Myosin binding protein C: implications for signal-transduction

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Les problèmes d'ordonnancement de type flow-shop hybride : état de l'art

A special class of scheduling problems is studied in this paper, named Hybrid Flowshop, n jobs have to be performed in a shop and each of them has the same routing (so this is a flowshop). A job consists in k different operations. A set of machines are able to perform each operation and this set is called a stage. So when a job consists in two operations, there are two stages in the shop. After introducing the scheduling generalities, we define our preocupations and we propose a notation in order to identify precisely and rapidly a problem. Then a state of the art is proposed and presented in two parts. The first one is dedicated to the 2-stage hybrid flowshops and the second to the general case of the k-stage. Then a summary puts to the fore that many problems remain unsolved

Interactions between Crassostrea virginica larvae and Deepwater Horizon oil: Toxic effects via dietary exposure

International audienceThe Deepwater Horizon (DWH) disaster released crude oil in the Gulf of Mexico for 87 days, overlapping with the reproductive season and recruitment of the oyster Crassostrea virginica. The pelagic larval life stages of C. virginica are particularly vulnerable to contaminants such as polycyclic aromatic hydrocarbons (PAHs) and oil droplets. Based on their lipophilic properties, PAHs and oil droplets can adsorb onto phytoplankton and filter-feeding C. virginica larvae may be exposed to these contaminants bound to suspended sediment, adsorbed onto algal and other particles, or in solution. This study examined the effects of exposure of C. virginica larvae to algae mixed with DWH oil. In a 14-day laboratory exposure, 5 day-old C. virginica larvae were exposed to Tisochrysis lutea mixed with four concentrations of unfiltered DWH oil (HEWAF) in a static renewal system. Larval growth, feeding capacity, abnormality and mortality were monitored throughout the exposure. Total PAH (n = 50) content of the water medium, in which larvae were grown, were quantified by GC/MS-SIM. Oil droplets were observed bound to algae, resulting in particles in the size-range of food ingested by oyster larvae (1–30 μm). After 14 days of exposure, larval growth and survival were negatively affected at concentrations of tPAH50 as low as 1.6 μg L−1. GC/MS-SIM analysis of the exposure medium confirmed that certain PAHs were also adsorbed by T. lutea and taken up by oyster larvae via ingestion of oil droplets and/or contaminated algae. Long-term exposure to chronic levels of PAH (1.6–78 μg tPAH50 L−1) was shown to negatively affect larval survival. This study demonstrates that dietary exposure of oyster larvae to DWH oil is a realistic route of crude oil toxicity and may have serious implications on the planktonic community and the food chain