Conditional analysis of the major histocompatibility complex in rheumatoid arthritis

We performed a whole-genome association study of rheumatoid arthritis susceptibility using Illumina 550k single-nucleotide polymorphism (SNP) genotypes of 868 cases and 1194 controls from the North American Rheumatoid Arthritis Consortium (NARAC). Structured association analysis with adjustment for potential population stratification yielded 200 SNPs with p < 1 × 10-8 for association with RA, all of which were on chromosome 6 in a 2.7-Mb region of the major histocompatibility complex (MHC). Given the extensive linkage equilibrium in the region and known risk of HLA-DRB1 alleles, we then applied conditional analyses to ascertain independent signals for RA susceptibility among these 200 candidate SNPs. Conditional analyses incorporating risk categories of the HLA-DRB1 "shared epitope" revealed three SNPs having independent associations with RA (conditional p < 0.001). This supports the presence of significant effects on RA susceptibility in the MHC in addition to the shared epitope

Integrated System Test Approaches for the NASA Ares I Crew Launch Vehicle

The Ares I Crew Launch Vehicle (CLV) is being developed by the U.S. National Aeronautics and Space Administration (NASA) to provide crew access to the International Space Station (ISS) and, together with the Ares V Cargo Launch Vehicle (CaLV), serves as one component of a future launch capability for human exploration of the Moon. During the system requirements definition process and early design cycles, NASA defined and began implementing plans for integrated ground and flight testing necessary to achieve the first human launch of Ares I. The individual Ares I flight hardware elements: the first stage five segment booster (FSB), upper stage, and J-2X upper stage engine, will undergo extensive development, qualification, and certification testing prior to flight. Key integrated system tests include the Main Propulsion Test Article (MPTA), acceptance tests of the integrated upper stage and upper stage engine assembly, a full-scale integrated vehicle dynamic test (IVDT), aerodynamic testing to characterize vehicle performance, and integrated testing of the avionics and software components. The Ares I-X development flight test will provide flight data to validate engineering models for aerodynamic performance, stage separation, structural dynamic performance, and control system functionality. The Ares I-Y flight test will validate ascent performance of the first stage, stage separation functionality, and a highaltitude actuation of the launch abort system (LAS) following separation. The Orion-1 flight test will be conducted as a full, un-crewed, operational flight test through the entire ascent flight profile prior to the first crewed launch

Romantic Relationship Experiences from Late Adolescence to Young Adulthood: The Role of Older Siblings in Mexican-Origin Families

Youth\u27s experiences with romantic relationships during adolescence and young adulthood have far reaching implications for future relationships, health, and well-being; yet, although scholars have examined potential peer and parent influences, we know little about the role of siblings in youth\u27s romantic relationships. Accordingly, this study examined the prospective longitudinal links between Mexican-origin older and younger siblings\u27 romantic relationship experiences and variation by sibling structural and relationship characteristics (i.e., sibling age and gender similarity, younger siblings\u27 modeling) and cultural values (i.e., younger siblings\u27 familism values). Data from 246 Mexican-origin families with older (M = 20.65 years; SD = 1.57; 50% female) and younger (M = 17.72 years; SD = .57; 51% female) siblings were used to examine the likelihood of younger siblings\u27 involvement in dating relationships, sexual relations, cohabitation, and engagement/marriage with probit path analyses. Findings revealed older siblings\u27 reports of involvement in a dating relationship, cohabitation, and engagement/marriage predicted younger siblings\u27 relationship experiences over a two-year period. These links were moderated by sibling age spacing, younger siblings\u27 reports of modeling and familism values. Our findings suggest the significance of social learning dynamics as well as relational and cultural contexts in understanding the links between older and younger siblings\u27 romantic relationship experiences among Mexican-origin youth

Integrated Testing Approaches for the NASA Ares I Crew Launch Vehicle

The Ares I crew launch vehicle is being developed by the U.S. National Aeronautics and Space Administration (NASA) to provide crew and cargo access to the International Space Station (ISS) and, together with the Ares V cargo launch vehicle, serves as a critical component of NASA's future human exploration of the Moon. During the preliminary design phase, NASA defined and began implementing plans for integrated ground and flight testing necessary to achieve the first human launch of Ares I. The individual Ares I flight hardware elements - including the first stage five segment booster (FSB), upper stage, and J-2X upper stage engine - will undergo extensive development, qualification, and certification testing prior to flight. Key integrated system tests include the upper stage Main Propulsion Test Article (MPTA), acceptance tests of the integrated upper stage and upper stage engine assembly, a full-scale integrated vehicle ground vibration test (IVGVT), aerodynamic testing to characterize vehicle performance, and integrated testing of the avionics and software components. The Ares I-X development flight test will provide flight data to validate engineering models for aerodynamic performance, stage separation, structural dynamic performance, and control system functionality. The Ares I-Y flight test will validate ascent performance of the first stage, stage separation functionality, validate the ability of the upper stage to manage cryogenic propellants to achieve upper stage engine start conditions, and a high-altitude demonstration of the launch abort system (LAS) following stage separation. The Orion 1 flight test will be conducted as a full, un-crewed, operational flight test through the entire ascent flight profile prior to the first crewed launch

Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms

Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts

Resolution of Failed Financial Institutions: Orderly Liquidation Authority and a New Chapter 14

Studies by the Resolution Project at Stanford University\u27s Hoover Institution Working Group on Economic Polic