H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes.

Hydrogen sulfide (H2S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H2S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H2S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na2S/GYY4137, a H2S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na2S/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na2S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. In vivo studies using CBS+/-, a model for hyperhomocysteinemia, and sibling CBS+/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H2S-mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart

Integration of Digital Technology in Academics

The report aims to identify level of technological integration in academics. Digital literacy enhances learning and knowledge of learners. The benefits of digital literacy are evident in the students’ progress. Active learning is obtained through digital technology as well as literacy enhancement. Considering these benefits, an analysis of technology integration is conducted. The analysis reveals that desired level of technology integration is not achieved in academics. There are several barriers of poor technology integration. Poor technological infrastructure, budget deficit and poor access to technological resources are identified. Lack of time to devote learning of technological competencies is also reported by the analysis. Lack of resources, limited access, insufficient knowledge and skills of teachers and support staffs, lack of support from administrative and teachers, as well as other factors are found responsible for poor technological integration in academics. Institutional barriers are also identified as barriers such as poor leadership or structure of academic institutions. Leader’s inability to understand relevance of technology for learning is a major hindrance. In assessment, teachers do not have sufficient time to implement technology thus they do not use the technological aspects fruitfully. Lack of professional development of the teachers is also a barrier. Many teachers and supportive staff want to maintain the status quo and do not feel that technology integration is required. Such attitudes also prevent technology integration in the academic institutions. Thus, several recommendations are provided by the report such as providing professional development opportunities to the teachers, creating a shared vision, involving stakeholdes, findings cheaper alternatives for digital tools use, seeking grants and funds from government and private organizations, addressing resistance to change by providing training regarding benefits of technology adaption in the classroom etc. the recommendations also include rotating classes and students in groups for collaborative learning, appointing students helpers, allotting more times to the teachers for technological competencies, arranging regular meetings for technology integration, addressing issues of lack of resources, etc. These recommendations can help the academic institutions to integrate technology well in academic

Diabetic Cardiomyopathy: An Immunometabolic Perspective.

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation-contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation-contraction coupling as Ca(2+) is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca(2+) release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs

MiR-133a Mimic Alleviates T1DM-Induced Systolic Dysfunction in Akita: An MRI-Based Study

Diabetic cardiomyopathy is a leading cause of heart failure. Developing a novel therapeutic strategy for diabetic cardiomyopathy and characterizing animal models used for diabetes mellitus (DM) are important. Insulin 2 mutant (Ins2+/-) Akita is a spontaneous, genetic, mouse model for T1DM, which is relevant to humans. There are contrasting reports on systolic dysfunction and pathological remodeling (hypertrophy and fibrosis) in Akita heart. Here, we used magnetic resonance imaging (MRI) approach, a gold standard reference for evaluating cardiac function, to measure ejection fraction (indicator of systolic dysfunction) in Akita. Moreover, we performed Wheat Germ Agglutinin (WGA) and hematoxylin and Eosin stainings to determine cardiac hypertrophy, and Masson\u27s Trichrome and picrosirius red stainings to determine cardiac fibrosis in Akita. MiR-133a, an anti-hypertrophy and anti-fibrosis miRNA, is downregulated in Akita heart. We determined if miR-133a mimic treatment could mitigate systolic dysfunction and remodeling in Akita heart. Our MRI results revealed decreased ejection fraction in Akita as compared to WT and increased ejection fraction in miR-133a mimic-treated Akita. We also found that miR-133a mimic treatment mitigates T1DM-induced cardiac hypertrophy and fibrosis in Akita. We conclude that Akita shows cardiac hypertrophy, fibrosis and systolic dysfunction and miR-133a mimic treatment to Akita could ameliorate them

Public health insurance coverage in India before and after PM-JAY:Repeated cross-sectional analysis of nationally representative survey data

Introduction:The provision of non-contributory public health insurance (NPHI) to marginalised populations is a critical step along the path to universal health coverage. We aimed to assess the extent to which Ayushman Bharat-Pradhan Mantri Jan Arogya Yojana (PM-JAY) - potentially, the world's largest NPHI programme - has succeeded in raising health insurance coverage of the poorest two-fifths of the population of India. Methods:We used nationally representative data from the National Family Health Survey on 633 699 and 601 509 households in 2015-2016 (pre-PM-JAY) and 2019-2021 (mostly, post PM-JAY), respectively. We stratified by urban/rural and estimated NPHI coverage nationally, and by state, district and socioeconomic categories. We decomposed coverage variance between states, districts, and households and measured socioeconomic inequality in coverage. For Uttar Pradesh, we tested whether coverage increased most in districts where PM-JAY had been implemented before the second survey and whether coverage increased most for targeted poorer households in these districts. Results:We estimated that NPHI coverage increased by 11.7 percentage points (pp) (95% CI 11.0% to 12.4%) and 8.0 pp (95% CI 7.3% to 8.7%) in rural and urban India, respectively. In rural areas, coverage increased most for targeted households and pro-rich inequality decreased. Geographical inequalities in coverage narrowed. Coverage did not increase more in states that implemented PM-JAY. In Uttar Pradesh, the coverage increase was larger by 3.4 pp (95% CI 0.9% to 6.0%) and 4.2 pp (95% CI 1.2% to 7.1%) in rural and urban areas, respectively, in districts exposed to PM-JAY and the increase was 3.5 pp (95% CI 0.9% to 6.1%) larger for targeted households in these districts. Conclusion:The introduction of PM-JAY coincided with increased public health insurance coverage and decreased inequality in coverage. But the gains cannot all be plausibly attributed to PM-JAY, and they are insufficient to reach the goal of universal coverage of the poor.</p

Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading.

Autophagy is ubiquitous in all forms of heart failure and cardioprotective miR-133a is attenuated in human heart failure. Previous reports from heart failure patients undergoing left ventricular assist device (LVAD) implantation demonstrated that autophagy is upregulated in the LV of the failing human heart. Studies in the murine model show that diabetes downregulates miR-133a. However, the role of miR-133a in the regulation of autophagy in diabetic hearts is unclear. We tested the hypothesis that diabetes exacerbates cardiac autophagy by inhibiting miR-133a in heart failure patients undergoing LVAD implantation. The miRNA assay was performed on the LV of 15 diabetic (D) and 6 non-diabetic (ND) heart failure patients undergoing LVAD implantation. Four ND with highly upregulated and 5 D with highly downregulated miR-133a were analyzed for autophagy markers (Beclin1, LC3B, ATG3) and their upstream regulators (mTOR and AMPK), and hypertrophy marker (beta-myosin heavy chain) by RT-qPCR, Western blotting and immunofluorescence. Our results demonstrate that attenuation of miR-133a in diabetic hearts is associated with the induction of autophagy and hypertrophy, and suppression of mTOR without appreciable difference in AMPK activity. In conclusion, attenuation of miR-133a contributes to the exacerbation of diabetes mediated cardiac autophagy and hypertrophy in heart failure patients undergoing LVAD implantation

Precision Medicine for CRC Patients in the Veteran Population: State-of-the-Art, Challenges and Research Directions.

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA\u27s research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC