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Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes–induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.

Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.

Long noncoding RNAs (lncRNAs) have been shown to play a role in cardiac physiology and disease. Here the authors identify the lncRNA Caren as a cytoplasmic RNA that decreases the translation of a distant gene encoding Hint1, thereby maintaining cardiomyocyte function due to inactivation of the DNA damage response and activation of mitochondrial bioenergetics.

Abstract Background This study examined the prevalence and predictors of complementary and alternative medicine use among clinic patients with hypertension and/or type 2 diabetes mellitus in western Jamaica. Methods A cross-sectional study using an investigator-administered questionnaire was conducted from May to August 2017. Data on sociodemographic factors, complementary and alternative medicine use, and knowledge and perceptions of complementary and alternative medicine were collected from the patients. Multivariable logistic regression analysis was used to examine associations between patient characteristics and knowledge and perceptions of complementary and alternative medicine and complementary and alternative medicine use. Results A total of 362 patients were invited to participate and 345 (95.3%) completed the questionnaire; 311 (90.1%) had hypertension, 130 (37.7%) had type 2 diabetes mellitus and 96 (27.8%) had both diseases. Seventy-nine percent of the participants with hypertension and 65% with type 2 diabetes mellitus reported current use of complementary and alternative medicine. Self-reported knowledge of complementary and alternative medicine (none/poor vs average/good/excellent) was significantly associated with complementary and alternative medicine use for hypertension (AOR = 0.33, 95% CI = 0.13–0.87) and type 2 diabetes mellitus (AOR = 0.06, 95% CI = 0.01–0.37). Believing that complementary and alternative medicine is a natural method for treating hypertension was significantly associated with complementary and alternative medicine use among patients with hypertension (AOR = 3.9, 95% CI = 1.26–12.00), and belief that it is acceptable to use prescription medication and complementary and alternative medicine simultaneously was significantly associated with complementary and alternative medicine use among patients with type 2 diabetes mellitus (AOR =7.19, CI = 1.34–38.52). Conclusions Participants’ perceptions of their knowledge and beliefs regarding complementary and alternative medicine strongly influence their use of complementary and alternative medicine. These findings can be used in designing educational interventions to promote the proper use, and mitigate detrimental effects, of complementary and alternative medicine in this population.

β-propeller domains are an important class of folding substrates for the eukaryotic cytosolic chaperonin CTT. Here the authors find that CTT contributes to the folding and assembly of two β-propeller proteins from mTOR complexes, mLST8 and Raptor, and determine the 4.0 Å cryoEM structure of a human mLST8-CCT intermediate that shows mLST8 in a near-native state.

Objectives: This study investigated the knowledge, attitudes, and practices (KAP) of healthcare professionals (HCPs) regarding CAM use for Hypertension (HTN) and Type 2 Diabetes Mellitus (T2DM) among patients in western Jamaica, and to determine HCPs’ perceptions of the need for training on CAM. Design: A cross-sectional study was conducted from May to August 2019. Setting: HCPs serving patients with HTN and T2DM in chronic disease clinics in western Jamaica completed a self-administered questionnaire that provided data on their sociodemographic characteristics, training, and KAP of CAM. Main outcome measure: The data identified factors associated with discussion and recommendation of CAM to patients and personal use of CAM by HCPs. Results: Type of profession (physicians vs nurses OR = 2.17; 95 % CI = 1.07−4.42 and pharmacists vs nurses OR = 8.67; 95 % CI = 2.83−26.57) was significantly associated with discussion of CAM. Training on CAM was significantly associated with discussion (OR = 2.36; 95 % CI = 1.26−4.42), recommendation (OR = 2.72; 95 % CI = 1.36–5.42), and personal use of CAM (OR = 2.90; 95 % CI = 1.69−4.97). Dieticians and nutritionists had 4.56 higher odds of personal use of CAM (95 % CI = 1.16−17.86), and personal use of CAM was significantly associated with discussion (OR = 8.94; 95 % CI = 4.76−16.80) and recommendation (OR = 7.17; 95 % CI = 3.54–14.51) of CAM. The majority of HCPs (70–89 %) agreed that there is a need to include CAM in professional training programs. Conclusion: The results of this study can be used to guide development of programs for training HCPs on knowledge and safe use of CAM so that they can better serve their patients.

Summary: Accumulation of visceral (VIS) is a predictor of metabolic disorders and insulin resistance. This is due in part to the limited capacity of VIS fat to buffer lipids allowing them to deposit in insulin-sensitive tissues. Mechanisms underlying selective hypertrophic growth and tissue remodeling properties of VIS fat are not well understood. We identified subsets of adipose progenitors (APs) unique to VIS fat with differential Cd34 expression and adipogenic capacity. VIS low (Cd34 low) APs are adipogenic, whereas VIS high (Cd34 high) APs are not. Furthermore, VIS high APs inhibit adipogenic differentiation of SUB and VIS low APs in vitro through the secretion of soluble inhibitory factor(s). The number of VIS high APs increased with adipose tissue expansion, and their abundance in vivo caused hypertrophic growth, fibrosis, inflammation, and metabolic dysfunction. This study unveils the presence of APs unique to VIS fat involved in the paracrine regulation of adipogenesis and tissue remodeling. : Buffolo et al. show that the visceral fat of mice contains subsets of Cd34 positive stromal cells with distinct adipogenic potential. Stromal cells with high Cd34 expression inhibit adipogenic conversion of cells with low Cd34 expression. When implanted in vivo, Cd34 high stromal cells cause visceral adipose tissue remodeling and inflammation and impair insulin sensitivity. Keywords: adipose progenitors, fat expansion, cell sorting, transplantation, visceral fat

In addition to being one of the most iconic of the new reproductive technologies introduced in the late twentieth century, in vitro fertilization is also a technology of representation – a looking glass into conception, a window onto early human development, and as such a new form of public spectacle. Still a rapidly expanding global biomedical service sector, IVF technology is also the source of new images of human origins, and thus offers a new visual grammar of coming into being. This lecture explores these connections, and argues that the micromanipulation imagery associated with IVF, and now a routine feature of news coverage and popular debate of NRTs, also introduces a new connection between cells and tools, thus returning us to one of the oldest sociological questions – the question concerning technology. Moving between IVF as a technology of reproduction, and a visual technology, enables us to revisit a series of broad sociological questions concerning technology, reproduction, genealogy and the future of biological control from the unique perspective offered by the conversion of the human embryo into both a tool and a lens.

Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content.

Tightly regulated Ca2+ homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca2+ handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca2+ extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca2+ uptake and accelerates the transfer of Ca2+ from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca2+ sparks and thereby inhibits Ca2+ overload-induced erratic Ca2+ waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca2+ uptake in the regulation of cardiac rhythmicity.

Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/TBX3 repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes CDKN2A-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes CDKN2A-p16INK. Thus CAPERα/TBX3 and UCA1 constitute a coordinated, reinforcing mechanism to regulate both CDKN2A-p16INK transcription and mRNA stability. Dissociation of the CAPERα/TBX3 co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPERα and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of TBX3.

TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.