Citations

Allosteric regulation of heteromultimeric ATP-sensitive potassium (KATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for KATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948–962) of the SUR2A isoform, in the regulation of cardiac KATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of KATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the KATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore.

The cardiac neural crest is a subpopulation of neural crest cells (NCCs) that originates from the dorsal neural tube and later migrates to the heart and pharyngeal arch (PA), where they contribute to distinct aspects of cardiogenesis and PA patterning. Wnt family members have been implicated in general neural crest induction; however, the molecular mechanisms underlying the specification of distinct cell types such as cardiac NCCs remain unclear. Here, we have identified cysteine-rich intestinal protein 2 ( crip2 ), a gene encoding for a LIM domain–containing protein, as a novel marker for cardiac NCCs in zebrafish. We observed a dynamic expression pattern for crip2 , with expression being detected in the premigratory NCCs in rhombomere 6 (r6), migrating NCCs, ventricular cardiomyocytes, and aortic vessels in PAs 3 to 6. Interestingly, expression of wnt3a was detected in regions of the dorsal neural tube encompassing r6, and reduction of wnt3a led to disrupted expression of crip2 in r6, abnormal migration of NCCs, and defective cardiac function, as well as PA development. Furthermore, these phenotypes could be recapitulated by reduction of crip2 and rescued by overexpression of crip2 . In summary, our data suggest a specific role for Wnt3a in the development of cardiac NCCs. We propose that this function of wnt3a in r6 is partially mediated by crip2 expression in the premigratory cardiac NCCs, which subsequently affects cardiac function and PA patterning.

Activation of complement stimulates inflammation and provides an initial vigorous defense against infection. Insertion of the membrane attack complex in cell membranes of vascular endothelial cells induces changes in cell differentiation that promote coagulation, thrombosis, inflammation, and immunity. These changes are mediated by production of interleukin (IL)-1α by endothelial cells, which acts locally on endothelial cells to contain infection and promote healing of the affected site. In healthy tissues, however, promoting coagulation and inflammation would be dysphysiologic. Accordingly, endothelial cell activation by the membrane attack complex depends on both transcriptional regulation of IL-1α and availability of that cytokine to broadly modify endothelial cell physiology. Here, we report that the IL-1α gene contains a suppressor sequence that cooperates with histone modification to regulate production of IL-1α by endothelial cells. The suppressor sequence binds C/EBP (CCAAT enhancer–binding protein) family DNA-binding proteins isolated from the nucleus of quiescent endothelial cells. These results suggest constitutive suppression of IL-1α maintains quiescence of endothelium and that terminal complement complexes remove that suppression, allowing IL-1α transcription and, ultimately, activation of endothelium to proceed.

In September 2001, ethnoreligious rioting occurred in Jos, Nigeria. Using a multistage cluster sampling technique, 290 respondents were recruited in Jos 7 to 9 months after the riots. Data were collected regarding demographics, exposure to traumatic events, and psychological symptoms. Resting pulse and blood pressure were recorded. A total of 145 (52.5%) witnessed or were victims of personal attacks, 165 (59.6%) lost their possessions, 56 (20.7%) had their homes burned, 44 (16.2%) witnessed relatives' deaths, and 8 (2.9%) were robbed. A total of 252 (89.7%) of the respondents met reexperiencing criteria, 138 (49.1%) met avoidance criteria, and 236 (84.0%) met arousal criteria for posttraumatic stress disorder (PTSD). A total of 116 (41%, 95% confidence interval [CI] = 36% to 47%) met all three categories for PTSD. Only personal attacks (adjusted odds ratio = 2.8, 95% CI = 1.7 to 4.7) and a heart rate of 90 beats/min or more (adjusted odds ratio = 2.8, 95% CI = 1.4 to 5.8) were significantly related to PTSD in a multivariate model.