Mitochondrial Integrity Distinguishes Exercise-induced vs. Pathogenic Cardiac Hypertrophy

Cardiac hypertrophy is a consequence of exercise training, as well as certain cardiomyopathies. However, the key genetic drivers of cardiomyocellular remodeling in a healthy vs diseased heart are inadequately understood. PURPOSE: Determine the genetic architecture of exercise training-induced cardiomyocellular remodeling and hypertrophy. METHODS: The exercise hybrid mouse diversity panel (ExcHMDP) is comprised of 100 strains of Exc trained (TRN) and sedentary (SED) animals (n=4-8/strain per group). After 30d of exercise, running wheels were locked, and 24-hours post-exercise, 6h-fasted animals were euthanized and tissues harvested (~20 tissues/mouse). To interrogate pathogenic cardiac hypertrophy, isoproterenol (ISO, 30mg/kg/day for 21d) was administered to a second HMDP cohort, and similar to TRN hearts, RNAseq analyses were performed. RESULTS: TRN increased heart weight in 85% of 100 mouse strains vs. sedentary (SED). Of the nearly thirty heart phenotypes assessed, none correlated significantly with running distance. Interestingly, the heart showed relatively few differentially expressed genes when compared to other tissues (e.g. skeletal muscle and white adipose). Enrichment analysis of differential gene expression revealed mitochondrial function, inflammatory and immune processes, calcium signaling, muscle growth and development, and angiogenesis (FDRIL31ra, Fam167b, Tafa5, Crip3, and Nanos1(PCONCLUSION: Our studies provide important insight into the genetic architecture of cardiac remodeling associated with healthy vs. pathogenic hypertrophy. A primary goal is that our transcriptomics analyses are leveraged to advance therapeutics to combat hypertrophic cardiac myopathy-associated heart failure

Internet use among urban Malaysians: Network diversity effects

This study examines social network diversity in urban areas relative to residents’ usage of information and communication technologies (ICTs). Individual-level variation in social network diversity was measured using position generator data collected as part of a survey conducted in Malaysia’s Klang Valley (N = 808). Regression analyses were performed to assess the extent to which network diversity is related to ICTs. We find that most ICTs have a negative effect on diversity. Only frequent use of the Internet at work, mobile access to the Internet, and reading online news or blogs contribute positively to diversity. Findings support both a tendency toward ‘networked individualism’ and the more recent ‘glocalization’ thesis that some ICTs may also afford participation within local space rather than only across distant space

Exercise and Esr1 Control Mitochondrial Content and Function to Regulate Adiposity

Mechanisms that underlie adipose tissue remodeling to enhance metabolic health in response to exercise training remain inadequately understood. PURPOSE: We utilized mouse genetics and human GWAS to determine the impact of exercise training on mitochondrial DNA copy number, and interrogate the relationship between Esr1 and adipose tissue health. METHODS: We performed RNAseq on adipose tissue from 100 strains of inbred mice following exercise training and determined mitochondrial content by qPCR. We performed deep phenotyping of mice harboring conditional Esr1 overexpression selectively in adipose tissue. Adipose specific Esr1 overexpression and control mice were fed a high fat diet and placed in metabolic chambers to interrogate the effects of Esr1 on whole body metabolism. RESULTS: We determined that exercise training significantly increased adipose tissue mtDNA content in mouse and man and that increased mitochondrial content correlated with reduced adiposity. Adipocyte health was associated with increased expression of transcripts involved in mitochondrial cristae formation including OPA1, Polg1, and Dnm1l. Since Esr1 is a transcription factor negatively associated with adipose tissue mass, and since deletion of Esr1 disrupts mitochondrial function and reduces expression of Polg1, OPA1, and Dnm1l, we interrogated in impact of conditional Esr1 overexpression on mitochondrial function and adipose tissue health. Adipocyte-specific Esr1 overexpression increased expression of mitochondrial gene targets, increased mtDNA copy number and mitochondrial respiration, and enhanced whole body energy expenditure of animals challenged by high fat diet feeding. Adipocyte-specific Esr1 overexpression protected mice against HFD-induced obesity. CONCLUSION: Exercise promotes remodeling of adipose tissue mitochondria and is associated with fat mass reduction. Overexpression of Esr1 drives a similar adipose tissue remodeling and weight loss as exercise training, and protects against adipose tissue weight gain in the context of overnutrition. These data suggest that exercise responsive transcripts in adipose tissue can be selectively targeted to enhance weight loss and improve metabolic health

The people we know: Social network diversity among urban Malaysians

Social networks are an important source for individual social actors to access critical resources (e.g., information and support) and can be variably associated with tolerance, social harmony and nation building, also under conditions of rapid urbanisation. The purpose of this paper is to provide much-needed factual and quantitative details regarding the social networks of urban Malaysians. The approach includes self-report questionnaire data obtained in the first half of 2014 from a representative sample of 808 respondents, aged 31 to 55, living in five major cities/towns across the Klang Valley, Malaysia. Findings show that urban Malaysians function within social networks that are racially, culturally and socio-economically heterogeneous, interacting with all major groups in Malaysian society, including neighbours. For the vast majority, however, the observed degree of network diversity is medium to low. The analysis also suggests that social network diversity is no indication of the closeness or importance accorded to the social relationships involved. A final finding is that social network diversity weakly correlates with respondents’ sex, race and religion but not with their age or employment status. Overall, this study seems to point to the existence, among urban Malaysians, of a dual social network system: a more closely knit homogeneous network based on family ties versus a looser and more heterogeneous network of non-family contacts. Among the non-family contacts, the observed diversity can be hypothesised to be a diversity of necessity rather than one by choice. Potential political and social implications will be discussed

Graduate Student Reflections on Mentorship in a Training and Outreach Program for Families of Children with Autism Spectrum Disorder

Undergraduate (n = 19) and graduate students (n = 8) participated in a two semester training program focused on learning about Autism Spectrum Disorder (ASD) and how to create individualized communication supports for families of children with ASD. The focus of this paper is on the graduate students’ training and mentoring experiences. Graduate students’ philosophies of mentoring undergraduate students and their final reflections of the experience were analyzed for themes and subthemes. Mentoring philosophies yielded four major themes: role of the mentor, mentoring goals, the mentor-mentee relationship, and learning. Graduate student reflections on their skills gained, what they learned about themselves, their leadership, and the challenges they faced were also categorized into themes. Analyses revealed undergraduate student ratings and qualitative comments regarding graduate student support. Implications and future directions for the development of hands-on training programs allowing graduate students in Communication Sciences and Disorders to assume mentorship roles will be discussed

Factors associated with unrecognized cirrhosis in patients with hepatocellular carcinoma

Background/Aims Cirrhosis is the most important risk factor of hepatocellular carcinoma (HCC), and patients with cirrhosis are recommended to receive semiannual surveillance for early HCC detection. However, early cirrhosis is often asymptomatic and can go undiagnosed for years, leading to underuse of HCC surveillance in clinical practice. We characterized the frequency and associated factors of unrecognized cirrhosis in a national sample of patients with HCC from the United States. Methods HCC patients aged 68 years and older, diagnosed during 2011 to 2015 were included from the SEER-Medicare Linked Database. If cirrhosis was diagnosed within 6 months immediately preceding HCC diagnosis or after HCC diagnosis, cases were categorized as unrecognized cirrhosis. Factors associated with unrecognized cirrhosis were identified using logistic regression analyses. Factors associated with overall survival were evaluated using Cox regression analyses. Results Among 5,098 HCC patients, 74.8% patients had cirrhosis. Among those with cirrhosis, 57.4% had unrecognized cirrhosis, with the highest proportion (76.3%) among those with NAFLD-related HCC. Male sex (aOR: 2.12, 95% CI: 1.83–2.46), non-Hispanic Black race (aOR: 1.93, 95% CI: 1.45–2.57), and NAFLD etiology (aOR: 4.46, 95% CI: 3.68–5.41) were associated with having unrecognized cirrhosis. Among NAFLD-related HCC patients, male sex (aOR: 2.32, 95% CI: 1.71–3.14) was associated with unrecognized cirrhosis. Unrecognized cirrhosis was independently associated with worse overall survival (aHR: 1.17, 95% CI: 1.08–1.27) compared to recognized cirrhosis. Conclusions Unrecognized cirrhosis is common in NAFLD-related HCC, particularly among male and Black patients, highlighting these groups as important intervention targets to improve HCC surveillance uptake and outcomes

Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology