Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1*02601 and Mamu-B*08301 reveals HLA-A2 and HLA-A3 supertypic specificities

The Simian immunodeficiency virus (SIV)-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection and AIDS-related research, despite the potential that macaques of Chinese origin is a more relevant model. Ongoing efforts to further characterize the Chinese rhesus macaques’ major histocompatibility complex (MHC) for composition and function should facilitate greater utilization of the species. Previous studies have demonstrated that Chinese-origin M. mulatta (Mamu) class I alleles are more polymorphic than their Indian counterparts, perhaps inferring a model more representative of human MHC, human leukocyte antigen (HLA). Furthermore, the Chinese rhesus macaque class I allele Mamu-A1*02201, the most frequent allele thus far identified, has recently been characterized and shown to be an HLA-B7 supertype analog, the most frequent supertype in human populations. In this study, we have characterized two additional alleles expressed with high frequency in Chinese rhesus macaques, Mamu-A1*02601 and Mamu-B*08301. Upon the development of MHC–peptide-binding assays and definition of their associated motifs, we reveal that these Mamu alleles share peptide-binding characteristics with the HLA-A2 and HLA-A3 supertypes, respectively, the next most frequent human supertypes after HLA-B7. These data suggest that Chinese rhesus macaques may indeed be a more representative model of HLA gene diversity and function as compared to the species of Indian origin and therefore a better model for investigating human immune responses

The most common Chinese rhesus macaque MHC class I molecule shares peptide binding repertoire with the HLA-B7 supertype

Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques

ATLAS Run 1 searches for direct pair production of third-generation squarks at the Large Hadron Collider

This paper reviews and extends searches for the direct pair production of the scalar supersymmetric partners of the top and bottom quarks in proton-proton collisions collected by the ATLAS collaboration during the LHC Run 1. Most of the analyses use 20 fb$^{-1}$ of collisions at a centre-of-mass energy of $\sqrt{s}$ = 8 TeV, although in some case an additional 4.7 fb$^{-1}$ of collision data at $\sqrt{s}$ = 7 TeV are used. New analyses are introduced to improve the sensitivity to specific regions of the model parameter space. Since no evidence of third-generation squarks is found, exclusion limits are derived by combining several analyses and are presented in both a simplified model framework, assuming simple decay chains, as well as within the context of more elaborate phenomenological supersymmetric models

Airborne occupational exposures and risk of developing rheumatoid arthritis [Elektronisk resurs]

Background: Rheumatoid Arthritis (RA) is an autoimmune, inflammatory disease with multifaceted aetiology. Cigarette smoke is the strongest environmental risk factor of RA, and research suggests that airborne exposures may trigger RA among genetically susceptible individuals. The aim of this thesis was to investigate the influence of airborne, occupational exposures on the risk of developing RA. The purpose of Study I was to explore whether there was any association between occupation and risk of developing RA. The airborne occupational exposures later studied were textile dust (Study II), asbestos and crystalline silica dust (Study III) and five types of organic dusts (Study IV). Methods: All four PhD projects are case-control studies. Study I is based on the Swedish Eipidemiological Investigation of Rheumatoid Arthritis (EIRA) study. In Study I we identified newly diagnosed RA cases from the age of 18 in the southern and central parts of Sweden from May 1996 until September 2014. 1-2 controls per case were randomly selected from the population register, matched on age, sex and residential area. Data on occupational titles and environmental risk factors were collected through an extensive questionnaire. Study II is based on the Malaysian EIRA (MyEIRA) study. We identified newly diagnosed female RA cases from 18 to 70 years of age from Peninsular Malaysia between August 2005 and December 2009. One control per case was selected and matched on age and residential area. Data on occupational titles and environmental risk factors were collected through an interview, based on an extensive questionnaire. In Study III and IV the study base comprised of men and women in Sweden from 1996 until 2013. RA patients were selected based on the information from EIRA, the national patient register, the Swedish Rheumatology Quality Register (SRQ) and the Swedish Prescribed Drug Register. Apart fom the EIRA controls, ten additional controls per case were randomly selected from the total population register. For Study III and IV the occupational titles were retrieved from the national Population and Housing censuses (1960-1990) and from Statistics Sweden’s LISA-register (2001-2010). We assessed the occupational exposure to the inorganic dusts asbestos, silica and five organic dusts by applying job-exposure matrices (JEMs) to the occupations of the participants. In all four studies, we calculated odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) by means of logistic regression analysis to assess the association between the main exposure and risk of RA. Results: Among men the production-related occupations bricklayers and concrete workers, electrical and electronics workers and material handling operators were associated with an increased risk of RA compared to workers within the professional, administrative and technical sectors after adjustment for potential confounding from cigarette pack-years, alcohol use, education and body mass index (BMI). Among women, we observed an increased risk of RA among assistant nurses and attendants. Men working with crystalline silica or asbestos had an increased risk of developing RA compared to unexposed workers. This finding may partly explain the increased risk among men working in production related occupations. The highest risk estimates for both asbestos and crystalline silica were observed among male workers with the longest duration of exposure, and for seropositive RA there was a significant dose-response trend for both agents. We could not detect an increased risk among women from asbestos or crystalline silica exposure. But fewer women than men had been working in occupations where they had been exposed to inorganic dusts and they also tended to have been exposed for a shorter period of time and to lower intensities. For the organic dusts wood, animal, paper, textile and flour, the risk estimates were more similar for men and women. Among these five types of dust, animal dust showed the most solid association with an increased risk of RA. The OR also increased with duration of exposure to animal dust. We observed an increased risk of RA among women from exposure to textile dust in Malaysia. There was also an interaction between textile dust exposure and HLA-DRB1 shared epitope (SE) alleles, predominantly for the risk of developing Anti-Citrullinated Protein/Peptide Antibody (ACPA) + RA. Also in the Swedish population there were signs of an association between textile dust and seropositive RA. Conclusions: This thesis demonstrates that your occupation may be associated with an increased risk of developing both seropositive and seronegative RA, where exposures to inorganic but also organic dusts play a role. Duration of exposure to organic and inorganic dusts is associated mainly with seropositive RA. These findings support the notion that the lung plays an important role in the pathogenesis of RA. The results can contribute to preventive measures at workplaces where workers are associated with an increased risk. This doctoral thesis highlights the importance to study inorganic and organic airborne exposures in countries with high or long-term exposure