Cardiac myosin binding protein C, adrenergic stimulation and cardiac contractility

Myosin binding protein C remained a perplexing although integral component of the sarcomeric thick filament until the discovery that genetic defects in its corresponding gene is a frequent cause of hypertrophic cardiomyopathy. Basic science investigation subsequently revealed that it is one of the most potent regulators of cardiac contractility. Phosphorylation of its N-terminus upon adrenergic stimulation, causes increased order in myosin heads as well as increased ATPase activity, Fmax and Ca2+-sensitivity of contraction, while its dephosphorylation upon cholinergic stimulation or during low flow ischaemia leads to changes in the sarcomeric thick filament that diminish interaction between myosin heads and actin. This dynamic flux in phosphorylation upon adrenergic stimulation is not only crucial to normal cardiac function and structure, but also vital for protection against ischaemic injury. Genetically-driven deficiency or inadequacy in cMyBPC leads to severe cardiac dysfunction and structural changes, including cardiac hypertrophy and dilation, and particularly attenuates the adaptive increase in left ventricular contractility that follows on β-adrenergic stimulation or pressure overload, resulting in decreased systolic function, and reduced cardiac output

Evaluating The Relationship Between Integrated Reporting And Financial Indicators In Jse-Listed Companies

Journal ArticleThe paper explores the relationships between a comprehensive list of financial indicators and the quality of Integrated Reporting disclosed in companies listed on the Johannesburg Stock Exchange. These relationships were investigated using the Ernst & Young (EY) Integrated Reports Awards and financial information obtained from IRESS Ltd for a selection of 45 companies over four years (2014 to 2017), and using Spearman rank-order correlations, a Breusch Pagan test, and five multiple regression analyses. The results indicate a similar trend in the direction of relationships between the baseline and other models, except for price-earnings and net profit margin. Statistically significant positive relationships were identified between Integrated Report Quality (IRQ) and average debtors collection (DEBT), earnings before interest, taxes, depreciation and amortisation (EBIDTA) and return on equity (ROE). Statistically significant negative relationships were identified between IRQ and fixedassets turnover (FATURN), inventory turnover (INV), earnings before interest and taxes (EBIT) dividend yield (DIVYIELD), dividend cover (DIVCOV) and return on capital employed (ROCE). The results of this study can assist companies in the effective and productive allocation of their capitals, which in turn will enhance long-term sustainability

Molecular genetics of cardiomyopathy: changing times, shifting paradigms

The original publication is available at http://www.cvja.co.za/Includes bibliographyCongestive heart failure is a major problem in developed and developing countries alike. Primary dysfunction of the heart muscle accounts for a significant proportion of patients with a non-ischaemic cause of heart failure. Application of genetic techniques has facilitated identification of some molecular causes of the inherited form of these diseases, dramatically increasing our understanding of the pathogenesis of these primary, previously termed ‘idiopathic’, cardiomyopathies over the last few decades. Knowledge of the different causes is beginning to coalesce into aetiological principles underlying the clinically distinguished cardiomyopathies. Hypertrophic cardiomyopathy (HCM) now appears to be a disease caused by a dysfunctional sarcomere, dilated cardiomyopathy (DCM), a disease of myocytic structural instability, and arrhythmogenic right ventricular cardiomyopathy, a disease of accelerated myocyte death. The aetiology of both HCM and DCM probably also involves cardiac energy imbalances, while additional factors modify the clinical expression in all cardiomyopathies. Even though our knowledge of the genetic aetiology of the cardiomyopathies is still incomplete, it already has relevant clinical significance. Elucidation of the full genetic contribution to the development and progression of the cardiomyopathies represents a new challenge in the study of these diseases, and will undoubtedly lead to new therapeutic approaches in the not-too-distant future.Publishers' versio

Factors that motivate millennial accountancy professionals in industry to become academics

Orientation: Exploring the reasons why millennial chartered accountants choose to pursue a career in academia is fundamental to the future and advancement of the accountancy profession. Research purpose: This article examines the factors that could motivate a millennial accountancy professional to join academia and to describe the lived experiences of accountancy academics in the context of career identity and situational circumstances from London’s theory of career motivation. Motivation for the study: Tertiary accountancy education holds a national interest, which elevates the importance of attracting and retaining suitably qualified accountancy lecturers. Research approach/design and method: As part of interpretative phenomenological analysis, semi-structured face-to-face interviews were conducted with 14 current and former open distance learning accountancy academics in South Africa. Main findings: The research showed that flexible work schedules, the opportunity to teach, work in an autonomous environment and the desire to improve society were significant drivers for professional accountants to join academia. Research ranked as an insignificant motivating factor to join academia, although their retrospective views show the importance for those hoping to remain in academia to embrace it. Practical/managerial implications: This study may be useful to current and aspiring millennial accountancy academics, at universities offering accountancy or chartered accountancy programmes and to their human resource practitioners. Contribution/value-add: The research clarified the prospective perceptions and multi-layered motivational factors that could influence millennial accountancy professionals to join academia as well as the retrospective views from the lived experiences of accountancy lecturers in the context of London’s theory of career motivation

Long-term follow-up of R403W MYH7 and R92W TNNT2 HCM families : mutations determine left ventricular dimensions but not wall thickness during disease progression

The original publication is available at http://www.cvja.co.za/CVJA holds the copyrightThe clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s). Methods: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92WTNNT2 and R403WMYH7, both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92WTNNT2 and R403WMYH7 mutation carriers in these and additional South African R92WTNNT2 families after a mean 11.08 ± 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. Results: We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92WTNNT2 carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403WMYH7 carriers, which may require clinical follow-up over the longer term. Conclusions: Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly genderassociated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.Publishers' Versio

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure

Introduction. Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin—angiotensin—aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT1R). However, Ang II binding to Ang II type 2 receptors (AT2R) also has hypertrophy-modulating effects. Methods. We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT2R gene ( AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate. Results. We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ~0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates ( p = 0.020). Conclusion. This study therefore confirms a hypertrophy-modulating effect for AT2R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM

Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C

<p>Abstract</p> <p>Background</p> <p>Cardiac contractility is regulated by dynamic phosphorylation of sarcomeric proteins by kinases such as cAMP-activated protein kinase A (PKA). Efficient phosphorylation requires that PKA be anchored close to its targets by A-kinase anchoring proteins (AKAPs). Cardiac Myosin Binding Protein-C (cMyBPC) and cardiac troponin I (cTNI) are hypertrophic cardiomyopathy (HCM)-causing sarcomeric proteins which regulate contractility in response to PKA phosphorylation.</p> <p>Results</p> <p>During a yeast 2-hybrid (Y2H) library screen using a trisphosphorylation mimic of the C1-C2 region of cMyBPC, we identified isoform 4 of myomegalin (MMGL) as an interactor of this N-terminal cMyBPC region. As MMGL has previously been shown to interact with phosphodiesterase 4D, we speculated that it may be a PKA-anchoring protein (AKAP).</p> <p>To investigate this possibility, we assessed the ability of MMGL isoform 4 to interact with PKA regulatory subunits R1A and R2A using Y2H-based direct protein-protein interaction assays. Additionally, to further elucidate the function of MMGL, we used it as bait to screen a cardiac cDNA library. Other PKA targets, viz. CARP, COMMD4, ENO1, ENO3 and cTNI were identified as putative interactors, with cTNI being the most frequent interactor.</p> <p>We further assessed and confirmed these interactions by fluorescent 3D-co-localization in differentiated H9C2 cells as well as by <it>in vivo </it>co-immunoprecipitation. We also showed that quantitatively more interaction occurs between MMGL and cTNI under β-adrenergic stress. Moreover, siRNA-mediated knockdown of MMGL leads to reduction of cMyBPC levels under conditions of adrenergic stress, indicating that MMGL-assisted phosphorylation is requisite for protection of cMyBPC against proteolytic cleavage.</p> <p>Conclusions</p> <p>This study ascribes a novel function to MMGL isoform 4: it meets all criteria for classification as an AKAP, and we show that is involved in the phosphorylation of cMyBPC as well as cTNI, hence MMGL is an important regulator of cardiac contractility. This has further implications for understanding the patho-aetiology of HCM-causing mutations in the genes encoding cMyBPC and cTNI, and raises the question of whether MMGL might itself be considered a candidate HCM-causing or modifying factor.</p

Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy, a common, inherited cardiac muscle disease, is primarily caused by mutations in sarcomeric protein-encoding genes and is characterized by overgrowth of ventricular muscle that is highly variable in extent and location. This variability has been partially attributed to locus and allelic heterogeneity of the disease-causing gene, but other factors, including unknown genetic factors, also modulate the extent of hypertrophy that develops in response to the defective sarcomeric functioning. Components of the renin-angiotensin-aldosterone system are plausible candidate hypertrophy modifiers because of their role in controlling blood pressure and biological effects on cardiomyocyte hypertrophy

The reintroduction of large carnivores to the Eastern Cape, South Africa: an assessment

Recently, conservation estate in South Africa's Eastern Cape Province has increased 10-fold resulting in large predators being increasingly reintroduced to restore ecological integrity and maximize tourism. We describe the reintroductions of large carnivores (>10 kg) that have occurred in the Eastern Cape and use various criteria to assess their success. Lion Panthera leo reintroduction has been highly successful with a population of 56 currently extant in the region and problems of overpopulation arising. The African wild dog Lycaon pictus population has increased to 24 from a founder population of 11. Preliminary results for spotted hyaenas Crocuta crocuta also indicate success. Wild populations of leopards Panthera pardus exist on several reserves and have been supplemented by translocated individuals, although deaths of known individuals have occurred and no estimate of reproduction is available. Cheetah Acinonyx jubatus reintroduction has also been less successful with 36 individuals reintroduced and 23 cubs being born but only 41 individuals surviving in 2005. Criteria for assessing the success of reintroductions of species that naturally occur in low densities, such as top predators, generally have limited value. Carrying capacity for large predators is unknown and continued monitoring and intensive management will be necessary in enclosed, and possibly all, conservation areas in the Eastern Cape to ensure conservation success