Binding of myomesin to obscurin-like-1 to the muscle M-band provides a strategy for isoform-specific mechanical protection

The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signalling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1): myomesin complex. The crystal structure reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. Crucially, this unconventional architecture provides mechanical stability up to forces of 135 pN. A cellular competition assay in neonatal rat cardiomyocytes validates the complex and provides the rationale for the isoform specificity of the interaction. Altogether, our results reveal a novel binding strategy in sarcomere assembly, which might have implications on muscle nanomechanics and overall M-band organization.We thank the Diamond Light Source and the European Synchrotron Radiation Laboratory for access to MX and SAXS beamlines, respectively. This work was supported by a British Heart Foundation grant (PG/10/67/28527) awarded to R.A.S. and M.G. as well as MRC grant MR/J010456/1 to M.G. and a British Heart Foundation grant (PG/13/50/30426) and EPSRC Fellowship (K00641X/1) to S.G.-M

Piperidine renin inhibitors: from leads to drug candidates

Non-peptidomimetic renin inhibitors of the pipersine type represent the a novel structural class of compounds free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identificiation of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalized albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status

Irish Thoracic Society: Proceeds of Annual Scientific Meeting held Friday & Saturday 8th & 9th November, 1996

The abstract is included in the text

Ethnic-specific normative reference values for echocardiographic la and LV size, LV mass, and systolic function: The EchoNoRMAL study

Abstract OBJECTIVES: This study sought to derive age-, sex-, and ethnic-appropriate adult reference values for left atrial (LA) and left ventricular (LV) dimensions and volumes, LV mass, fractional shortening, and ejection fraction (EF) derived from geographically diverse population studies. BACKGROUND: The current recommended reference values for measurements from echocardiography may not be suitable to the diverse world population to which they are now applied. METHODS: Population-based datasets of echocardiographic measurements from 22,404 adults without clinical cardiovascular or renal disease, hypertension, or diabetes were combined in an individual person data meta-analysis. Quantile regression was used to derive reference values at the 95th percentile (upper reference value [URV]) and fifth percentile (lower reference value [LRV]) of each measurement against age (treated as linear), separately within sex and ethnic groups. RESULTS: The URVs for left ventricular end-diastolic volume (LVEDV), LV end-systolic volume, and LV stroke volume (SV) were highest in Europeans and lowest in South Asians. Important sex and ethnic differences remained after indexation by body surface area or height for these measurements, as well as for the LRV for SV. LVEDV and SV decreased with increasing age for all groups. Importantly, the LRV for EF differed by ethnicity; there was a clear apparent difference between Europeans and Asians. The URVs for LV end-diastolic diameter and LV end-systolic diameter were higher for Europeans than those for East Asian, South Asian, and African people, particularly among men. Similarly, the URVs for LA diameter and volume were highest for Europeans. CONCLUSIONS: Sex- and/or ethnic-appropriate echocardiographic reference values are indicated for many measurements of LA and LV size, LV mass, and EF. Reference values for LV volumes and mass also differ across the age range

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

10.1371/journal.pone.0139981PLoS ONE1010e013998