Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls

Towards a global partnership model in interprofessional education for cross-sector problem-solving

Objectives A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. Methods This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students’ data. Results We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest–posttest differences in students’ readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students’ social interaction anxiety after the IPE simulation. Conclusions The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Heart Failure Genetics in Mice and Men

The genetics of heart failure is complex. In familial cases of cardiomyopathy, where mutations of large effects predominate in theory, genetic testing using a gene panel of up to 76 genes returned negative results in about half of the cases. In common forms of heart failure (HF), where a large number of genes with small to modest effects are expected to modify disease, only a few candidate genomic loci have been identified through genome-wide association (GWA) analyses in humans. We aimed to use exome sequencing to rapidly identify rare causal mutations in familial cardiomyopathy cases and effectively filter and classify the variants based on family pedigree and family member samples. We identified a number of existing variants and novel genes with great potential to be disease causing. On the other hand, we also set out to understand genetic factors that predispose to common late-onset forms of heart failure by performing GWA in the isoproterenol-induced HF model across the Hybrid Mouse Diversity Panel (HMDP) of 105 strains of mice. We performed fine phenotyping using serial echocardiograms and controlled for environmental heterogeneity in the experimental setting. As a result, we achieved high heritability estimates of 64% to 84% for all cardiac traits and had superior power for mapping HF-related trait, compared to human studies. Association analyses of cardiac traits, corrected for population structure and multiple comparisons, revealed genome-wide significant loci across the spectrum of cardiac traits. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Future directions will be to further bridge the gap of understanding between rare Mendelian and common cardiovascular diseases, which together will have wide spread therapeutic implications in delaying or reversing HF progression in human populations

Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls

Population distribution of echocardiographic measures at each time point.

<p>The violin plot is a combination of a boxplot and a kernel density plot (a smooth histogram) rotated on its side. The white dot represents the median. The black box represents the interquartile range (IQR). The black vertical line represents the whiskers spanning the lowest and the highest data within 1.5 IQR from the lower and upper quartile. A) The population distribution at each ISO treatment time point. B) The distribution of the changes in echocardiographic measures from baseline. C) The changes in echocardiographic measures compared to baseline at each ISO time point for individual classical inbred strains.</p

<i>Myh14</i> deficiency under ISO results in LVM hypertrophy, LVIDd dilation, increased cardiomyocyte size, fibrosis, intercalated disc disarray, and hypertrophic signals.

<p>Female mice of wild-type (WT), heterozygous (HET) and knockout (KO) <i>Myh14</i> genotypes were treated with ISO at 10–12 weeks of age (n = 6, 9, and 7, respectively). <i>Myh14</i> deficiency conferred an increase in ISO-induced LVM hypertrophy (A) and LVID dilation (B). There was a trend towards decreased ISO-induced EF (C) due to <i>Myh14</i> deficiency. Cardiomyocyte cross-sectional area, as measured by wheat germ agglutinin (WGA) staining (D), showed that cardiomyocytes from ISO-treated KO mice were more significantly hypertrophied compared to HET and WT mice (E). Dark gray bars (baseline in A and B; average of baseline and week 1 in C; control in E). Light gray bars (average of weeks 1–3 measures in A and B; average of weeks 2–3 measures in C; ISO-treated in E). <i>Myh14</i> deficiency conferred an increase in ISO-induced fibrosis (blue arrow) by Masson’s trichrome staining (F) and an increase in intercalated disc disarray (blue arrow) by β-catenin staining (G). Cardiac tissue gene expression of hypertrophic and fibrosis markers were examined by RT-PCR at the end of a 3-week ISO infusion (H). <i>Myc</i>, <i>Nppb</i>, and <i>Lgals3</i> were increased with <i>Myh14</i> deficiency. Error bars are SEM, n = 3. * represents t-test p-value < 0.05. ** represents t-test p-value < 0.005.</p

Variation in echocardiographic measures of cardiac structure and function among HMDP mouse strains.

<p>Black bars represent measurements under the baseline condition in ranked order. White bars represent measurements after 3 weeks of continuous ISO infusion. IVSd = interventricular septal wall thickness; LVIDd = left ventricular diastolic diameter; LVM = left ventricular mass; FS = fractional shortening. Error bars represent the standard errors of the means.</p