Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region

The intensely studied MHC has become the paradigm for understanding the architectural evolution of vertebrate multigene families. The 4-Mb human MHC (also known as the HLA complex) encodes genes critically involved in the immune response, graft rejection, and disease susceptibility. Here we report the continuous 1,796,938-bp genomic sequence of the HLA class I region, linking genes between MICB and HLA-F. A total of 127 genes or potentially coding sequences were recognized within the analyzed sequence, establishing a high gene density of one per every 14.1 kb. The identification of 758 microsatellite provides tools for high-resolution mapping of HLA class I-associated disease genes. Most importantly, we establish that the repeated duplication and subsequent diversification of a minimal building block, MIC-HCGIX-3.8–1-P5-HCGIV-HLA class I-HCGII, engendered the present-day MHC. That the currently nonessential HLA-F and MICE genes have acted as progenitors to today’s immune-competent HLA-ABC and MICA/B genes provides experimental evidence for evolution by “birth and death,” which has general relevance to our understanding of the evolutionary forces driving vertebrate multigene families.

Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism

The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE α1 and α2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE.

Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.

A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model.

A pathogenic role for self-reactive cells against the stress protein Hsp60 has been proposed as one of the events leading to autoimmune destruction of pancreatic beta cells in the diabetes of nonobese diabetic (NOD) mice. To examine this hypothesis, we generated transgenic NOD mice carrying a murine Hsp60 transgene driven by the H-2E alpha class II promoter. This would be expected to direct expression of the transgene to antigen-presenting cells including those in the thymus and so induce immunological tolerance by deletion. Detailed analysis of Hsp60 expression revealed that the endogenous gene is itself expressed strongly in thymic medullary epithelium (and weakly in cortex) yet fails to induce tolerance. Transgenic mice with retargeted Hsp60 showed overexpression of the gene in thymic cortical epithelium and in bone marrow-derived cells. Analysis of spontaneous T-cell responses to a panel of self and heterologous Hsp60 antigens showed that tolerance to the protein had not been induced, although responses to an immunodominant 437-460 epitope implicated in disease were suppressed, probably indicating an epitope shift. This correlated with changes in disease susceptibility: insulitis in transgenic mice was substantially reduced so that pathology rarely progressed beyond periislet infiltration. This was reflected in a substantial reduction in hyperglycemia and disease. These data indicate that T cells specific for some epitopes of murine Hsp60 are likely to be involved in the islet-cell destruction that occurs in NOD mice.

La atención sostenida como marcador de vulnerabilidad de la esquizofrenia: una serie de Meta-análisis de estudios con Test de Ejecución Continua (CPT

Los déficit cognitivos son una característica nuclear de la esquizofrenia (Heinrichs, 2005). En la actualidad, su estudio ha cobrado una gran relevancia debido a su estrecha relación con el funcionamiento de las personas con esquizofrenia (Malhotra y Schooler, 2014) y a su uso como marcadores de vulnerabilidad y endofenotipos de este trastorno (Ritsner y Gottesman, 2011). La atención sostenida, evaluada con Tareas de Ejecución Continua (CPT; Rosvold et al., 1956), es una de las principales áreas afectadas en la esquizofrenia (Cornblatt y Keilp, 1994; Nuechterlein, 1991). Numerosos estudios han mostrado que las personas con esquizofrenia tienen un rendimiento deficitario en estas tareas en comparación con controles normales, que los déficit en la atención sostenida son estables e independientes de factores clínicos, y que están presentes en sus familiares. En el marco de los modelos de vulnerabilidad-estrés (Zubin y Spring, 1977; Nuechterlein et al., 1992), los déficit en la atención sostenida medidos con CPT han sido propuestos como marcador de vulnerabilidad y endofenotipo del trastorno (Cornblatt y Malhotra, 2001; Gur et al., 2007; Greenwood et al., 2013). Hasta la fecha, ningún estudio ha integrado cuantitativamente los resultados de estudios sobre la atención sostenida evaluada con CPT en la esquizofrenia. El objetivo principal de este trabajo fue integrar la evidencia empírica existente sobre déficit en la atención sostenida medida con tareas CPT en la esquizofrenia mediante técnicas de meta-análisis. La hipótesis central planteada es que estos déficit son marcadores de vulnerabilidad, al reunir los siguientes criterios: a) Están presentes en personas con esquizofrenia en mayor magnitud que en controles normales; b) Son independientes de variables clínicas; c) Son específicos; su magnitud es mayor en comparación con otros grupos clínicos; d) Están presentes en sus familiares en mayor magnitud que en controles normales...

[ Bāî:bûḍhāî:jo:saṁvad:tathā:gûgrījā:gīnān:10]

Pīr Imām Shāh, Bāî Bûḍhāî, Gur Imām Shāh..

[ 12 grañthne 103 ginān

Pīr Ḥasan Kabīr ad-Dīn, Pīr Imām Shāh, Pīr Ṣadr ad-Dīn, ... [et al.]].

An Exploration of the challenges associated with software logging in large systems

Thesis (Master, Computing) -- Queen's University, 2016-05-29 18:11:34.114

Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study

A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. METHODS: We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. FINDINGS: 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. INTERPRETATION: MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. FUNDING: European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.

Los Francmasones; lo que son, lo que hacen, lo que quieren.

Mode of access: Internet.

Zgodovina brezoviške župinje /

"Ponatisek iz 'Zgodovinskega Zbornika'"--T.p.

Pedestrian injury causation study - (PICS). Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Estimation of an origin-destination trip table based on observed link volumes and turning movements. Executive summary. Final report.

Federal Highway Administration, Washington, D.C.

Estimation of an origin-destination trip table based on observed link volumes and turning movements. Volume 1: technical report. Final report.

Federal Highway Administration, Washington, D.C.