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Significance Recently, histone deacetylase 11 (HDAC11) was shown to function as an enzyme that removes lipids such as myristoyl groups from lysines in proteins, yet only one substrate of HDAC11 has been reported. Here, we define gravin-α/A kinase–anchoring protein 12 as a second HDAC11 substrate. By demyristoylating gravin-α in adipocytes, HDAC11 prevents β-adrenergic receptors (β-ARs), which are G protein–coupled receptors (GPCRs), from translocating to membrane microdomains that are required for downstream protective signaling by protein kinase A (PKA). These findings demonstrate a role for reversible lysine myristoylation in the control of GPCR signaling and lay the foundation for developing therapeutics for obesity based on enhancing β-AR signaling in adipose tissue by manipulating the HDAC11:gravin-α axis.

PURPOSE OF REVIEW: The giant protein titin forms the “elastic” filament of the sarcomere, essential for the mechanical compliance of the heart muscle. Titin serves a biological spring, and therefore structural modifications of titin affect function of the myocardium and are associated with heart failure and cardiomyopathy. RECENT FINDINGS: In this review, we discuss the current understanding of titin’s biophysical properties and how modifications contribute to cardiac function and heart failure. In addition, we review the most recent data on the clinical impact and phenotype heterogeneity of TTN truncating variants, including diseases involving striated muscles, and prospects for future therapies. SUMMARY: Because of the giant structure of the titin protein and the complexity of its function, titin’s role in health and disease is not yet completely understood. Future research efforts need to focus on novel therapeutic approaches able to modulate titin transcriptional and post-translational modification.

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.

Corporate wrongdoing is damaging investor confidence and tarnishing the credibility of the U.S. business community, guilty and innocent alike. Some misdeeds are clearly criminal, others simply unethical or damaging to reputations. They range from “massaging” numbers (“managed earnings”), which tests the limits of financial prudence, to outright fraud. Caught in the limelight are U.S. corporate giants representing some of the world's best-known brands and most famous CEOs, many only yesterday lionized in the business press. We have explored this issue from the perspective of the HR function through a survey of the senior HR professionals who attended the Human Resources Forum. The survey was augmented with focus groups. Our purpose was to understand current practices, attitudes, and behaviors with respect to legal standards and professional and ethical codes. We also explored the roles of the CEO, HR leadership, and the HR function in minimizing ethical breaches that have diminished investor and public trust. We hope to shed light on the responsibilities, actions, and risks of the HR function and its leadership now and in the future. © 2004 Wiley Periodicals, Inc.

Dilated cardiomyopathy (DCM) is an autosomal dominant disease characterised by dilation of the left ventricle and reduced systolic function. Although hundreds of mutations in more than 40 genes have been attributed to DCM, affecting a wide variety of structural proteins, conduction pathways and contraction mechanisms, this accounts for approximately 40% of familial genetic causes. Additionally, due to low prevalence of any particular single gene mutation in the population, as well as genetic overlap with other cardiomyopathies and diagnostic technology limitations, the diagnosis of DCM remains difficult. The introduction of high-throughput deoxyribonucleic acid (DNA) sequencing through multigene testing panels has improved diagnostic sensitivity. Furthermore, functional studies have provided innovative approaches to advance collective understanding of DCM aetiology, pathogenesis and diagnosis. Key Concepts: DCM is an autosomal dominant disease affecting 1 in 2500 individuals with up to 50% of cases attributed to genetic causes. Approximately 40 genes have been discovered as part of DCM aetiology, but this accounts for only 40% of genetic cases. Mutations causing DCM have been discovered in multiple cardiomyocyte proteins and pathways, with most mutations representing a rare cause of DCM and each contributing a low frequency of DCM cases. Mutated genes involved in DCM include those encoding sarcomeric, cytoskeleton, nuclear membrane and ion channel proteins; most mutations leads to a similar DCM phenotype. DCM-associated rare gene variants found both in research and clinical settings require confirmatory and follow-up studies, because some of them may eventually result in benign common variations. Functional studies model systems and animal models, such as in zebrafish, are useful for clearly observing the heart, and these studies have been successful in demonstrating distinct cardiac phenotypes for DCM-related gene mutations. Keywords: dilated cardiomyopathy; cardiovascular disease; cardiomyopathy; zebrafish; next-generation sequencing; autosomal dominant disease; allelic heterogeneity; cardiomyocyte

Failure to consider succession objectives when planning executive compensation can lead to intradepartmental transfer problems. This article shows how to plan ahead and avoid future headaches.