to the pressurization. Heating hydrated uranyl peroxides produced during in situ mining can produce an amorphous compound, as shown by X-ray powder diffraction of material from impacted drums. Subsequently, studtite, [(UO2)(O2)(H2O)2](H2O)2, was heated in the laboratory. Its thermal decomposition produced a hygroscopic anhydrous uranyl peroxide that reacts with water to release O2 gas and form metaschoepite, a uranyl-oxide hydrate. Quantum chemical calculations indicate that the most stable U2O7 conformer consists of two bent (UO2)(2+) uranyl ions bridged by a peroxide group bidentate and parallel to each uranyl ion, and a µ2-O atom, resulting in charge neutrality. A pair distribution function from neutron total scattering supports this structural model, as do (1)H- and (17)O-nuclear magnetic resonance spectra. The reactivity of U2O7 in water and with water in air is higher than that of other uranium oxides, and this can be both hazardous and potentially advantageous in the nuclear fuel cycle.

Not low hanging but still sweet: Metabolic proteomes in cardiovascular disease.

The application of proteomics in biology and medicine has reached a moment of truth. The demand of biologists for transformative insights into how cells work, plus the mandate of basic science research to ultimately impact clinical medicine, crystallize as a test on the rigor and reproducibility of any 'omics measurement. Studies like that by Boylston et al. indicate that proteomics can pass that test.