Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.
Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (RyR1) die when exposed to short periods of temperature elevation (≥ 37 °C). We demonstrate that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in Y524S mice. The AICAR protection is independent of AMPK activation and results from a newly identified action on the mutant RyR1 to reduce Ca2+ leak, preventing Ca2+ dependent increases in both reactive oxygen and reactive nitrogen species that act to further increase resting Ca2+ concentrations. If unchecked, the temperature driven increases in resting Ca2+ and ROS/RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents the heat induced death in vivo. Our findings suggest that AICAR is likely to be effective in prophylactic treatment of humans with enhanced susceptibility to exercise/heat-induced sudden death associated with RyR1 mutations.
Mobile elements (MEs) collectively contribute to at least 50% of the human genome. Due to their past incremental accumulation and ongoing DNA transposition, MEs serve as a significant source for both inter- and intra-species genetic and phenotypic diversity during primate and human evolution. By making use of the most recent genome sequences for human and many other closely related primates and robust multi-way comparative genomic approach, we identified a total of 14,870 human-specific MEs (HS-MEs) with more than 8,000 being newly identified. Collectively, these HS-MEs contribute to a total of 14.2 Mbp net genome sequence increase. Several new observations were made based on these HS-MEs, including the finding of Y chromosome as a strikingly hot target for HS-MEs and a strong mutual preference for SINE-R/VNTR/Alu (SVAs). Furthermore, ∼8,000 of these HS-MEs were found to locate in the vicinity of ∼4,900 genes, and collectively they contribute to ∼84 kb sequences in the human reference transcriptome in association with over 300 genes, including protein-coding sequences for 40 genes. In conclusion, our results demonstrate that MEs made a significant contribution to the evolution of human genome by participating in gene function in a human-specific fashion.
Postoperative acute renal failure after thoracoabdominal and total descending thoracic aortic aneurysm surgery is associated with preoperative creatinine level, visceral perfusion, left renal artery reattachment, and simple cross-clamp technique.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.