Rocker jaw: Global context for a Polynesian characteristic

Our goal is to describe the global distribution of the ‘rocker jaw’ variant in human populations. Rocker jaw refers to mandibles that lack the antegonial notch, making them unstable on a flat surface. Data were collected by C.G. Turner II on 9207 individuals from Asia, Europe, the Pacific, and the Americas, and by J.D. Irish on 3526 individuals from North and South Africa. With a focus on Polynesia, where the trait is most common, frequencies are presented for subdivisions of Oceania, Australasia, Eurasia, the Americas, and Africa. While the rocker jaw is a Polynesian characteristic, the trait is found throughout the world. Within major geographic regions, there are interesting contrasts, e.g. (1) the similarity of Jomon and Ainu and their difference from modern Japanese; (2) Aleuts and Northwest Coast Indians are similar and both are distinct from the Inuit and other Native Americans; and (3) North and Sub-Saharan Africans show a regional difference that parallels genetic and dental distinctions. Skeletons in South America that exhibit the rocker jaw have been interpreted as Polynesian voyagers who ventured to the west coast of South America. The rarity of rocker jaw in South American natives supports this view. The rocker jaw can be attributed to the unique basicranium morphology and large upper facial height of Polynesians, which highlights the integrated growth of a functional module (i.e., mastication) of the craniofacial complex. The unusually high frequency of the trait in Polynesians is a product of both function and founder effect/genetic drift

The curious role of sarcomeric proteins in control of diverse processes in cardiac myocytes

Introduction Relatively recent developments in our understanding of sarcomeric proteins have expanded their role from the home of molecular motors generating force and shortening to a cellular organelle fully integrated in the control of structural, electrical, mechanical, chemical, and metabolic homeostasis. Even so, in some cases these diverse functions of sarcomeric proteins appear to remain a curiosity, not fully appreciated in the analysis of major controllers of cardiac function. This attitude toward the function of sarcomeric proteins in cardiac myocytes is summarized in the following definition of “curiosity,” which seems particularly apropos: “meddlesome; thrusting oneself into and taking an active part in others’ affairs.” We focus in this Perspective on how sarcomeric proteins function in integration with membrane channels and transporters in control of cardiac dynamics, especially in adrenergic control of cardiac function. Understanding these mechanisms at the level of cardiac sarcomeres took on special significance with the identification of mutations in sarcomeric proteins as the most common cause of familial hypertrophic and dilated cardiomyopathies. These mutations commonly lead to structural, electrical, and metabolic remodeling and to sudden death. These disorders indicate a critical role of processes at the level of the sarcomeres in homeostatic control of cardiac energetics, dynamics, and structure. Yet, control of Ca2+ delivery to and removal from the myofilaments has dominated discussions of mechanisms regulating cardiac contractility. We first provide an alternative perspective in which rate processes at the level of the sarcomeres appear to be dominant during the rise and maintenance of systolic elastance and of isovolumic relaxation. A discussion of established adrenergic mechanisms and newly understood anti-adrenergic mechanisms controlling sarcomere response to Ca2+ follows and expands on this perspective

Rates of Influenza and Pneumococcal Vaccination and Correlation With Survival in Multiple Myeloma Patients

Background Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM. Materials and Methods We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019. Results Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV. Conclusion Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www.clinicaltrials.gov as #NCT02761187

Anti-inflammatory Components from Functional Foods for Obesity

Obesity, defined as excessive fat accumulation that may impair health, has been described throughout human history, but it has now reached epidemic proportions with the WHO estimating that 39% of the world’s adults over 18 years of age were overweight or obese in 2016. Obesity is a chronic low-grade inflammatory state leading to organ damage with an increased risk of common diseases including cardiovascular and metabolic disease, non-alcoholic fatty liver disease, osteo-arthritis and some cancers. This inflammatory state may be influenced by adipose tissue hypoxia and changes in the gut microbiota. There has been an increasing focus on functional foods and nutraceuticals as treatment options for obesity as drug treatments are limited in efficacy. This chapter summarises the importance of anthocyanin-containing fruits and vegetables, coffee and its components, tropical fruit and food waste as sources of phytochemicals for obesity treatment. We emphasise that preclinical studies can form the basis for clinical trials to determine the effectiveness of these treatments in humans

Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin-dependent and -independent kinase activities

The well-known, muscle-specific smooth muscle myosin light chain kinase (MLCK) (smMLCK) and skeletal muscle MLCK (skMLCK) are dedicated protein kinases regulated by an autoregulatory segment C terminus of the catalytic core that blocks myosin regulatory light chain (RLC) binding and phosphorylation in the absence of Ca(2+)/calmodulin (CaM). Although it is known that a more recently discovered cardiac MLCK (cMLCK) is necessary for normal RLC phosphorylation in vivo and physiological cardiac performance, information on cMLCK biochemical properties are limited. We find that a fourth uncharacterized MLCK, MLCK4, is also expressed in cardiac muscle with high catalytic domain sequence similarity with other MLCKs but lacking an autoinhibitory segment. Its crystal structure shows the catalytic domain in its active conformation with a short C-terminal "pseudoregulatory helix" that cannot inhibit catalysis as a result of missing linker regions. MLCK4 has only Ca(2+)/CaM-independent activity with comparable Vmax and Km values for different RLCs. In contrast, the Vmax value of cMLCK is orders of magnitude lower than those of the other three MLCK family members, whereas its Km (RLC and ATP) and KCaM values are similar. In contrast to smMLCK and skMLCK, which lack activity in the absence of Ca(2+)/CaM, cMLCK has constitutive activity that is stimulated by Ca(2+)/CaM. Potential contributions of autoregulatory segment to cMLCK activity were analyzed with chimeras of skMLCK and cMLCK. The constitutive, low activity of cMLCK appears to be intrinsic to its catalytic core structure rather than an autoinhibitory segment. Thus, RLC phosphorylation in cardiac muscle may be regulated by two different protein kinases with distinct biochemical regulatory properties

Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin-dependent and -independent kinase activities

The well-known, muscle-specific smooth muscle myosin light chain kinase (MLCK) (smMLCK) and skeletal muscle MLCK (skMLCK) are dedicated protein kinases regulated by an autoregulatory segment C terminus of the catalytic core that blocks myosin regulatory light chain (RLC) binding and phosphorylation in the absence of Ca(2+)/calmodulin (CaM). Although it is known that a more recently discovered cardiac MLCK (cMLCK) is necessary for normal RLC phosphorylation in vivo and physiological cardiac performance, information on cMLCK biochemical properties are limited. We find that a fourth uncharacterized MLCK, MLCK4, is also expressed in cardiac muscle with high catalytic domain sequence similarity with other MLCKs but lacking an autoinhibitory segment. Its crystal structure shows the catalytic domain in its active conformation with a short C-terminal "pseudoregulatory helix" that cannot inhibit catalysis as a result of missing linker regions. MLCK4 has only Ca(2+)/CaM-independent activity with comparable Vmax and Km values for different RLCs. In contrast, the Vmax value of cMLCK is orders of magnitude lower than those of the other three MLCK family members, whereas its Km (RLC and ATP) and KCaM values are similar. In contrast to smMLCK and skMLCK, which lack activity in the absence of Ca(2+)/CaM, cMLCK has constitutive activity that is stimulated by Ca(2+)/CaM. Potential contributions of autoregulatory segment to cMLCK activity were analyzed with chimeras of skMLCK and cMLCK. The constitutive, low activity of cMLCK appears to be intrinsic to its catalytic core structure rather than an autoinhibitory segment. Thus, RLC phosphorylation in cardiac muscle may be regulated by two different protein kinases with distinct biochemical regulatory properties