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Sample records for complex class i-related

  1. Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.

    PubMed

    Dambrauskas, Zilvinas; Svensson, Helena; Joshi, Meghnad; Hyltander, Anders; Naredi, Peter; Iresjö, Britt-Marie

    2014-01-01

    Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.

  2. Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): Antibodies to Major Histocompatibility Complex Class I-Related Chain A (MICA) as Markers of ILD

    PubMed Central

    Furukawa, Hiroshi; Oka, Shomi; Shimada, Kota; Masuo, Kiyoe; Nakajima, Fumiaki; Funano, Shunichi; Tanaka, Yuki; Komiya, Akiko; Fukui, Naoshi; Sawasaki, Tatsuya; Tadokoro, Kenji; Nose, Masato; Tsuchiya, Naoyuki; Tohma, Shigeto

    2015-01-01

    Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients’ prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10−5). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6). PMID:26327779

  3. Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): Antibodies to Major Histocompatibility Complex Class I-Related Chain A (MICA) as Markers of ILD.

    PubMed

    Furukawa, Hiroshi; Oka, Shomi; Shimada, Kota; Masuo, Kiyoe; Nakajima, Fumiaki; Funano, Shunichi; Tanaka, Yuki; Komiya, Akiko; Fukui, Naoshi; Sawasaki, Tatsuya; Tadokoro, Kenji; Nose, Masato; Tsuchiya, Naoyuki; Tohma, Shigeto

    2015-01-01

    Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients' prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10(-5)). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6).

  4. Role of major histocompatibility complex class I-related molecules A*A5·1 allele in ulcerative colitis in Chinese patients

    PubMed Central

    Lü, Min; Xia, Bing; Ge, Liuqing; Li, Yi; Zhao, Jie; Chen, Fan; Zhou, Feng; Zhang, Xiaolian; Tan, Jinquan

    2009-01-01

    The major histocompatibility complex (MHC) class I-related molecules A (MICA) is a stress-inducible cell surface antigen that is recognized by intestinal epithelial Vδ1 γδ T cells, natural killer (NK) cells and CD8+ T cells with NKG2D receptor participating in the immunological reaction in the intestinal mucosa. The present study aimed to investigate the functions of the MICA*A5.1 allele in the development of ulcerative colitis (UC) in the Chinese population. The microsatellite polymorphisms of MICA were genotyped in 124 unrelated Chinese patients with UC and 172 ethnically matched healthy controls using a semiautomatic fluorescently labelled polymerase chain reaction. MICA*A5.1-expressing Raji cells were generated by gene transfection. Cytotoxicity of NK cells to Raji cells expressing different MICA molecules was detected using the lactate dehydrogenase method. Soluble MICA in the culture supernatant was detected by enzyme-linked immunosorbent assay. The frequency of MICA*A5.1 was significantly higher in UC patients compared with the healthy controls (29·0% versus 17·4%, P= 0·001, corrected P= 0·005, OR = 1·936, 95% CI 1·310–2·863) and the frequency of a MICA*A5.1/A5.1 homozygous genotype was increased in UC patients (18·5% versus 7% in healthy controls, P= 0·0032, corrected P= 0·048, OR = 3·036, 95% CI 1·447–6·372). Raji cells with MICA*A5.1 expression produced more soluble MICA (t = 5·75, P < 0·01) than Raji cells with full-length MICA expression in culture supernatant. Raji cells with MICA*A5.1 expression were more resistant to killing by NK cells than Raji cells with full-length MICA expression. The MICA*A5.1 allele and MICA*A5.1/A5.1 genotype are significantly associated with Chinese UC patients in central China. MICA*A5.1 may play a role in the development of UC by producing more soluble MICA and resistance to NK cells. PMID:19016911

  5. Efficient In Vitro Refolding and Characterization of Major Histocompatibility Complex Class I-Related Chain Molecules A (MICA) and Natural Killer Group 2 Member D (NKG2D) Expressed in E. coli.

    PubMed

    Zhao, Xin; Acheampong, Desmond Omane; Wang, Youfu; Tang, Mingying; Xie, Wei; Chen, Zhiguo; Wang, Min; Zhang, Juan

    2015-01-01

    Major Histocompatibility Complex class I-related chain molecules A (MICA) and receptor Natural killer group 2 member D (NKG2D) are important membrane proteins with immunosurveillance properties which could serve as therapeutic targets for immunotherapy. However, expression of MICA and NKG2D in E. coli often leads to the formation of inclusion bodies. Here, we present simple, inexpensive and convenient protocol for the solubilization and refolding of inclusion bodies of MICA and NKG2D expressed in E. coli. The inclusion bodies were firstly dissolved in strong chaotropic reagent (8M urea) and subsequently purified by immobilized-metal affinity column. The denatured MICA/NKG2D was refolded by gradually removing both denaturant (8M urea) and imidazole via dialysis in dialysis buffer of pH 7.4. The appropriate pH of the dialysis buffer was selected based on the theoretical isoelectric points of MICA and NKG2D which were 5.0 and 5.2 respectively. The folded MICA and NKG2D demonstrated the capacity to bind to recombinant NKG2D and MICA respectively by ELISA, Western blot and Surface Plasmon Resonance (SPR) assays. Additionally, the folded MICA and NKG2D demonstrated significant binding to NKG2D-positive Human leukemic cell line U937 and MICA-positive Human pancreatic carcinoma, epithelial-like cell line (PANC-1) respectively, suggesting successful refolding. Successful refolding was further confirmed by Circular Dichroism spectroscopy (CD). We have successfully dissolved, refolded and characterized inclusion bodies of MICA/NKG2D expressed in E. coli using simple, inexpensive and convenient protocol which can be carried out in laboratories under-resourced.

  6. MHC class I-related molecule, MR1, and mucosal-associated invariant T cells.

    PubMed

    Franciszkiewicz, Katarzyna; Salou, Marion; Legoux, Francois; Zhou, Qian; Cui, Yue; Bessoles, Stéphanie; Lantz, Olivier

    2016-07-01

    The MHC-related 1, MR1, molecule presents a new class of microbial antigens (derivatives of the riboflavin [Vitamin B2] biosynthesis pathway) to mucosal-associated invariant T (MAIT) cells. This raises many questions regarding antigens loading and intracellular trafficking of the MR1/ligand complexes. The MR1/MAIT field is also important because MAIT cells are very abundant in humans and their frequency is modified in many infectious and non-infectious diseases. Both MR1 and the invariant TCRα chain expressed by MAIT cells are strikingly conserved among species, indicating important functions. Riboflavin is synthesized by plants and most bacteria and yeasts but not animals, and its precursor derivatives activating MAIT cells are short-lived unless bound to MR1. The recognition of MR1 loaded with these compounds is therefore an exquisite manner to detect invasive bacteria. Herein, we provide an historical perspective of the field before describing the main characteristics of MR1, its ligands, and the few available data regarding its cellular biology. We then summarize the current knowledge of MAIT cell differentiation and discuss the definition of MAIT cells in comparison to related subsets. Finally, we describe the phenotype and effector activities of MAIT cells. PMID:27319347

  7. Expression and purification of human MHC class I-related chain molecule B-α1 domain.

    PubMed

    Wang, Shufen; Xiang, Zemin; Wang, Ya; Xu, Huanhuan; Zhang, Dengyang; Wang, Xuanjun; Sheng, Jun

    2016-07-01

    Major histocompatibility complex (MHC) class I-related chain A/B (MICA/B) is a type of stress-induced molecule that plays an important role in tumor surveillance. MICA/B shares a similar structure with MHC class I molecules, but MICA/B contains a closed cleft, not an open one, in its N-terminal alpha1 domain. The alpha 1 domain was believed to have no roles in antigen presentation, because the closed cleft provides limited space for binding with known molecules, and the cleft of MICA/B have been reported no known functions. To study the possible function of the cleft located in human MICA/B's alpha 1 domain, we attempted to express the human MICB-α1 (hMICB-α1) domain allele protein, which is approximately 20.5 kDa, by utilizing an Escherichia coli (E. coli) secretory pathway. Protein expression was accomplished through the phosphate-limited inducible promoter. After purification using ammonium sulfate precipitation, phenyl hydrophobic Sepharose, SP Sepharose and HisTrap affinity Sepharose, recombinant human MICB-α1 (rhMICB-α1) was obtained with 94.3% purity. The binding capacity of rhMICB-α1 with natural killer group 2, member D (NKG2D) was evaluated in vitro. The results demonstrated that rhMICB-α1 can be prepared through the E. coli secretory pathway. Purified rhMICB-α1 protein was able to functionally bind with NKG2D. This method can be further used to obtain functionally active rhMICB-α1 protein, which can served as the basis for further studies of the possible function of the MICB cleft. PMID:27036081

  8. MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells.

    PubMed

    Zhu, X; Meng, G; Dickinson, B L; Li, X; Mizoguchi, E; Miao, L; Wang, Y; Robert, C; Wu, B; Smith, P D; Lencer, W I; Blumberg, R S

    2001-03-01

    The neonatal Fc receptor (FcRn) for IgG, an MHC class I-related molecule, functions to transport IgG across polarized epithelial cells and protect IgG from degradation. However, little is known about whether FcRn is functionally expressed in immune cells. We show here that FcRn mRNA was identifiable in human monocytes, macrophages, and dendritic cells. FcRn heavy chain was detectable as a 45-kDa protein in monocytic U937 and THP-1 cells and in purified human intestinal macrophages, peripheral blood monocytes, and dendritic cells by Western blot analysis. FcRn colocalized in vivo with macrosialin (CD68) and Ncl-Macro, two macrophage markers, in the lamina propria of human small intestine. The heavy chain of FcRn was associated with the beta(2)-microglobulin (beta(2)m) light chain in U937 and THP-1 cells. FcRn bound human IgG at pH 6.0, but not at pH 7.5. This binding could be inhibited by human IgG Fc, but not Fab. FcRn could be detected on the cell surface of activated, but not resting, THP-1 cells. Furthermore, FcRn was uniformly present intracellularly in all blood monocytes and intestinal macrophages. FcRn was detectable on the cell surface of a significant fraction of monocytes at lower levels and on a small subset of tissue macrophages that expressed high levels of FcRn on the cell surface. These data show that FcRn is functionally expressed and its cellular distribution is regulated in monocytes, macrophages, and dendritic cells, suggesting that it may confer novel IgG binding functions upon these cell types relative to typical Fc gamma Rs: Fc gamma RI, Fc gamma RII, and Fc gamma RIII.

  9. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.

    PubMed

    Sutherland, Claire L; Chalupny, N Jan; Schooley, Kenneth; VandenBos, Tim; Kubin, Marek; Cosman, David

    2002-01-15

    The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-gamma production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors. PMID:11777960

  10. Loss of expression of MHC class I-related chain A (MICA) is a frequent event and predicts poor survival in patients with hepatocellular carcinoma.

    PubMed

    Zhang, Jie; Xu, Zhuding; Zhou, Xingchun; Zhang, Haibin; Yang, Ning; Wu, Yousheng; Chen, Yibing; Yang, Guangshun; Ren, Tingting

    2014-01-01

    Natural killer (NK) cells are important effector cells for the first line of defense against tumor. Distant MHC class I homolog MICA has been identified as human ligand for NK cell activating receptor NKG2D. Engagement of MICA triggers NK cells and augments antigen-specific CTL anti-tumor immunity. However, the expression level of MICA and its clinical significance in hepatocellular carcinoma remains to be elucidated. In the present study, a hospital-based study cohort of 143 HCC patients was involved. MICA expression levels were determined by immunohistochemical staining. The association of MICA expression with tumor clinicopathologic features, disease-free survival, and overall survival of HCC patients were analyzed. Significantly decreased expression of MICA was detected in tumor specimens. MICA expression was significantly associated with AFP level (P < 0.001) and tumor node metastasis stage (P = 0.003). Patients with reduced level of MICA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of MICA. However, in multivariate analysis, MICA expression level was found not to be an independent prognostic factor for both disease-free survival and overall survival of HCC patients. Our findings suggest that decreased MICA expression may play an important role in HCC tumor evasion of host immunity, which warrants further investigation in future studies.

  11. On the structure of valiant's complexity classes

    NASA Astrophysics Data System (ADS)

    Bürgisser, Peter

    In [25,27] Valiant developed an algebraic analogue of the theory of NP-completeness for computations with polynomials over a field. We further develop this theory in the spirit of structural complexity and obtain analogues of well-known results by Baker, Gill, and Solovay [1], Ladner [18], and Schöning [23,24].

  12. Evolution of major histocompatibility complex class I and class II genes in the brown bear

    PubMed Central

    2012-01-01

    Background Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. Results We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Conclusions Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South–north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia. PMID:23031405

  13. Liquid class predictor for liquid handling of complex mixtures

    DOEpatents

    Seglke, Brent W.; Lekin, Timothy P.

    2008-12-09

    A method of establishing liquid classes of complex mixtures for liquid handling equipment. The mixtures are composed of components and the equipment has equipment parameters. The first step comprises preparing a response curve for the components. The next step comprises using the response curve to prepare a response indicator for the mixtures. The next step comprises deriving a model that relates the components and the mixtures to establish the liquid classes.

  14. Caenorhabditis elegans expressing the Saccharomyces cerevisiae NADH alternative dehydrogenase Ndi1p, as a tool to identify new genes involved in complex I related diseases

    PubMed Central

    Cossard, Raynald; Esposito, Michela; Sellem, Carole H.; Pitayu, Laras; Vasnier, Christelle; Delahodde, Agnès; Dassa, Emmanuel P.

    2015-01-01

    Isolated complex I deficiencies are one of the most commonly observed biochemical features in patients suffering from mitochondrial disorders. In the majority of these clinical cases the molecular bases of the diseases remain unknown suggesting the involvement of unidentified factors that are critical for complex I function. The Saccharomyces cerevisiae NDI1 gene, encoding the mitochondrial internal NADH dehydrogenase was previously shown to complement a complex I deficient strain in Caenorhabditis elegans with notable improvements in reproduction and whole organism respiration. These features indicate that Ndi1p can functionally integrate the respiratory chain, allowing complex I deficiency complementation. Taking into account the Ndi1p ability to bypass complex I, we evaluate the possibility to extend the range of defects/mutations causing complex I deficiencies that can be alleviated by NDI1 expression. We report here that NDI1 expressing animals unexpectedly exhibit a slightly shortened lifespan, a reduction in the progeny, and a depletion of the mitochondrial genome. However, Ndi1p is expressed and targeted to the mitochondria as a functional protein that confers rotenone resistance to those animals without affecting their respiration rate and ATP content. We show that the severe embryonic lethality level caused by the RNAi knockdowns of complex I structural subunit encoding genes (e.g., NDUFV1, NDUFS1, NDUFS6, NDUFS8, or GRIM-19 human orthologs) in wild type animals is significantly reduced in the Ndi1p expressing worm. All together these results open up the perspective to identify new genes involved in complex I function, assembly, or regulation by screening an RNAi library of genes leading to embryonic lethality that should be rescued by NDI1 expression. PMID:26124772

  15. "Distribution and functional identification of complex class 1 integrons".

    PubMed

    Quiroga, María Paula; Arduino, Sonia Marina; Merkier, Andrea Karina; Quiroga, Cecilia; Petroni, Alejandro; Roy, Paul H; Centrón, Daniela

    2013-10-01

    The emergence of extended-spectrum β-lactamases and plasmid-mediated resistance to quinolones has been previously found to be associated with the dissemination of complex class 1 integrons in Argentina. In this study, we analyzed their distribution through time and evaluated the functionality of the Orf513 protein, which is the putative recombinase of the ISCR1 mobile element. We investigated the presence of the orf513, blaCTX-M-2, dfrA3b, qnrB10 and blaDHA-1 genes by PCR and DNA sequencing as well as their linkage to class 1 integrons in 451 non-epidemiologically related nosocomial strains resistant to at least one expanded-spectrum cephalosporin and to one aminoglycoside, isolated between 1989 and 2010 from 7 hospitals from Buenos Aires City. The epidemiology of complex class 1 integrons was found to be notably different among fermenting (94/171) and non-fermenting clinical bacilli isolates (1/280). The ISCR1::qnrB10 positive isolates were found since 1993, confirming its presence in clinical isolates more than a decade before its first description. As expected, In35::ISCR1::blaCTX-M-2 was the most common complex class 1 integron among Enterobacteriaceae isolates, particularly in Proteus mirabilis. Experimental analysis corroborated the activity of the Orf513 protein, which was found to bind specific DNA sequences containing the previously suggested oriIS region. These findings showed the high dispersion and maintenance of complex class 1 integrons across time in our nosocomial isolates. The contribution of the ISCR1 mobile element to multidrug resistant phenotypes is significant due to its sustained association to class 1 integrons. PMID:23838285

  16. Physiological Roles of Class I HDAC Complex and Histone Demethylase

    PubMed Central

    Hayakawa, Tomohiro; Nakayama, Jun-ichi

    2011-01-01

    Epigenetic gene silencing is one of the fundamental mechanisms for ensuring proper gene expression patterns during cellular differentiation and development. Histone deacetylases (HDACs) are evolutionally conserved enzymes that remove acetyl modifications from histones and play a central role in epigenetic gene silencing. In cells, HDAC forms a multiprotein complex (HDAC complex) in which the associated proteins are believed to help HDAC carry out its cellular functions. Though each HDAC complex contains distinct components, the presence of isoforms for some of the components expands the variety of complexes and the diversity of their cellular roles. Recent studies have also revealed a functional link between HDAC complexes and specific histone demethylases. In this paper, we summarize the distinct and cooperative roles of four class I HDAC complexes, Sin3, NuRD, CoREST, and NCoR/SMRT, with respect to their component diversity and their relationship with specific histone demethylases. PMID:21049000

  17. Regulation of major histocompatibility complex class II genes

    PubMed Central

    Choi, Nancy M.; Majumder, Parimal; Boss, Jeremy M.

    2010-01-01

    Summary The major histocompatibility complex class II (MHC-II) genes are regulated at the level of transcription. Recent studies have shown that chromatin modification is critical for efficient transcription of these genes, and a number of chromatin modifying complexes recruited to MHC-II genes have been described. The MHC-II genes are segregated from each other by a series of chromatin elements, termed MHC-II insulators. Interactions between MHC-insulators and the promoters of MHC-II genes are mediated by the insulator factor CCCTC-binding protein and are critical for efficient expression. This regulatory mechanism provides a novel view of how the entire MHC-II locus is assembled architecturally and can be coordinately controlled. PMID:20970972

  18. Bidirectional selection between two classes in complex social networks

    NASA Astrophysics Data System (ADS)

    Zhou, Bin; He, Zhe; Jiang, Luo-Luo; Wang, Nian-Xin; Wang, Bing-Hong

    2014-12-01

    The bidirectional selection between two classes widely emerges in various social lives, such as commercial trading and mate choosing. Until now, the discussions on bidirectional selection in structured human society are quite limited. We demonstrated theoretically that the rate of successfully matching is affected greatly by individuals' neighborhoods in social networks, regardless of the type of networks. Furthermore, it is found that the high average degree of networks contributes to increasing rates of successful matches. The matching performance in different types of networks has been quantitatively investigated, revealing that the small-world networks reinforces the matching rate more than scale-free networks at given average degree. In addition, our analysis is consistent with the modeling result, which provides the theoretical understanding of underlying mechanisms of matching in complex networks.

  19. Polyelectrolyte-Surfactant Complexes: A New Class of Organogelators

    NASA Astrophysics Data System (ADS)

    Cavicchi, Kevin; Liu, Yuqing; Guzman, Gustavo

    2011-03-01

    Polyelectrolyte-surfactant complexes (PE-SURFs) are a class of polymers generated by neutralizing a polyelectrolyte with an oppositely charged surfactant. It has been found that PE-SURFs composed of polystyrene sulfonate and long chain alkyl dimethyl amines act as good organogelators for a range of hydrophobic, organic solvents. Thermo-reversible organogels are formed by heating and cooling PE-SURF/solvent solutions. The gel transition temperature is influenced by the degree of polymerization, the length of the alkyl side-chain, the solubility parameter of the solvent, and the concentration of the gelator. Freeze-drying and scanning electron microscopy characterization of the resultant xerogels shows the formation of rod- and plate-like network morphologies depending on the system parameters. This behavior is consistent with gelation driven by the self-assembly of the amphiphilic PE-SURFs into micellar networks.

  20. Bidirectional selection between two classes in complex social networks.

    PubMed

    Zhou, Bin; He, Zhe; Jiang, Luo-Luo; Wang, Nian-Xin; Wang, Bing-Hong

    2014-12-19

    The bidirectional selection between two classes widely emerges in various social lives, such as commercial trading and mate choosing. Until now, the discussions on bidirectional selection in structured human society are quite limited. We demonstrated theoretically that the rate of successfully matching is affected greatly by individuals' neighborhoods in social networks, regardless of the type of networks. Furthermore, it is found that the high average degree of networks contributes to increasing rates of successful matches. The matching performance in different types of networks has been quantitatively investigated, revealing that the small-world networks reinforces the matching rate more than scale-free networks at given average degree. In addition, our analysis is consistent with the modeling result, which provides the theoretical understanding of underlying mechanisms of matching in complex networks.

  1. Bidirectional selection between two classes in complex social networks

    PubMed Central

    Zhou, Bin; He, Zhe; Jiang, Luo-Luo; Wang, Nian-Xin; Wang, Bing-Hong

    2014-01-01

    The bidirectional selection between two classes widely emerges in various social lives, such as commercial trading and mate choosing. Until now, the discussions on bidirectional selection in structured human society are quite limited. We demonstrated theoretically that the rate of successfully matching is affected greatly by individuals' neighborhoods in social networks, regardless of the type of networks. Furthermore, it is found that the high average degree of networks contributes to increasing rates of successful matches. The matching performance in different types of networks has been quantitatively investigated, revealing that the small-world networks reinforces the matching rate more than scale-free networks at given average degree. In addition, our analysis is consistent with the modeling result, which provides the theoretical understanding of underlying mechanisms of matching in complex networks. PMID:25524835

  2. Clinical significance of tumor expression of major histocompatibility complex class I-related chains A and B (MICA/B) in gastric cancer patients.

    PubMed

    Ribeiro, Carolina Hager; Kramm, Karina; Gálvez-Jirón, Felipe; Pola, Víctor; Bustamante, Marco; Contreras, Hector R; Sabag, Andrea; Garrido-Tapia, Macarena; Hernández, Carolina J; Zúñiga, Roberto; Collazo, Norberto; Sotelo, Pablo Hernán; Morales, Camila; Mercado, Luis; Catalán, Diego; Aguillón, Juan Carlos; Molina, María Carmen

    2016-03-01

    Gastric cancer (GC) is the third most common cause of cancer death worldwide. Natural killer cells play an important role in the immune defense against transformed cells. They express the activating receptor NKG2D, whose ligands belong to the MIC and ULBP/RAET family. Although it is well established that these ligands are generally expressed in tumors, the association between their expression in the tumor and gastric mucosa and clinical parameters and prognosis of GC remains to be addressed. In the present study, MICA and MICB expression was analyzed, by flow cytometry, in 23 and 20 pairs of gastric tumor and adjacent non-neoplasic gastric mucosa, respectively. Additionally, ligands expression in 13 tumors and 7 gastric mucosa samples from GC patients were evaluated by immunohistochemistry. The mRNA levels of MICA in 9 pairs of tumor and mucosa were determined by quantitative PCR. Data were associated with the clinicopathological characteristics and the patient outcome. MICA expression was observed in 57% of tumors (13/23) and 44% of mucosal samples (10/23), while MICB was detected in 50% of tumors (10/20) and 45% of mucosal tissues (9/20). At the protein level, ligand expression was significantly higher in the tumor than in the gastric mucosa. MICA mRNA levels were also increased in the tumor as compared to the mucosa. However, clinicopathological analysis indicated that, in patients with tumors >5 cm, the expression of MICA and MICB in the tumor did not differ from that of the mucosa, and tumors >5 cm showed significantly higher MICA and MICB expression than tumors ≤5 cm. Patients presenting tumors >5 cm that expressed MICA and MICB had substantially shorter survival than those with large tumors that did not express these ligands. Our results suggest that locally sustained expression of MICA and MICB in the tumor may contribute to the malignant progression of GC and that expression of these ligands predicts an unfavorable prognosis in GC patients presenting large tumors.

  3. Clinical significance of tumor expression of major histocompatibility complex class I-related chains A and B (MICA/B) in gastric cancer patients

    PubMed Central

    RIBEIRO, CAROLINA HAGER; KRAMM, KARINA; GÁLVEZ-JIRÓN, FELIPE; POLA, VÍCTOR; BUSTAMANTE, MARCO; CONTRERAS, HECTOR R.; SABAG, ANDREA; GARRIDO-TAPIA, MACARENA; HERNÁNDEZ, CAROLINA J.; ZÚÑIGA, ROBERTO; COLLAZO, NORBERTO; SOTELO, PABLO HERNÁN; MORALES, CAMILA; MERCADO, LUIS; CATALÁN, DIEGO; AGUILLÓN, JUAN CARLOS; MOLINA, MARÍA CARMEN

    2016-01-01

    Gastric cancer (GC) is the third most common cause of cancer death worldwide. Natural killer cells play an important role in the immune defense against transformed cells. They express the activating receptor NKG2D, whose ligands belong to the MIC and ULBP/RAET family. Although it is well established that these ligands are generally expressed in tumors, the association between their expression in the tumor and gastric mucosa and clinical parameters and prognosis of GC remains to be addressed. In the present study, MICA and MICB expression was analyzed, by flow cytometry, in 23 and 20 pairs of gastric tumor and adjacent non-neoplasic gastric mucosa, respectively. Additionally, ligands expression in 13 tumors and 7 gastric mucosa samples from GC patients were evaluated by immunohistochemistry. The mRNA levels of MICA in 9 pairs of tumor and mucosa were determined by quantitative PCR. Data were associated with the clinicopathological characteristics and the patient outcome. MICA expression was observed in 57% of tumors (13/23) and 44% of mucosal samples (10/23), while MICB was detected in 50% of tumors (10/20) and 45% of mucosal tissues (9/20). At the protein level, ligand expression was significantly higher in the tumor than in the gastric mucosa. MICA mRNA levels were also increased in the tumor as compared to the mucosa. However, clinicopathological analysis indicated that, in patients with tumors >5 cm, the expression of MICA and MICB in the tumor did not differ from that of the mucosa, and tumors >5 cm showed significantly higher MICA and MICB expression than tumors ≤5 cm. Patients presenting tumors >5 cm that expressed MICA and MICB had substantially shorter survival than those with large tumors that did not express these ligands. Our results suggest that locally sustained expression of MICA and MICB in the tumor may contribute to the malignant progression of GC and that expression of these ligands predicts an unfavorable prognosis in GC patients presenting large tumors. PMID:26708143

  4. Characterization of class I- and class II-like major histocompatibility complex loci in pedigrees of North Atlantic right whales.

    PubMed

    Gillett, Roxanne M; Murray, Brent W; White, Bradley N

    2014-01-01

    North Atlantic right whales have one of the lowest levels of genetic variation at minisatellite loci, microsatellite loci, and mitochondrial control region haplotypes among mammals. Here, adaptive variation at the peptide binding region of class I and class II DRB-like genes of the major histocompatibility complex was assessed. Amplification of a duplicated region in 222 individuals revealed at least 11 class II alleles. Six alleles were assigned to the locus Eugl-DRB1 and 5 alleles were assigned to the locus Eugl-DRB2 by assessing segregation patterns of alleles from 81 parent/offspring pedigrees. Pedigree analysis indicated that these alleles segregated into 12 distinct haplotypes. Genotyping a smaller subset of unrelated individuals (n = 5 and 10, respectively) using different primer sets revealed at least 2 class II pseudogenes (with ≥ 4 alleles) and at least 3 class I loci (with ≥ 6 alleles). Class II sequences were significantly different from neutrality at peptide binding sites suggesting loci may be under the influence of balancing selection. Trans-species sharing of alleles was apparent for class I and class II sequences. Characterization of class II loci represents the first step in determining the relationship between major histocompatibility complex variability and factors affecting health and reproduction in this species.

  5. Characterization of class I- and class II-like major histocompatibility complex loci in pedigrees of North Atlantic right whales.

    PubMed

    Gillett, Roxanne M; Murray, Brent W; White, Bradley N

    2014-01-01

    North Atlantic right whales have one of the lowest levels of genetic variation at minisatellite loci, microsatellite loci, and mitochondrial control region haplotypes among mammals. Here, adaptive variation at the peptide binding region of class I and class II DRB-like genes of the major histocompatibility complex was assessed. Amplification of a duplicated region in 222 individuals revealed at least 11 class II alleles. Six alleles were assigned to the locus Eugl-DRB1 and 5 alleles were assigned to the locus Eugl-DRB2 by assessing segregation patterns of alleles from 81 parent/offspring pedigrees. Pedigree analysis indicated that these alleles segregated into 12 distinct haplotypes. Genotyping a smaller subset of unrelated individuals (n = 5 and 10, respectively) using different primer sets revealed at least 2 class II pseudogenes (with ≥ 4 alleles) and at least 3 class I loci (with ≥ 6 alleles). Class II sequences were significantly different from neutrality at peptide binding sites suggesting loci may be under the influence of balancing selection. Trans-species sharing of alleles was apparent for class I and class II sequences. Characterization of class II loci represents the first step in determining the relationship between major histocompatibility complex variability and factors affecting health and reproduction in this species. PMID:24381183

  6. Complexities and complications: intersections of class and sexuality.

    PubMed

    Taylor, Yvette

    2009-01-01

    I explore some questions and dilemmas raised by considering social class, gender, and sexuality within the same interconnecting research framework. I begin with attention to the theoretical development of intersectionality, arising from feminist conceptualizations of "differences that matter," and the ways these are included in or excluded from research agendas. Arguing that interconnections between class and sexuality have often been neglected in such moves, I seek to progress beyond intersectionality as a theoretical paradigm, toward understanding intersectionality as a lived experience. I draw on a case study of working-class lesbian lives to bridge the gap between theorization of intersectionality and the research application of this. PMID:19363764

  7. Major histocompatibility complex class II genes and systemic sclerosis.

    PubMed

    Briggs, D; Welsh, K I

    1991-11-01

    susceptibility to the disease is conferred by neutral residues (Val, Ser, Ala), at position 57 of the DQ beta chain, while Asp at this position correlates with resistance. A similar phenomenon has been described in rheumatoid arthritis. Although DR4 in general is associated with rheumatoid arthritis, it is heterogeneous, but a subtype of DR4 which is characterised by positively charged residues at positions 70 and 71 of the beta chains is not found in patients with rheumatoid arthritis (Wordsworth B P et al, unpublished data). A similar approach applied to the study of systemic sclerosis is likely to be similarly rewarding. The precise subtyping of the class II genes and the characterisation of their associated haplotypes is therefore required for a complete understanding of the contribution of the MHC to the disease. Additional genes linked to the MHC must not be overlooked, and are relevant to associations of haplotypes with the disease. Of particular interest are the recent reports of a new class of proteins, which are determined by genes in the MHC and which are considered to play a part in the assembly of the antigen peptide/MHC molecule complex. PMID:1750798

  8. β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome

    PubMed Central

    Tanimura, Kenji; Jin, Hui; Suenaga, Tadahiro; Morikami, Satoko; Arase, Noriko; Kishida, Kazuki; Hirayasu, Kouyuki; Kohyama, Masako; Ebina, Yasuhiko; Yasuda, Shinsuke; Horita, Tetsuya; Takasugi, Kiyoshi; Ohmura, Koichiro; Yamamoto, Ken; Katayama, Ichiro; Sasazuki, Takehiko; Lanier, Lewis L.; Atsumi, Tatsuya; Yamada, Hideto

    2015-01-01

    Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact β2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA class II complexes in the absence of phospholipids. In situ association between β2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against β2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that β2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. PMID:25733579

  9. Specific suppression of major histocompatibility complex class I and class II genes in astrocytes by brain-enriched gangliosides

    PubMed Central

    1993-01-01

    The effect of brain-enriched gangliosides on constitutive and cytokine- inducible expression of major histocompatibility complex (MHC) class I and II genes in cultured astrocytes was studied. Before treatment with gangliosides, astrocytes expressed constitutive MHC class I but not class II molecules, however, the expression of both MHC class I and II cell surface molecules on astrocytes was induced to high levels by interferon gamma (IFN-gamma). Constitutive and IFN-gamma-inducible expression of MHC class I and II molecules was suppressed by treatment of astrocytes with exogenous bovine brain gangliosides in a dose- dependent manner. Constitutive and induced MHC class I and II mRNA levels were also suppressed by gangliosides, indicating control through transcriptional mechanisms. This was consistent with the ability of gangliosides to suppress the binding activity of transcription factors, especially NF-kappa B-like binding activity, important for the expression of both MHC class I and II genes. These studies may be important for understanding mechanisms of central nervous system (CNS)- specific regulation of major histocompatibility molecules in neuroectodermal cells and the role of gangliosides in regulating MHC- restricted antiviral and autoimmune responses within the CNS. PMID:8376939

  10. Characterisation of Major Histocompatibility Complex Class I in the Australian Cane Toad, Rhinella marina

    PubMed Central

    Lillie, Mette; Shine, Richard; Belov, Katherine

    2014-01-01

    The Major Histocompatibility Complex (MHC) class I is a highly variable gene family that encodes cell-surface receptors vital for recognition of intracellular pathogens and initiation of immune responses. The MHC class I has yet to be characterised in bufonid toads (Order: Anura; Suborder: Neobatrachia; Family: Bufonidae), a large and diverse family of anurans. Here we describe the characterisation of a classical MHC class I gene in the Australian cane toad, Rhinella marina. From 25 individuals sampled from the Australian population, we found only 3 alleles at this classical class I locus. We also found large number of class I alpha 1 alleles, implying an expansion of class I loci in this species. The low classical class I genetic diversity is likely the result of repeated bottleneck events, which arose as a result of the cane toad's complex history of introductions as a biocontrol agent and its subsequent invasion across Australia. PMID:25093458

  11. Wide complex tachycardia in the presence of class I antiarrhythmic agents: a diagnostic challenge.

    PubMed

    Bhardwaj, Bhaskar; Lazzara, Ralph; Stavrakis, Stavros

    2014-05-01

    We present two patients with paroxysmal atrial fibrillation on class 1C antiarrhythmic drugs without concomitant atrioventricular (AV) nodal blocking agents who developed atrial flutter with 1:1 AV conduction. Their electrocardiogram revealed wide complex tachycardia with rates >200/minute. Atrial flutter with 1:1 conduction in the presence of class IC antiarrhythmic drugs may present a diagnostic challenge. These cases illustrate the importance of coadministering an AV nodal blocking agent with class IC antiarrhythmic agents in patients with atrial fibrillation. The differential diagnosis of wide complex tachycardia in patients taking class IC agents should include atrial flutter with 1:1 AV conduction.

  12. Dynamics of Major Histocompatibility Complex Class I Association with the Human Peptide-loading Complex*

    PubMed Central

    Panter, Michaela S.; Jain, Ankur; Leonhardt, Ralf M.; Ha, Taekjip; Cresswell, Peter

    2012-01-01

    Although the human peptide-loading complex (PLC) is required for optimal major histocompatibility complex class I (MHC I) antigen presentation, its composition is still incompletely understood. The ratio of the transporter associated with antigen processing (TAP) and MHC I to tapasin, which is responsible for MHC I recruitment and peptide binding optimization, is particularly critical for modeling of the PLC. Here, we characterized the stoichiometry of the human PLC using both biophysical and biochemical approaches. By means of single-molecule pulldown (SiMPull), we determined a TAP/tapasin ratio of 1:2, consistent with previous studies of insect-cell microsomes, rat-human chimeric cells, and HeLa cells expressing truncated TAP subunits. We also report that the tapasin/MHC I ratio varies, with the PLC population comprising both 2:1 and 2:2 complexes, based on mutational and co-precipitation studies. The MHC I-saturated PLC may be particularly prevalent among peptide-selective alleles, such as HLA-C4. Additionally, MHC I association with the PLC increases when its peptide supply is reduced by inhibiting the proteasome or by blocking TAP-mediated peptide transport using viral inhibitors. Taken together, our results indicate that the composition of the human PLC varies under normal conditions and dynamically adapts to alterations in peptide supply that may arise during viral infection. These findings improve our understanding of the quality control of MHC I peptide loading and may aid the structural and functional modeling of the human PLC. PMID:22829594

  13. Human Herpesvirus 7 U21 Tetramerizes To Associate with Class I Major Histocompatibility Complex Molecules

    PubMed Central

    May, Nathan A.; Wang, Qiuhong; Balbo, Andrea; Konrad, Sheryl L.; Buchli, Rico; Hildebrand, William H.; Schuck, Peter

    2014-01-01

    ABSTRACT The U21 gene product from human herpesvirus 7 binds to and redirects class I major histocompatibility complex (MHC) molecules to a lysosomal compartment. The molecular mechanism by which U21 reroutes class I MHC molecules to lysosomes is not known. Here, we have reconstituted the interaction between purified soluble U21 and class I MHC molecules, suggesting that U21 does not require additional cellular proteins to interact with class I MHC molecules. Our results demonstrate that U21, itself predicted to contain an MHC class I-like protein fold, interacts tightly with class I MHC molecules as a tetramer, in a 4:2 stoichiometry. These observations have helped to elucidate a refined model describing the mechanism by which U21 escorts class I MHC molecules to the lysosomal compartment. IMPORTANCE In this report, we show that the human herpesvirus 7 (HHV-7) immunoevasin U21, itself a class I MHC-like protein, binds with high affinity to class I MHC molecules as a tetramer and escorts them to lysosomes, where they are degraded. While many class I MHC-like molecules have been described in detail, this unusual viral class I-like protein functions as a tetramer, associating with class I MHC molecules in a 4:2 ratio, illuminating a functional significance of homooligomerization of a class I MHC-like protein. PMID:24390327

  14. Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

    PubMed

    Gaur, Vidhi; Connor, Timothy; Sanigorski, Andrew; Martin, Sheree D; Bruce, Clinton R; Henstridge, Darren C; Bond, Simon T; McEwen, Kevin A; Kerr-Bayles, Lyndal; Ashton, Trent D; Fleming, Cassandra; Wu, Min; Pike Winer, Lisa S; Chen, Denise; Hudson, Gregg M; Schwabe, John W R; Baar, Keith; Febbraio, Mark A; Gregorevic, Paul; Pfeffer, Frederick M; Walder, Ken R; Hargreaves, Mark; McGee, Sean L

    2016-09-13

    Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

  15. Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

    PubMed

    Gaur, Vidhi; Connor, Timothy; Sanigorski, Andrew; Martin, Sheree D; Bruce, Clinton R; Henstridge, Darren C; Bond, Simon T; McEwen, Kevin A; Kerr-Bayles, Lyndal; Ashton, Trent D; Fleming, Cassandra; Wu, Min; Pike Winer, Lisa S; Chen, Denise; Hudson, Gregg M; Schwabe, John W R; Baar, Keith; Febbraio, Mark A; Gregorevic, Paul; Pfeffer, Frederick M; Walder, Ken R; Hargreaves, Mark; McGee, Sean L

    2016-09-13

    Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity. PMID:27626651

  16. Parental Reasoning Complexity, Social Class, and Child-Rearing Behaviors.

    ERIC Educational Resources Information Center

    Dekovic, Maja; Gerris, Jan R. M.

    1992-01-01

    Examined whether parental reasoning complexity predicts parental behavior during interaction with child. Findings from 226 parents revealed that higher levels of reasoning were related to authoritative pattern of child rearing, use of indirect positive control, warmth, acceptance, and support. Negative relationships were found with an…

  17. A Tale of Three Classes: Case Studies in Course Complexity

    ERIC Educational Resources Information Center

    Gill, T. Grandon; Jones, Joni

    2010-01-01

    This paper examines the question of decomposability versus complexity of teaching situations by presenting three case studies of MIS courses. Because all three courses were highly successful in their observed outcomes, the paper hypothesizes that if the attributes of effective course design are decomposable, one would expect to see a large number…

  18. The Zhamanshin impact feature: A new class of complex crater?

    NASA Technical Reports Server (NTRS)

    Garvin, J. B.; Schnetzler, C. C.

    1992-01-01

    The record of 10-km-scale impact events of Quaternary age includes only two 'proven' impact structures: the Zhamanshin Impact Feature (ZIF) and the Bosumtwi Impact Crater (BIC). What makes these impact landforms interesting from the standpoint of recent Earth history is their almost total lack of morphologic similarity, in spite of similar absolute ages and dimensions. The BIC resembles pristine complex craters on the Moon to first order (i.e., 'U'-shaped topographic cross section with preserved rim), while the ZIF displays virtually none of the typical morphologic elements of a 13- to 14-km-diameter complex crater. Indeed, this apparent lack of a craterlike surficial topographic expression initially led Soviet geologists to conclude that the structure was only 5.5 to 6 km in diameter and at least 4.5 Ma in age. However, more recent drilling and geophysical observations at the ZIF have indicated that its pre-erosional diameter is at least 13.5 km, and that its age is most probably 0.87 Ma. Why the present topographic expression of a 13.5-km complex impact crater less than 1 m.y. old most closely resembles heavily degraded Mesozoic shield craters such as Lappajarvi is a question of considerable debate. Hypotheses for the lack of a clearly defined craterlike form at the ZIF include a highly oblique impact, a low-strength 'cometary' projectile, weak or water-saturated target materials, and anomalous erosion patterns. The problem remains unresolved because typical erosion rates within the arid sedimentary platform environment of central Kazakhstan in which the ZIF is located are typically low; it would require at least a factor of 10 greater erosion at the ZIF in order to degrade the near-rim ejecta typical of a 13.5-km complex crater by hundreds of meters in only 0.87 Ma, and to partially infill an inner cavity with 27 cu km (an equivalent uniform thickness of infill of 166 m). Our analysis of the degree of erosion and infill at the ZIF calls for rates in the 0.19 to

  19. Half-Heusler thermoelectrics: a complex class of materials.

    PubMed

    Bos, Jan-Willem G; Downie, Ruth A

    2014-10-29

    Half-Heusler thermoelectrics first attracted interest in the late-1990s and are currently undergoing a renaissance. This has been driven by improved synthesis, processing and characterisation methods, leading to increases in the thermoelectric figure of merit and the observation of novel phenomena such as carrier filtering in nanocomposite samples. The difficulty in extracting good thermoelectric performance is at first glance surprising given the relative simplicity of the ideal crystal structure with only site occupancies and lattice parameter as crystallographic variables. However, the observed thermoelectric properties are found to depend sensitively on sample processing. Recent work has shown that prepared ingots can contain a range of inhomogeneities, including interstitials, nano- and micron sized Heusler inclusions and multiple half-Heusler phases. For this reason, the prepared materials are far more complex than initially appreciated and this may offer opportunities to enhance the thermoelectric figure of merit.

  20. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes.

    PubMed

    Kropshofer, H; Spindeldreher, S; Röhn, T A; Platania, N; Grygar, C; Daniel, N; Wölpl, A; Langen, H; Horejsi, V; Vogt, A B

    2002-01-01

    Complexes of peptide and major histocompatibility complex (MHC) class II are expressed on the surface of antigen-presenting cells but their molecular organization is unknown. Here we show that subsets of MHC class II molecules localize to membrane microdomains together with tetraspan proteins, the peptide editor HLA-DM and the costimulator CD86. Tetraspan microdomains differ from other membrane areas such as lipid rafts, as they enrich MHC class II molecules carrying a selected set of peptide antigens. Antigen-presenting cells deficient in tetraspan microdomains have a reduced capacity to activate CD4+ T cells. Thus, the organization of uniformly loaded peptide-MHC class II complexes in tetraspan domains may be a very early event that determines both the composition of the immunological synapse and the quality of the subsequent T helper cell response.

  1. Major histocompatibility complex class II compatibility, but not class I, predicts mate choice in a bird with highly developed olfaction.

    PubMed

    Strandh, Maria; Westerdahl, Helena; Pontarp, Mikael; Canbäck, Björn; Dubois, Marie-Pierre; Miquel, Christian; Taberlet, Pierre; Bonadonna, Francesco

    2012-11-01

    Mate choice for major histocompatibility complex (MHC) compatibility has been found in several taxa, although rarely in birds. MHC is a crucial component in adaptive immunity and by choosing an MHC-dissimilar partner, heterozygosity and potentially broad pathogen resistance is maximized in the offspring. The MHC genotype influences odour cues and preferences in mammals and fish and hence olfactory-based mate choice can occur. We tested whether blue petrels, Halobaena caerulea, choose partners based on MHC compatibility. This bird is long-lived, monogamous and can discriminate between individual odours using olfaction, which makes it exceptionally well suited for this analysis. We screened MHC class I and II B alleles in blue petrels using 454-pyrosequencing and quantified the phylogenetic, functional and allele-sharing similarity between individuals. Partners were functionally more dissimilar at the MHC class II B loci than expected from random mating (p = 0.033), whereas there was no such difference at the MHC class I loci. Phylogenetic and non-sequence-based MHC allele-sharing measures detected no MHC dissimilarity between partners for either MHC class I or II B. Our study provides evidence of mate choice for MHC compatibility in a bird with a high dependency on odour cues, suggesting that MHC odour-mediated mate choice occurs in birds.

  2. Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice

    PubMed Central

    1993-01-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin- producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP- transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease. PMID:8101862

  3. Expression Regulation of Major Histocompatibility Complex Class I and Class II Encoding Genes

    PubMed Central

    van den Elsen, Peter J.

    2011-01-01

    Major histocompatibility complex (MHC)-I and MHC-II molecules play an essential role in the immune response to pathogens by virtue of their ability to present peptides to CD8+ and CD4+ T cells, respectively. Given this critical role, MHC-I and MHC-II genes are regulated in a tight fashion at the transcriptional level by a variety of transcription factors that interact with conserved cis-acting regulatory promoter elements. In addition to the activities of these regulatory factors, modification of chromatin also plays an essential role in the efficient transcription of these genes to meet with local requirement for an effective immune response. The focus of this review is on the transcription factors that interact with conserved cis-acting promoter elements and the epigenetic mechanisms that modulate induced and constitutive expression of these MHC genes. PMID:22566838

  4. A class of reduced-complexity Viterbi detectors for partial response continuous phase modulation

    NASA Astrophysics Data System (ADS)

    Svensson, A.; Sundberg, C.-E.; Aulin, T.

    1984-10-01

    Partial response continuous phase modulation (CPM) gives constant envelope digital modulation schemes with excellent power spectra. Both narrow main lobe and low spectral tails can be achieved. When these signals are detected in an optimum coherent maximum likelihood sequence detector (Viterbi detector), power efficient schemes can also be designed, sometimes at the expense of receiver complexity. This paper describes a general class of simple Viterbi detectors with reduced complexity compared to the optimum case. The key idea is that the approximate receiver is based on a less complex CPM scheme than the transmitted scheme. The asymptotically optimum reduced-complexity receiver is found for a variety of transmitted schemes and various complexity reduction factors, for a specific class of receivers and modulation indexes. A new distance measure is introduced for the performance analysis. Smooth schemes based on raised cosine pulses are analyzed and simulated for the case of simplified reception. A graceful performance degradation occurs with the reduction of complexity.

  5. Early Endosomes Are Required for Major Histocompatiblity Complex Class II Transport to Peptide-loading Compartments

    PubMed Central

    Brachet, Valérie; Péhau-Arnaudet, Gérard; Desaymard, Catherine; Raposo, Graça; Amigorena, Sebastian

    1999-01-01

    Antigen presentation to CD4+ T lymphocytes requires transport of newly synthesized major histocompatibility complex (MHC) class II molecules to the endocytic pathway, where peptide loading occurs. This step is mediated by a signal located in the cytoplasmic tail of the MHC class II-associated Ii chain, which directs the MHC class II-Ii complexes from the trans-Golgi network (TGN) to endosomes. The subcellular machinery responsible for the specific targeting of MHC class II molecules to the endocytic pathway, as well as the first compartments these molecules enter after exit from the TGN, remain unclear. We have designed an original experimental approach to selectively analyze this step of MHC class II transport. Newly synthesized MHC class II molecules were caused to accumulate in the Golgi apparatus and TGN by incubating the cells at 19°C, and early endosomes were functionally inactivated by in vivo cross-linking of transferrin (Tf) receptor–containing endosomes using Tf-HRP complexes and the HRP-insoluble substrate diaminobenzidine. Inactivation of Tf-containing endosomes caused a marked delay in Ii chain degradation, peptide loading, and MHC class II transport to the cell surface. Thus, early endosomes appear to be required for delivery of MHC class II molecules to the endocytic pathway. Under cross-linking conditions, most αβIi complexes accumulated in tubules and vesicles devoid of γ-adaptin and/or mannose-6-phosphate receptor, suggesting an AP1-independent pathway for the delivery of newly synthesized MHC class II molecules from the TGN to endosomes. PMID:10473634

  6. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice

    PubMed Central

    1995-01-01

    Rather unexpectedly, major histocompatibility complex class II- deficient mice have a significant population of peripheral CD4+ T lymphocytes. We have investigated these cells at the population and clonal levels. CD4+ T lymphocytes from class II-deficient animals are thymically derived, appear early in ontogeny, exhibit the phenotype of resting memory cells, are potentially functional by several criteria, and have a diverse T cell receptor repertoire. They do not include substantially elevated numbers of NK1.1+ cells. Hybridomas derived after polyclonal stimulation of the CD4+ lymphocytes from class II- deficient animals include a subset with an unusual reactivity pattern, responding to splenocytes from many mouse strains including the strain of origin. Most members of this subset recognize the major histocompatibility complex class Ib molecule CD1; their heterogeneous reactivities and T cell receptor usage further suggest the involvement of peptides and/or highly variable posttranslational modifications. PMID:7561702

  7. Regulation of calreticulin-major histocompatibility complex (MHC) class I interactions by ATP.

    PubMed

    Wijeyesakere, Sanjeeva Joseph; Gagnon, Jessica K; Arora, Karunesh; Brooks, Charles L; Raghavan, Malini

    2015-10-13

    The MHC class I peptide loading complex (PLC) facilitates the assembly of MHC class I molecules with peptides, but factors that regulate the stability and dynamics of the assembly complex are largely uncharacterized. Based on initial findings that ATP, in addition to MHC class I-specific peptide, is able to induce MHC class I dissociation from the PLC, we investigated the interaction of ATP with the chaperone calreticulin, an endoplasmic reticulum (ER) luminal, calcium-binding component of the PLC that is known to bind ATP. We combined computational and experimental measurements to identify residues within the globular domain of calreticulin, in proximity to the high-affinity calcium-binding site, that are important for high-affinity ATP binding and for ATPase activity. High-affinity calcium binding by calreticulin is required for optimal nucleotide binding, but both ATP and ADP destabilize enthalpy-driven high-affinity calcium binding to calreticulin. ATP also selectively destabilizes the interaction of calreticulin with cellular substrates, including MHC class I molecules. Calreticulin mutants that affect ATP or high-affinity calcium binding display prolonged associations with monoglucosylated forms of cellular MHC class I, delaying MHC class I dissociation from the PLC and their transit through the secretory pathway. These studies reveal central roles for ATP and calcium binding as regulators of calreticulin-substrate interactions and as key determinants of PLC dynamics.

  8. Major histocompatibility complex class I-restricted alloreactive CD4+ T cells.

    PubMed

    Boyle, Louise H; Goodall, Jane C; Gaston, J S Hill

    2004-05-01

    Although it is well established that CD4+ T cells generally recognize major histocompatibility complex (MHC) class II molecules, MHC class I-reactive CD4+ T cells have occasionally been reported. Here we describe the isolation and characterization of six MHC class I-reactive CD4+ T-cell lines, obtained by co-culture of CD4+ peripheral blood T cells with the MHC class II-negative, transporter associated with antigen processing (TAP)-negative cell line, T2, transfected with human leucocyte antigen (HLA)-B27. Responses were inhibited by the MHC class I-specific monoclonal antibody (mAb), W6/32, demonstrating the direct recognition of MHC class I molecules. In four cases, the restriction element was positively identified as HLA-A2, as responses by these clones were completely inhibited by MA2.1, an HLA-A2-specific mAb. Interestingly, three of the CD4+ T-cell lines only responded to cells expressing HLA-B27, irrespective of their restricting allele, implicating HLA-B27 as a possible source of peptides presented by the stimulatory MHC class I alleles. In addition, these CD4+ MHC class I alloreactive T-cell lines could recognize TAP-deficient cells and therefore may have particular clinical relevance to situations where the expression of TAP molecules is decreased, such as viral infection and transformation of cells. PMID:15096184

  9. A molecular map of the chicken major histocompatibility complex: the class II beta genes are closely linked to the class I genes and the nucleolar organizer.

    PubMed Central

    Guillemot, F; Billault, A; Pourquié, O; Béhar, G; Chaussé, A M; Zoorob, R; Kreibich, G; Auffray, C

    1988-01-01

    We have cloned in a cosmid vector four DNA clusters covering 320 kb of the chicken MHC (B complex), including five class II (B-L) beta genes defining two related isotypic families. Additional B complex genes have been revealed using tissue-specific cDNA probes. A cosmid fragment has been used to isolate a cDNA for a class I (B-F) transcript. This transcript, that is by far the most divergent known member of the class I gene family, hybridized to six B-F genes present in the cosmids. One of the clusters was shown to contain two rRNA transcriptional units from the nucleolar organizer region (NOR), marking the telomeric boundary of the B complex. None of the other B complex genes hybridizes to, or has the transcriptional characteristics of mammalian MHC class II alpha or class III genes. The map we have obtained shows that the B complex does not contain well defined class I and class II regions since B-F and B-L beta genes are closely associated with unrelated genes. Moreover, class II beta genes are very closely linked to class I genes in two clusters, and to the NOR in a third one. Images PMID:3141149

  10. Properties and Applications of Single-Chain Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Kotsiou, Eleni; Brzostek, Joanna

    2011-01-01

    Abstract Stable major histocompatibility complex (MHC) class I molecules at the cell surface consist of three separate, noncovalently associated components: the class I heavy chain, the β2-microglobulin light chain, and a presented peptide. These three components are assembled inside cells via complex pathways involving many other proteins that have been studied extensively. Correct formation of disulfide bonds in the endoplasmic reticulum is central to this process of MHC class I assembly. For a single specific peptide to be presented at the cell surface for possible immune recognition, between hundreds and thousands of peptide-containing precursor polypeptides are required, so the overall process is relatively inefficient. To increase the efficiency of antigen presentation by MHC class I molecules, and for possible therapeutic purposes, single-chain molecules have been developed in which the three, normally separate components have been joined together via flexible linker sequences in a single polypeptide chain. Remarkably, these single-chain MHC class I molecules fold up correctly, as judged by functional recognition by cells of the immune system, and more recently by X-ray crystallographic structural data. This review focuses on the interesting properties and potential of this new type of engineered MHC class I molecule. Antioxid. Redox Signal. 15, 645–655. PMID:21126187

  11. Challenges in Integrating a Complex Systems Computer Simulation in Class: An Educational Design Research

    ERIC Educational Resources Information Center

    Loke, Swee-Kin; Al-Sallami, Hesham S.; Wright, Daniel F. B.; McDonald, Jenny; Jadhav, Sheetal; Duffull, Stephen B.

    2012-01-01

    Complex systems are typically difficult for students to understand and computer simulations offer a promising way forward. However, integrating such simulations into conventional classes presents numerous challenges. Framed within an educational design research, we studied the use of an in-house built simulation of the coagulation network in four…

  12. Efficient Tor Signaling Requires a Functional Class C Vps Protein Complex in Saccharomyces cerevisiae

    PubMed Central

    Zurita-Martinez, Sara A.; Puria, Rekha; Pan, Xuewen; Boeke, Jef D.; Cardenas, Maria E.

    2007-01-01

    The Tor kinases regulate responses to nutrients and control cell growth. Unlike most organisms that only contain one Tor protein, Saccharomyces cerevisiae expresses two, Tor1 and Tor2, which are thought to share all of the rapamycin-sensitive functions attributable to Tor signaling. Here we conducted a genetic screen that defined the global TOR1 synthetic fitness or lethal interaction gene network. This screen identified mutations in distinctive functional categories that impaired vacuolar function, including components of the EGO/Gse and PAS complexes that reduce fitness. In addition, tor1 is lethal in combination with mutations in class C Vps complex components. We find that Tor1 does not regulate the known function of the class C Vps complex in protein sorting. Instead class C vps mutants fail to recover from rapamycin-induced growth arrest or to survive nitrogen starvation and have low levels of amino acids. Remarkably, addition of glutamate or glutamine restores viability to a tor1 pep3 mutant strain. We conclude that Tor1 is more effective than Tor2 at providing rapamycin-sensitive Tor signaling under conditions of amino acid limitation, and that an intact class C Vps complex is required to mediate intracellular amino acid homeostasis for efficient Tor signaling. PMID:17565946

  13. Porcine major histocompatibility complex (MHC) class I molecules and analysis of their peptide-binding specificities

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules, which are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating cytotoxic lymphocytes (CTLs). The polymorp...

  14. Major histocompatibility complex class II A gene polymorphism in the striped bass

    SciTech Connect

    Hardee, J.J.; Godwin, U.; Benedetto, R.; McConnell, T.J.

    1995-02-01

    Adaptions of the polymerase chain reaction were used to isolate cDNA sequences encoding the Major histocompatibility complex (Mhc) class II A gene(s) of the striped bass (Morone saxatilis). Four complete Mhc class II A genes were cloned and sequenced from a specimen originating on the Roanoke River, North Carolina, and another three A genes from a specimen originating from the Santee-Cooper Reservoir, South Carolina, identifying a total of seven unique sequences. The sequence suggests the presence of at least two Mhc class II A loci. The extensive sequence variability observed between the seven different Mhc class II clones was concentrated in the {alpha}1 encoding domain. The encoded {alpha}2, transmembrane, and cytoplasmic regions of all seven striped bass genes correlated well with those of known vertebrate Mhc class II proteins. Overall, the striped bass sequences showed greatest similarity to the Mhc class II A genes of the zebrafish. Southern blot analysis demonstrated extensive polymorphism in the Mhc class II A genes in members of a Roanoke river-caught population of striped bass versus a lesser degree of polymorphism in an aquacultured Santee-Cooper population of striped bass. 55 refs., 5 figs., 1 tab.

  15. Major histocompatibility complex class II A gene polymorphism in the striped bass.

    PubMed

    Hardee, J J; Godwin, U; Benedetto, R; McConnell, T J

    1995-01-01

    Adaptions of the polymerase chain reaction were used to isolate cDNA sequences encoding the Major histocompatibility complex (Mhc) class II A gene(s) of the striped bass (Morone saxatilis). Four complete Mhc class II A genes were cloned and sequenced from a specimen originating in the Roanoke River, North Carolina, and another three A genes from a specimen originating from the Santee-Cooper Reservoir, South Carolina, identifying a total of seven unique sequences. The sequence suggests the presence of at least two Mhc class II A loci. The extensive sequence variability observed between the seven different Mhc class II clones was concentrated in the alpha 1 encoding domain. The encoded alpha 2, transmembrane, and cytoplasmic regions of all seven striped bass genes correlated well with those of known vertebrate Mhc class II proteins. Overall, the striped bass sequences showed greatest similarity to the Mhc class II A genes of the zebrafish. Southern blot analysis demonstrated extensive polymorphism in the Mhc class II A genes in members of a Roanoke river-caught population of striped bass versus a lesser degree of polymorphism in an aquacultured Santee-Cooper population of striped bass.

  16. Lipopeptides: a novel antigen repertoire presented by major histocompatibility complex class I molecules.

    PubMed

    Morita, Daisuke; Sugita, Masahiko

    2016-10-01

    Post-translationally modified peptides, such as those containing either phosphorylated or O-glycosylated serine/threonine residues, may be presented to cytotoxic T lymphocytes (CTLs) by MHC class I molecules. Most of these modified peptides are captured in the MHC class I groove in a similar manner to that for unmodified peptides. N-Myristoylated 5-mer lipopeptides have recently been identified as a novel chemical class of MHC class I-presented antigens. The rhesus classical MHC class I allele, Mamu-B*098, was found to be capable of binding N-myristoylated lipopeptides and presenting them to CTLs. A high-resolution X-ray crystallographic analysis of the Mamu-B*098:lipopeptide complex revealed that the myristic group as well as conserved C-terminal serine residue of the lipopeptide ligand functioned as anchors, whereas the short stretch of three amino acid residues located in the middle of the lipopeptides was only exposed externally with the potential to interact directly with specific T-cell receptors. Therefore, the modes of lipopeptide-ligand interactions with MHC class I and with T-cell receptors are novel and fundamentally distinct from that for MHC class I-presented peptides. Another lipopeptide-presenting MHC class I allele has now been identified, leading us to the prediction that MHC class I molecules may be separated on a functional basis into two groups: one presenting long peptides and the other presenting short lipopeptides. Since the N-myristoylation of viral proteins is often linked to pathogenesis, CTLs capable of sensing N-myristoylation may serve to control pathogenic viruses, raising the possibility for the development of a new type of lipopeptide vaccine. PMID:27402593

  17. Major Histocompatibility Complex class IIB polymorphism in an ancient Spanish breed.

    PubMed

    Atlija, Marina; Gutíerrez-Gil, Beatriz; Arranz, Juan-Jose; Semmer, Jördis; Stear, Michael J; Buitkamp, Johannes

    2015-09-01

    Genes from the Major Histocompatibility Complex class II region are involved in the presentation of antigens. Therefore, they have the key role in regulating the immune response and in the resistance to infections. We investigated the Major Histocompatibility Complex class IIB genes, DRB and DQB, in Churra sheep, one of the most important indigenous breeds of Spain. These genes are among the most polymorphic in the mammalian genome. Furthermore, often different numbers of class IIB genes per haplotype exist, complicating the genotyping and sequencing of these genes. Especially the DQB region is only partially characterized in sheep and the repertoire of DRB and DQB alleles in Churra sheep, an ancient breed, is unknown. Here, we sequenced the class IIB genes for 15 rams that are the pedigree heads of a selection Nucleus herd. In total, we found 12 DRB and 25 DQB alleles. From these, 3 and 15 were new, respectively. Fourteen haplotypes carrying one or two DQB alleles could be deduced and the evolutionary relationship of these was investigated by phylogenetic trees. Based on the sequences of these most common class II alleles, a more efficient genotyping system for larger numbers of Churra sheep will be developed. PMID:26184839

  18. DNase I hypersensitive sites flank the mouse class II major histocompatibility complex during B cell development.

    PubMed Central

    Carson, S

    1991-01-01

    The mouse class II major histocompatibility complex (MHC) encodes a polymorphic, multigene family important in the immune response, and is expressed mainly on mature B cells, on certain types of dendritic cells and is also inducible by gamma-interferon on antigen presenting cells. To study the regulatory elements which control this expression pattern, we have examined the chromatin structure flanking the class II MHC region, in particular during B cell differentiation. Using a panel of well-characterised mouse cell lines specific for different stages of B cell development (pre-B, B, plasma cell) as well as non-B cell lines, we have mapped the DNase I hypersensitive (DHS) sites adjacent to the mouse MHC class II region. The results presented show, for the first time that there are specific hypersensitive sites flanking the class II MHC locus during pre B cell, B cell and plasma cell stages of B cell differentiation, irrespective of the status of class II MHC expression. These hypersensitive sites are not found in T cell, fibroblast or uninduced myelomonocytic cell lines. This suggests that these DHS sites define a developmentally stable, chromatin structure, which can be used as a marker of B cell lineage commitment and may indicate that a combination of these hypersensitive sites reflect regulatory proteins involved in the immediate expression of a particular class II MHC gene or possibly control of the entire locus. Images PMID:1923768

  19. Evolutionary instability of the major histocompatibility complex class I loci in New World primates

    PubMed Central

    Cadavid, Luis F.; Shufflebotham, Clare; Ruiz, Francisco J.; Yeager, Meredith; Hughes, Austin L.; Watkins, David I.

    1997-01-01

    Homologues of the human major histocompatibility complex (MHC) HLA-A, -B, -E, -F, and -G loci are present in all the Catarrhini (Old World primates, apes, and humans), and some of their allelic lineages have survived several speciation events. Analysis of 26 MHC class I cDNAs from seven different genera of New World primates revealed that the Callitrichinae (tamarins and marmosets) are an exception to these rules of MHC stability. In gene trees of primate MHC class I genes, sequences from the Callitrichinae cluster in a genus-specific fashion, whereas in the other genera of New World primates, as in the Catarrhini, they cluster in a transgeneric way. The genus-specific clustering of the Callitrichinae cDNAs indicates that there is no orthology between MHC class I loci in genera of this phyletic group. Additionally, the Callitrichinae genera exhibit limited variability of their MHC class I genes, in contrast to the high variability displayed by all other primates. Each Callitrichinae genus, therefore, expresses its own set of MHC class I genes, suggesting that an unusually high rate of turnover of loci occurs in this subfamily. The limited variability of MHC class I genes in the Callitrichinae is likely the result of the recent origin of these loci. PMID:9405648

  20. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor

    SciTech Connect

    Nielsen, Tine Kragh; Hildmann, Christian; Riester, Daniel; Wegener, Dennis; Schwienhorst, Andreas; Ficner, Ralf

    2007-04-01

    The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.

  1. Multi-class and multi-scale models of complex biological phenomena.

    PubMed

    Yu, Jessica S; Bagheri, Neda

    2016-06-01

    Computational modeling has significantly impacted our ability to analyze vast (and exponentially increasing) quantities of experimental data for a variety of applications, such as drug discovery and disease forecasting. Single-scale, single-class models persist as the most common group of models, but biological complexity often demands more sophisticated approaches. This review surveys modeling approaches that are multi-class (incorporating multiple model types) and/or multi-scale (accounting for multiple spatial or temporal scales) and describes how these models, and combinations thereof, should be used within the context of the problem statement. We end by highlighting agent-based models as an intuitive, modular, and flexible framework within which multi-scale and multi-class models can be implemented. PMID:27115496

  2. Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

    PubMed Central

    Buettner, Alexander; Goerner, Christian; Hertel, Michael; van Rijn, Jeaphianne; Wallrapp, Frank; Eisenreich, Wolfgang; Sieber, Volker; Kourist, Robert; Brück, Thomas

    2016-01-01

    Class I terpene synthases generate the structural core of bioactive terpenoids. Deciphering structure–function relationships in the reactive closed complex and targeted engineering is hampered by highly dynamic carbocation rearrangements during catalysis. Available crystal structures, however, represent the open, catalytically inactive form or harbor nonproductive substrate analogs. Here, we present a catalytically relevant, closed conformation of taxadiene synthase (TXS), the model class I terpene synthase, which simulates the initial catalytic time point. In silico modeling of subsequent catalytic steps allowed unprecedented insights into the dynamic reaction cascades and promiscuity mechanisms of class I terpene synthases. This generally applicable methodology enables the active-site localization of carbocations and demonstrates the presence of an active-site base motif and its dominating role during catalysis. It additionally allowed in silico-designed targeted protein engineering that unlocked the path to alternate monocyclic and bicyclic synthons representing the basis of a myriad of bioactive terpenoids. PMID:26842837

  3. Expression of major histocompatibility complex class II and costimulatory molecules in oral carcinomas in vitro.

    PubMed

    Villarroel-Dorrego, Mariana; Speight, Paul M; Barrett, A William

    2005-01-01

    Recognition in the 1980 s that keratinocytes can express class II molecules of the Major Histocompatibility Complex (MHC) first raised the possibility that these cells might have an immunological function, and may even act as antigen presenting cells (APC). For effective T lymphocyte activation, APC require, in addition to MHC II, appropriate costimulatory signals. The aim of this study was to determine the expression of MHC class II and the co-stimulatory molecules CD40, CD80 and CD86 in keratinocytes derived from healthy oral mucosa and oral carcinomas. Using flow cytometry, it was confirmed that oral keratinocytes, switch on, expression of MHC class II molecules after stimulation with IFNgamma in vitro. All keratinocyte lines expressed CD40 constitutively; by contrast, CD80 and CD86 were universally absent. Loss of CD80 and CD86 may be one means whereby tumours escape immunological surveillance.

  4. Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases.

    PubMed

    Schrepfer, Patrick; Buettner, Alexander; Goerner, Christian; Hertel, Michael; van Rijn, Jeaphianne; Wallrapp, Frank; Eisenreich, Wolfgang; Sieber, Volker; Kourist, Robert; Brück, Thomas

    2016-02-23

    Class I terpene synthases generate the structural core of bioactive terpenoids. Deciphering structure-function relationships in the reactive closed complex and targeted engineering is hampered by highly dynamic carbocation rearrangements during catalysis. Available crystal structures, however, represent the open, catalytically inactive form or harbor nonproductive substrate analogs. Here, we present a catalytically relevant, closed conformation of taxadiene synthase (TXS), the model class I terpene synthase, which simulates the initial catalytic time point. In silico modeling of subsequent catalytic steps allowed unprecedented insights into the dynamic reaction cascades and promiscuity mechanisms of class I terpene synthases. This generally applicable methodology enables the active-site localization of carbocations and demonstrates the presence of an active-site base motif and its dominating role during catalysis. It additionally allowed in silico-designed targeted protein engineering that unlocked the path to alternate monocyclic and bicyclic synthons representing the basis of a myriad of bioactive terpenoids.

  5. Genomic organization of duplicated major histocompatibility complex class I regions in Atlantic salmon (Salmo salar)

    PubMed Central

    Lukacs, Morten F; Harstad, Håvard; Grimholt, Unni; Beetz-Sargent, Marianne; Cooper, Glenn A; Reid, Linda; Bakke, Hege G; Phillips, Ruth B; Miller, Kristina M; Davidson, William S; Koop, Ben F

    2007-01-01

    Background We have previously identified associations between major histocompatibility complex (MHC) class I and resistance towards bacterial and viral pathogens in Atlantic salmon. To evaluate if only MHC or also closely linked genes contributed to the observed resistance we ventured into sequencing of the duplicated MHC class I regions of Atlantic salmon. Results Nine BACs covering more than 500 kb of the two duplicated MHC class I regions of Atlantic salmon were sequenced and the gene organizations characterized. Both regions contained the proteasome components PSMB8, PSMB9, PSMB9-like and PSMB10 in addition to the transporter for antigen processing TAP2, as well as genes for KIFC1, ZBTB22, DAXX, TAPBP, BRD2, COL11A2, RXRB and SLC39A7. The IA region contained the recently reported MHC class I Sasa-ULA locus residing approximately 50 kb upstream of the major Sasa-UBA locus. The duplicated class IB region contained an MHC class I locus resembling the rainbow trout UCA locus, but although transcribed it was a pseudogene. No other MHC class I-like genes were detected in the two duplicated regions. Two allelic BACs spanning the UBA locus had 99.2% identity over 125 kb, while the IA region showed 82.5% identity over 136 kb to the IB region. The Atlantic salmon IB region had an insert of 220 kb in comparison to the IA region containing three chitin synthase genes. Conclusion We have characterized the gene organization of more than 500 kb of the two duplicated MHC class I regions in Atlantic salmon. Although Atlantic salmon and rainbow trout are closely related, the gene organization of their IB region has undergone extensive gene rearrangements. The Atlantic salmon has only one class I UCA pseudogene in the IB region while trout contains the four MHC UCA, UDA, UEA and UFA class I loci. The large differences in gene content and most likely function of the salmon and trout class IB region clearly argues that sequencing of salmon will not necessarily provide information

  6. Interactions between the Class II Transactivator and CREB Binding Protein Increase Transcription of Major Histocompatibility Complex Class II Genes

    PubMed Central

    Fontes, Joseph D.; Kanazawa, Satoshi; Jean, Dickson; Peterlin, B. Matija

    1999-01-01

    Class II major histocompatibility (class II) genes are regulated in a B-cell-specific and gamma interferon-inducible fashion. The master switch for the expression of these genes is the class II transactivator (CIITA). In this report, we demonstrate that one of the functions of CIITA is to recruit the CREB binding protein (CBP) to class II promoters. Not only functional but also specific binding interactions between CIITA and CBP were demonstrated. Moreover, a dominant negative form of CBP decreased the activity of class II promoters and levels of class II determinants on the surface of cells. Finally, the inhibition of class II gene expression by the glucocorticoid hormone could be attributed to the squelching of CBP by the glucocorticoid receptor. We conclude that CBP, a histone acetyltransferase, plays an important role in the transcription of class II genes. PMID:9858618

  7. Cytokines Regulate Proteolysis in Major Histocompatibility Complex Class II–Dependent Antigen Presentation by Dendritic Cells

    PubMed Central

    Fiebiger, Edda; Meraner, Paul; Weber, Ekkehard; Fang, I-Fei; Stingl, Georg; Ploegh, Hidde; Maurer, Dieter

    2001-01-01

    Endo/lysosomal proteases control two key events in antigen (Ag) presentation: the degradation of protein Ag and the generation of peptide-receptive major histocompatibility complex (MHC) class II molecules. Here we show that the proinflammatory cytokines tumor necrosis factor α and interleukin (IL)-1β rapidly increase the activity of cathepsin (cat) S and catB in human dendritic cells (DCs). As a consequence, a wave of MHC class II sodium dodecyl sulfate stable dimer formation ensues in a catS-dependent fashion. In contrast, the antiinflammatory cytokine IL-10 renders DCs incapable of upregulating catS and catB activity and in fact, attenuates the level of both enzymes. Suppressed catS and catB activity delays MHC class II sodium dodecyl sulfate stable dimer formation and impairs Ag degradation. In DCs exposed to tetanus toxoid, IL-10 accordingly reduces the number of MHC class II–peptide complexes accessible to tetanus toxoid–specific T cell receptors, as analyzed by measuring T cell receptor downregulation in Ag-specific T cell clones. Thus, the control of protease activity by pro- and antiinflammatory cytokines is an essential feature of the Ag presentation properties of DCs. PMID:11304549

  8. Reassociation with beta 2-microglobulin is necessary for Kb class I major histocompatibility complex binding of exogenous peptides.

    PubMed Central

    Rock, K L; Rothstein, L E; Gamble, S R; Benacerraf, B

    1990-01-01

    T lymphocytes recognize endogenously produced antigenic peptides in association with major histocompatibility complex (MHC)-encoded molecules. Peptides from the extracellular fluid can be displayed in association with class I and class II MHC molecules. Here we report that mature Kb class I MHC molecules bind peptides upon dissociation and reassociation of their light chain. Intact Kb heterodimers, unlike class II MHC molecules, are relatively unreceptive to binding peptides. This property may maintain segregation of class I and class II MHC-restricted peptides and has implications for the use of peptides as vaccines. Images PMID:2217182

  9. The major histocompatibility complex class II-linked cim locus controls the kinetics of intracellular transport of a classical class I molecule

    PubMed Central

    1991-01-01

    The dominant trans-acting major histocompatibility complex (MHC)-linked class I modifier (cim) locus, previously recognized through its ability to determine altered alloantigenicity of a rat class I molecule, RT1.A3, is shown here to influence class I intracellular transport. The MHC recombinant laboratory rat strains PVG.R1 and PVG.R8 display unusually long retention of RT1.Aa within the endoplasmic reticulum or cis-Golgi. In appropriate F1 hybrid cells heterozygous for RT1.Aa and another class I MHC allele, RT1.Ac, only the RT1.Aa protein is subject to slow transport. The cim gene product therefore shows class I allele specificity in its action, cim appears to be a polymorphic locus whose product is directly involved in the processes of class I MHC assembly and/or intracellular transport. PMID:2007857

  10. Characterization of Two Classes of Small Molecule Inhibitors of Arp2/3 Complex

    SciTech Connect

    Nolen, B.; Tomasevic, N; Russell, A; Pierce, D; Jia, Z; McCormick, C; Hartman, J; Sakowicz, R; Pollard, T

    2009-01-01

    Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.

  11. Antibody recognition of an immunogenic influenza hemagglutinin-human leukocyte antigen class II complex

    PubMed Central

    1991-01-01

    The A/Japan/57 influenza hemagglutin (HA) peptide HA 128-145, when bound by human histocompatibility leukocyte antigen-DRw11 cells, is recognized by the human CD4+ T cell clone V1. A rabbit antiserum has been raised against HA 128-145 which recognizes not only the free peptide, but also the HA 128-145/DRw11 complex on a solid matrix, in solution, or on the surface of viable cells. The detection of these complexes on viable cells was shown to be class II specific, DRw11 restricted, and commensurate with the level of DRw11 expression. The identity of DRw11 as the cell surface molecule binding HA 128-145 was confirmed by immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and tryptic peptide mapping. Using this antiserum HA 128-145/DRw11 complexes could be detected on the cell surface as soon as 30 min after the peptide was added, and increased up to 24 h. Dissociation kinetics showed these complexes were long-lived, with a half-life of approximately 14 h. This anti-HA peptide antiserum represents the first direct means of studying antigenic peptide-human leukocyte antigen class II complexes on the surface of living cells without the addition of a non-amino acid moiety to the peptide. The properties of this antiserum thus provide the potential to study naturally processed antigenic peptides as well as the mechanism of processing itself in a physiologically relevant system. PMID:2056278

  12. Crystal Structure of Staphylococcal Enterotoxin I (SEI) in Complex with a Human Major Histocompatibility Complex Class II Molecule*

    PubMed Central

    Fernández, Marisa M.; Guan, Rongjin; Swaminathan, Chittoor P.; Malchiodi, Emilio L.; Mariuzza, Roy A.

    2009-01-01

    Superantigens are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to major histocompatibility complex (MHC) class II and T cell receptors. This activation results in uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable property of superantigens, which distinguishes them from T cell receptors, is their ability to interact with multiple MHC class II alleles independently of MHC-bound peptide. Previous crystallographic studies have shown that staphylococcal and streptococcal superantigens belonging to the zinc family bind to a high affinity site on the class II β-chain. However, the basis for promiscuous MHC recognition by zinc-dependent superantigens is not obvious, because the β-chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To understand how zinc-dependent superantigens recognize MHC, we determined the crystal structure, at 2.0 Å resolution, of staphylococcal enterotoxin I bound to the human class II molecule HLA-DR1 bearing a peptide from influenza hemagglutinin. Interactions between the superantigen and DR1 β-chain are mediated by a zinc ion, and 22% of the buried surface of peptide·MHC is contributed by the peptide. Comparison of the staphylococcal enterotoxin I·peptide·DR1 structure with ones determined previously revealed that zinc-dependent superantigens achieve promiscuous binding to MHC by targeting conservatively substituted residues of the polymorphic β-chain. Additionally, these superantigens circumvent peptide specificity by engaging MHC-bound peptides at their conformationally conserved N-terminal regions while minimizing sequence-specific interactions with peptide residues to enhance cross-reactivity. PMID:16829512

  13. Carbonic Anhydrase Inhibitors. Part 541: Metal Complexes of Heterocyclic Sulfonamides: A New Class of Antiglaucoma Agents

    PubMed Central

    Scozzafava, Andrea; Jitianu, Andrei

    1997-01-01

    Metal complexes of heterocyclic sulfonamides possessing carbonic anhydrase (CA) inhibitory properties were recently shown to be useful as intraocular pressure (IOP) lowering agents in experimental animals, and might be developed as a novel class of antiglaucoma drugs. Here we report the synthesis of a heterocyclic sulfonamide CA inhibitor and of the metal complexes containing main group metal ions, such as Be(II), Mg(II), Al(III), Zn(II), Cd(II) and Hg(II) and the new sulfonamide as well as 5-amino-1,3,4-thiadiazole-2-sulfonamide as ligands. The new complexes were characterized by standard physico-chemical procedures, and assayed as inhibitors of three CA isozymes, CA I, II and IV. Some of them (but not the parent sulfonamides) strongly lowered IOP in rabbits when administered as a 2% solution into the eye. PMID:18475811

  14. The Atiyah class and complex structure stabilization in heterotic Calabi-Yau compactifications

    NASA Astrophysics Data System (ADS)

    Anderson, Lara B.; Gray, James; Lukas, Andre; Ovrut, Burt

    2011-10-01

    Holomorphic gauge fields in N = 1 supersymmetri cheterotic compactifications can constrain the complex structure moduli of a Calabi-Yau manifold. In this paper, the tools necessary to use holomorphic bundles as a mechanism for moduli stabilization are systematically developed. We review the requisite deformation theory — including the Atiyah class, which determines the deformations of the complex structure for which the gauge bundle becomes non-holomorphic and, hence, non-supersymmetric. In addition, two equivalent approaches to this mechanism of moduli stabilization are presented. The first isan efficient computational algorithm for determining the supersymmetric moduli space, while the second is an F-term potential in the four-dimensional theory associated with vector bundle holomorphy. These three methods are proven to be rigorously equivalent. We present explicit examples in which large numbers of complex structure moduli are stabilized. Finally, higher-order corrections to the moduli space are discussed.

  15. Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins

    NASA Technical Reports Server (NTRS)

    Beharka, A. A.; Armstrong, J. W.; Iandolo, J. J.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Macrophages from C2D transgenic mice deficient in the expression of major histocompatibility complex (MHC) class II proteins were used to identify binding sites for superantigens distinct from the MHC class II molecule. Iodinated staphylococcal enterotoxins A and B (SEA and SEB) and exfoliative toxins A and B (ETA and ETB) bound to C2D macrophages in a concentration-dependent and competitive manner. All four toxins increased F-actin concentration within 30 s of their addition to C2D macrophages, indicating that signal transduction occurred in response to toxin in the absence of class II MHC. Furthermore, ETA, ETB, SEA, and, to a lesser extent, SEB induced C2D macrophages to produce interleukin 6. Several molecular species on C2D macrophages with molecular masses of 140, 97, 61, 52, 43, and 37 kDa bound SEA in immunoprecipitation experiments. These data indicate the presence of novel, functionally active toxin binding sites on murine macrophages distinct from MHC class II molecules.

  16. Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

    PubMed Central

    Cram, Erik D.; Simmons, Ryan S.; Palmer, Amy L.; Hildebrand, William H.; Rockey, Daniel D.

    2015-01-01

    The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8+ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8+ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8+ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins. PMID:26597986

  17. Covalent assembly of a soluble T cell receptor-peptide-major histocompatibility class I complex.

    PubMed Central

    Grégoire, C; Lin, S Y; Mazza, G; Rebai, N; Luescher, I F; Malissen, B

    1996-01-01

    We used stepwise photochemical cross-linking for specifically assembling soluble and covalent complexes made of a T-cell antigen receptor (TCR) and a class I molecule of the major histocompatibility complex (MHC) bound to an antigenic peptide. For that purpose, we have produced in myeloma cells a single-chain Fv construct of a TCR specific for a photoreactive H-2Kd-peptide complex. Photochemical cross-linking of this TCR single-chain Fv with a soluble form of the photoreactive H-2Kd-peptide ligand resulted in the formation of a ternary covalent complex. We have characterized the soluble ternary complex and showed that it reacted with antibodies specific for epitopes located either on the native TCR or on the Kd molecules. By preventing the fast dissociation kinetics observed with most T cell receptors, this approach provides a means of preparing soluble TCR-peptide-MHC complexes on large-scale levels. Images Fig. 3 Fig. 4 PMID:8692966

  18. Characterisation of four major histocompatibility complex class II genes of the koala (Phascolarctos cinereus).

    PubMed

    Lau, Quintin; Jobbins, Sarah E; Belov, Katherine; Higgins, Damien P

    2013-01-01

    Major histocompatibility complex (MHC) class II molecules have an integral role in the adaptive immune response, as they bind and present antigenic peptides to T helper lymphocytes. In this study of koalas, species-specific primers were designed to amplify exon 2 of the MHC class II DA and DB genes, which contain much of the peptide-binding regions of the α and β chains. A total of two DA α1 domain variants and eight DA β1 (DAB), three DB α1 and five DB β1 variants were amplified from 20 koalas from two free-living populations from South East Queensland and the Port Macquarie region in northern New South Wales. We detected greater variation in the β1 than in the α1 domains as well as evidence of positive selection in DAB. The present study provides a springboard to future investigation of the role of MHC in disease susceptibility in koalas.

  19. Isolation and characterization of major histocompatibility complex class II B genes in cranes.

    PubMed

    Kohyama, Tetsuo I; Akiyama, Takuya; Nishida, Chizuko; Takami, Kazutoshi; Onuma, Manabu; Momose, Kunikazu; Masuda, Ryuichi

    2015-11-01

    In this study, we isolated and characterized the major histocompatibility complex (MHC) class II B genes in cranes. Genomic sequences spanning exons 1 to 4 were amplified and determined in 13 crane species and three other species closely related to cranes. In all, 55 unique sequences were identified, and at least two polymorphic MHC class II B loci were found in most species. An analysis of sequence polymorphisms showed the signature of positive selection and recombination. A phylogenetic reconstruction based on exon 2 sequences indicated that trans-species polymorphism has persisted for at least 10 million years, whereas phylogenetic analyses of the sequences flanking exon 2 revealed a pattern of concerted evolution. These results suggest that both balancing selection and recombination play important roles in the crane MHC evolution. PMID:26452363

  20. Toxic shock syndrome toxin 1 binds to major histocompatibility complex class II molecules.

    PubMed Central

    Scholl, P; Diez, A; Mourad, W; Parsonnet, J; Geha, R S; Chatila, T

    1989-01-01

    Toxic shock syndrome toxin 1 (TSST-1) is a 22-kDa exotoxin produced by strains of Staphylococcus aureus and implicated in the pathogenesis of toxic shock syndrome. In common with other staphylococcal exotoxins, TSST-1 has diverse immunological effects. These include the induction of interleukin 2 receptor expression, interleukin 2 synthesis, proliferation of human T lymphocytes, and stimulation of interleukin 1 synthesis by human monocytes. In the present study, we demonstrate that TSST-1 binds with saturation kinetics and with a dissociation constant of 17-43 nM to a single class of binding sites on human mononuclear cells. There was a strong correlation between the number of TSST-1 binding sites and the expression of major histocompatibility complex class II molecules, and interferon-gamma induced the expression of class II molecules as well as TSST-1 binding sites on human skin-derived fibroblasts. Monoclonal antibodies to HLA-DR, but not to HLA-DP or HLA-DQ, strongly inhibited TSST-1 binding. Affinity chromatography of 125I-labeled cell membranes over TSST-1-agarose resulted in the recovery of two bands of 35 kDa and 31 kDa that comigrated, respectively, with the alpha and beta chains of HLA-DR and that could be immunoprecipitated with anti-HLA-DR monoclonal antibodies. Binding of TSST-1 was demonstrated to HLA-DR and HLA-DQ L-cell transfectants. These results indicate that major histocompatibility complex class II molecules represent the major binding site for TSST-1 on human cells. Images PMID:2542966

  1. Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny

    PubMed Central

    1994-01-01

    All mature B cells coexpress major histocompatibility complex (MHC) class II molecules, I-A and I-E, which are restriction elements required for antigen presentation to CD4+ T cells. However, the expression of class II during the early stages of B cell development has been unclear. We demonstrate here that there is a difference in the expression of class II during murine B cell development in the fetal liver and adult bone marrow (BM). These differences define two distinct B cell developmental pathways. The Fetal-type (FT) pathway is characterized by pre-B and immature IgM+ B cells generated in the fetal liver which initially lack all class II expression. In contrast, the Adult-type (AT) pathway is typified by B cells developing in the adult BM which express class II molecules from the pre-B cell stage. In vitro stromal cell cultures of sorted fetal liver and adult BM pro-B cells indicated that the difference in I-A expression during B cell development is intrinsic to the progenitors. In addition, we show that FT B cell development is not restricted to the fetal liver but occurs in the peritoneal cavities, spleens, liver, and BM of young mice up to at least 1 mo of age. The AT B cell development begins to emerge after birth but is, however, restricted to the BM environment. These findings indicate that there are two distinct B cell developmental pathways during ontogeny, each of which could contribute differentially to the immune repertoire and thus the functions of B cell subsets and lineages. PMID:7913950

  2. Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem

    SciTech Connect

    Schneider, Kyle D.; Ortega, Caleb J.; Renck, Nicholas A.; Bonomo, Robert A.; Powers, Rachel A.; Leonard, David A.

    2012-02-08

    The emergence of class D {beta}-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D {beta}-lactamases with carbapenemase activity are resistant to {beta}-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6a hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors.

  3. The analysis of eight transcriptomes from all poriferan classes reveals surprising genetic complexity in sponges.

    PubMed

    Riesgo, Ana; Farrar, Nathan; Windsor, Pamela J; Giribet, Gonzalo; Leys, Sally P

    2014-05-01

    Sponges (Porifera) are among the earliest evolving metazoans. Their filter-feeding body plan based on choanocyte chambers organized into a complex aquiferous system is so unique among metazoans that it either reflects an early divergence from other animals prior to the evolution of features such as muscles and nerves, or that sponges lost these characters. Analyses of the Amphimedon and Oscarella genomes support this view of uniqueness-many key metazoan genes are absent in these sponges-but whether this is generally true of other sponges remains unknown. We studied the transcriptomes of eight sponge species in four classes (Hexactinellida, Demospongiae, Homoscleromorpha, and Calcarea) specifically seeking genes and pathways considered to be involved in animal complexity. For reference, we also sought these genes in transcriptomes and genomes of three unicellular opisthokonts, two sponges (A. queenslandica and O. carmela), and two bilaterian taxa. Our analyses showed that all sponge classes share an unexpectedly large complement of genes with other metazoans. Interestingly, hexactinellid, calcareous, and homoscleromorph sponges share more genes with bilaterians than with nonbilaterian metazoans. We were surprised to find representatives of most molecules involved in cell-cell communication, signaling, complex epithelia, immune recognition, and germ-lineage/sex, with only a few, but potentially key, absences. A noteworthy finding was that some important genes were absent from all demosponges (transcriptomes and the Amphimedon genome), which might reflect divergence from main-stem lineages including hexactinellids, calcareous sponges, and homoscleromorphs. Our results suggest that genetic complexity arose early in evolution as shown by the presence of these genes in most of the animal lineages, which suggests sponges either possess cryptic physiological and morphological complexity and/or have lost ancestral cell types or physiological processes.

  4. Complex networks for data-driven medicine: the case of Class III dentoskeletal disharmony

    NASA Astrophysics Data System (ADS)

    Scala, A.; Auconi, P.; Scazzocchio, M.; Caldarelli, G.; McNamara, JA; Franchi, L.

    2014-11-01

    In the last decade, the availability of innovative algorithms derived from complexity theory has inspired the development of highly detailed models in various fields, including physics, biology, ecology, economy, and medicine. Due to the availability of novel and ever more sophisticated diagnostic procedures, all biomedical disciplines face the problem of using the increasing amount of information concerning each patient to improve diagnosis and prevention. In particular, in the discipline of orthodontics the current diagnostic approach based on clinical and radiographic data is problematic due to the complexity of craniofacial features and to the numerous interacting co-dependent skeletal and dentoalveolar components. In this study, we demonstrate the capability of computational methods such as network analysis and module detection to extract organizing principles in 70 patients with excessive mandibular skeletal protrusion with underbite, a condition known in orthodontics as Class III malocclusion. Our results could possibly constitute a template framework for organising the increasing amount of medical data available for patients’ diagnosis.

  5. Ethanol Metabolism Alters Major Histocompatibility Complex Class I-Restricted Antigen Presentation In Liver Cells

    PubMed Central

    Osna, Natalia A.; White, Ronda L.; Thiele, Geoffrey M.; Donohue, Terrence M.

    2009-01-01

    The proteasome is a major enzyme that cleaves proteins for antigen presentation. Cleaved peptides traffic to the cell surface, where they are presented in the context of MHC class I. Recognition of these complexes by cytotoxic T lymphocytes is crucial for elimination of cells bearing “non-self” proteins. Our previous studies revealed that ethanol suppresses proteasome function in ethanol-metabolizing liver cells. We hypothesized that proteasome suppression reduces the hydrolysis of antigenic peptides, thereby decreasing the presentation of the peptide-MHC class I-complexes on the cell surface. To test this, we used the mouse hepatocyte cell line (CYP2E1/ADH-transfected HepB5 cells) or primary mouse hepatocytes, both derived from livers of C57Bl/6 mice, which present the ovalbumin peptide, SIINFEKL, complexed with H2Kb. To induce H2Kb expression, HepB5 cells were treated with interferon gamma (IFNγ) and then exposed to ethanol. In these cells, ethanol metabolism decreased not only proteasome activity, but also hydrolysis of the C-extended peptide, SIINFEKL-TE and the presentation of SIINFEKL-H2Kb complexes measured after the delivery of SIINFEKL-TE to cytoplasm. The suppressive effects of ethanol were, in part, attributed to ethanol-elicited impairment of IFNγ signaling. However, in primary hepatocytes, even in the absence of IFNγ, we observed a similar decline in proteasome activity and antigen presentation after ethanol exposure. We conclude that proteasome function is directly suppressed by ethanol metabolism and indirectly, by preventing the activating effects of IFNγ. Ethanol-elicited reduction in proteasome activity contributes to the suppression of SIINFEKL-H2Kb presentation on the surface of liver cells. Immune response to viral antigens plays a crucial role in the pathogenesis of hepatitis C or B viral infections (HCV and HBV, respectively). Professional antigen-presenting cells (dendritic cells and macrophages) are responsible for priming the

  6. Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation.

    PubMed Central

    Reith, W; Barras, E; Satola, S; Kobr, M; Reinhart, D; Sanchez, C H; Mach, B

    1989-01-01

    The regulation of major histocompatibility complex class II gene expression is directly involved in the control of normal and abnormal immune responses. In humans, HLA-DR, -DQ, and -DP class II heterodimers are encoded by a family of alpha- and beta-chain genes clustered in the major histocompatibility complex. Their expression is developmentally controlled and normally restricted to certain cell types. This control is mediated by cis-acting sequences in class II promoters and by trans-acting regulatory factors. Several nuclear proteins bind to class II promoter sequences. In a form of hereditary immunodeficiency characterized by a defect in a trans-acting regulatory factor controlling class II gene transcription, we have observed that one of these nuclear factors (RF-X) does not bind to its target sequence (the class II X box). A cDNA encoding RF-X was isolated by screening a phage expression library with an X-box binding-site probe. The recombinant protein has the binding specificity of RF-X, including a characteristic gradient of affinity for the X boxes of HLA-DR, -DP, and -DQ promoters. RF-X mRNA is present in the regulatory mutants, indicating a defect in the synthesis of a functional form of the RF-X protein. Images PMID:2498880

  7. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages.

    PubMed Central

    Kovacsovics-Bankowski, M; Clark, K; Benacerraf, B; Rock, K L

    1993-01-01

    Antigens in extracellular fluids can be processed and presented with major histocompatibility complex (MHC) class I molecules by a subset of antigen presenting cells (APCs). Chicken egg ovalbumin (Ova) linked to beads was presented with MHC class I molecules by these cells up to 10(4)-fold more efficiently than soluble Ova. This enhanced presentation was observed with covalently or noncovalently linked Ova and with beads of different compositions. A key parameter in the activity of these conjugates was the size of the beads. The APC that is responsible for this form of presentation is a macrophage. These cells internalize the antigen constructs through phagocytosis, since cytochalasin B inhibited presentation. Processing of the antigen and association with MHC class I molecules appears to occur intracellularly as presentation was observed under conditions where there was no detectable release of peptides into the extracellular fluids. When injected in vivo in C57BL/6 mice, Ova-beads, but not soluble Ova, primed CD4- CD8+ cytotoxic T lymphocytes (CTLs). Similar results were obtained in BALB/c mice immunized with beta-galactosidase-beads. The implications of these findings for development of nonliving vaccines that stimulate CTL immunity are discussed. PMID:8506338

  8. Isolation and characterization of major histocompatibility complex class IIB genes from the nurse shark.

    PubMed Central

    Bartl, S; Weissman, I L

    1994-01-01

    The major histocompatibility complex (MHC) contains a set of linked genes which encode cell surface proteins involved in the binding of small peptide antigens for their subsequent recognition by T lymphocytes. MHC proteins share structural features and the presence and location of polymorphic residues which play a role in the binding of antigens. In order to compare the structure of these molecules and gain insights into their evolution, we have isolated two MHC class IIB genes from the nurse shark, Ginglymostoma cirratum. Two clones, most probably alleles, encode proteins which differ by 13 amino acids located in the putative antigen-binding cleft. The protein structure and the location of polymorphic residues are similar to their mammalian counterparts. Although these genes appear to encode a typical MHC protein, no T-cell-mediated responses have been demonstrated in cartilaginous fish. The nurse shark represents the most phylogenetically primitive organism in which both class IIA [Kasahara, M., Vazquez, M., Sato, K., McKinney, E.C. & Flajnik, M.F. (1992) Proc. Natl. Acad. Sci USA 89, 6688-6692] and class IIB genes, presumably encoding the alpha/beta heterodimer, have been isolated. Images Fig. 2 PMID:8278377

  9. Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens.

    PubMed Central

    Wu, T C; Guarnieri, F G; Staveley-O'Carroll, K F; Viscidi, R P; Levitsky, H I; Hedrick, L; Cho, K R; August, J T; Pardoll, D M

    1995-01-01

    The presentation of antigenic peptides by major histocompatibility complex (MHC) class II molecules to CD4+ T cells is critical to the function of the immune system. In this study, we have utilized the sorting signal of the lysosomal-associated membrane protein LAMP-1 to target a model antigen, human papillomavirus 16 E7 (HPV-16 E7), into the endosomal and lysosomal compartments. The LAMP-1 sorting signal reroutes the antigen into the MHC class II processing pathway, resulting in enhanced presentation to CD4+ cells in vitro. In vivo immunization experiments in mice demonstrated that vaccinia containing the chimeric E7/LAMP-1 gene generated greater E7-specific lymphoproliferative activity, antibody titers, and cytotoxic T-lymphocyte activities than vaccinia containing the wild-type HPV-16 E7 gene. These results suggest that specific targeting of an antigen to the endosomal and lysosomal compartments enhances MHC class II presentation and vaccine potency. Images Fig. 2 Fig. 3 PMID:8524826

  10. Activation of CD8-dependent cytotoxic T lymphocyte adhesion and degranulation by peptide class I antigen complexes.

    PubMed

    Kane, K P; Mescher, M F

    1993-06-01

    Activation of CTL requires engagement of both the TCR and the CD8 coreceptor. Immobilized class I proteins and in vitro-formed peptide class I Ag complexes have been used to examine the relative contributions of TCR and CD8 to the adhesion and response of cloned, class I-restricted CTL. The extent of degranulation was found to be directly proportional to the concentration of peptide used to pulse class I, suggesting that activation is a direct function of TCR occupancy level. In contrast, activation of degranulation as a function of the amount of class I on the surface displayed a marked threshold density dependence. Essentially the same density dependence was found for the response of CTL to fluid phase anti-TCR mAb and non-Ag class I, indicating that CD8-class I interaction must exceed a threshold before effective cosignaling can occur. Adhesion and degranulation of CTL was minimal in response to in vitro peptide-class I complexes prepared at a class I density below the threshold. However, the same density of peptide class I initiated both adhesion and response if additional non-Ag class I was coimmobilized on the same surface at levels above threshold. Thus, when surface levels of peptide class I complex are low, as is likely to be the case under physiologic conditions, the level of TCR occupancy achieved is, by itself, insufficient to mediate cell adhesion or activate degranulation. The results demonstrate, however, that low TCR occupancy is sufficient to provide the signal to prime CD8. Provided that the surface density of class I is sufficiently high, CD8 then mediates strong adhesion and provides the costimulatory signal(s) to activate response.

  11. Peptide-dependent Conformational Fluctuation Determines the Stability of the Human Leukocyte Antigen Class I Complex*

    PubMed Central

    Yanaka, Saeko; Ueno, Takamasa; Shi, Yi; Qi, Jianxun; Gao, George F.; Tsumoto, Kouhei; Sugase, Kenji

    2014-01-01

    In immune-mediated control of pathogens, human leukocyte antigen (HLA) class I presents various antigenic peptides to CD8+ T-cells. Long-lived peptide presentation is important for efficient antigen-specific T-cell activation. Presentation time depends on the peptide sequence and the stability of the peptide-HLA complex (pHLA). However, the determinant of peptide-dependent pHLA stability remains elusive. Here, to reveal the pHLA stabilization mechanism, we examined the crystal structures of an HLA class I allomorph in complex with HIV-derived peptides and evaluated site-specific conformational fluctuations using NMR. Although the crystal structures of various pHLAs were almost identical independent of the peptides, fluctuation analyses identified a peptide-dependent minor state that would be more tightly packed toward the peptide. The minor population correlated well with the thermostability and cell surface presentation of pHLA, indicating that this newly identified minor state is important for stabilizing the pHLA and facilitating T-cell recognition. PMID:25028510

  12. The Integrator complex controls the termination of transcription at diverse classes of gene targets

    PubMed Central

    Skaar, Jeffrey R; Ferris, Andrea L; Wu, Xiaolin; Saraf, Anita; Khanna, Kum Kum; Florens, Laurence; Washburn, Michael P; Hughes, Stephen H; Pagano, Michele

    2015-01-01

    Complexes containing INTS3 and either NABP1 or NABP2 were initially characterized in DNA damage responses, but their biochemical function remained unknown. Using affinity purifications and HIV Integration targeting-sequencing (HIT-Seq), we find that these complexes are part of the Integrator complex, which binds RNA Polymerase II and regulates specific target genes. Integrator cleaves snRNAs as part of their processing to their mature form in a mechanism that is intimately coupled with transcription termination. However, HIT-Seq reveals that Integrator also binds to the 3′ end of replication-dependent histones and promoter proximal regions of genes with polyadenylated transcripts. Depletion of Integrator subunits results in transcription termination failure, disruption of histone mRNA processing, and polyadenylation of snRNAs and histone mRNAs. Furthermore, promoter proximal binding of Integrator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruitment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites. PMID:25675981

  13. Diacylglycerol kinase α regulates tubular recycling endosome biogenesis and major histocompatibility complex class I recycling.

    PubMed

    Xie, Shuwei; Naslavsky, Naava; Caplan, Steve

    2014-11-14

    Major histocompatibility complex class I (MHC I) presents intracellular-derived peptides to cytotoxic T lymphocytes and its subcellular itinerary is important in regulating the immune response. While a number of diacylglycerol kinase isoforms have been implicated in clathrin-dependent internalization, MHC I lacks the typical motifs known to mediate clathrin-dependent endocytosis. Here we show that depletion of diacylglycerol kinase α (DGKα), a kinase devoid of a clathrin-dependent adaptor protein complex 2 binding site, caused a delay in MHC I recycling to the plasma membrane without affecting the rate of MHC I internalization. We demonstrate that DGKα knock-down causes accumulation of intracellular and surface MHC I, resulting from decreased degradation. Furthermore, we provide evidence that DGKα is required for the generation of phosphatidic acid required for tubular recycling endosome (TRE) biogenesis. Moreover, we show that DGKα forms a complex with the TRE hub protein, MICAL-L1. Given that MICAL-L1 and the F-BAR-containing membrane-tubulating protein Syndapin2 associate selectively with phosphatidic acid, we propose a positive feedback loop in which DGKα generates phosphatidic acid to drive its own recruitment to TRE via its interaction with MICAL-L1. Our data support a novel role for the involvement of DGKα in TRE biogenesis and MHC I recycling.

  14. Identification of 32 major histocompatibility complex class I alleles in African green monkeys.

    PubMed

    Cao, Y; Li, A; Li, L; Yan, X; Fa, Y; Zeng, L; Fan, J; Liu, B; Sun, Z

    2014-09-01

    The African green monkey may be an ideal replacement for the rhesus monkey in biomedical research, but relatively little is known about the genetic background of major histocompatibility complex (MHC) class I molecules. In analysis of 12 African green monkeys, 13 Chae-A and 19 Chae-B alleles were identified. Among these alleles, 12 Chae-A and 9 Chae-B were new lineages. The full amino acid length deduced for Chae-A genes is 365 amino acids, but for Chae-B genes, the lengths are 365, 362, 361, and 359 amino acids, respectively. There were 1-3 Chae-A alleles and 2-5 Chae-B alleles in each animal. In African green monkeys, rhesus monkeys, and cynomolgus monkeys, the MHC-A and MHC-B alleles display trans-species polymorphism, rather than being clustered in a species-specific fashion.

  15. H ∞ Cluster Synchronization for a Class of Neutral Complex Dynamical Networks with Markovian Switching

    PubMed Central

    2014-01-01

    H ∞ cluster synchronization problem for a class of neutral complex dynamical networks (NCDNs) with Markovian switching is investigated in this paper. Both the retarded and neutral delays are considered to be interval mode dependent and time varying. The concept of H ∞ cluster synchronization is proposed to quantify the attenuation level of synchronization error dynamics against the exogenous disturbance of the NCDNs. Based on a novel Lyapunov functional, by employing some integral inequalities and the nature of convex combination, mode delay-range-dependent H ∞ cluster synchronization criteria are derived in the form of linear matrix inequalities which depend not only on the disturbance attenuation but also on the initial values of the NCDNs. Finally, numerical examples are given to demonstrate the feasibility and effectiveness of the proposed theoretical results. PMID:24892088

  16. Major histocompatibility complex class I genes of the coelacanth Latimeria chalumnae.

    PubMed

    Betz, U A; Mayer, W E; Klein, J

    1994-11-01

    The coelacanth fish Latimeria chalumnae is the sole surviving species of a phylogenetic lineage that was founded more than 400 million years ago and that has changed morphologically very little since that time. Little is known about the molecular evolution of this "living fossil," considered by some taxonomists to be the closest living relative of tetrapods. Here we describe the isolation and characterization of L. chalumnae major histocompatibility complex (MHC) class I genes. The exon-intron organization of these genes is the same as that of their mammalian counterparts. The genes fall into four families, which we designate Lach-UA through Lach-UD. There are multiple loci in all of the families. Genes of the first two families are transcribed. The Lach-UA family bears the characteristics of functional, polymorphic class I genes; the other three families may be represented by nonclassical genes. All the Lach loci arose by duplication from an ancestral gene after the foundation of the coelacanth lineage. Intergenic variation is highest at positions corresponding to the mammalian peptide-binding region. The closest relatives of the Lach genes among the MHC genes sequenced thus far are those of the amphibian Xenopus.

  17. Increasing complexity: which drug class to choose for treatment of hypertension in the elderly?

    PubMed Central

    Kaiser, Edelgard Anna; Lotze, Ulrich; Schäfer, Hans Hendrik

    2014-01-01

    Treatment of hypertension in the elderly is expected to become more complex in the coming decades. Based on the current landscape of clinical trials, guideline recommendations remain inconclusive. The present review discusses the latest evidence derived from studies available in 2013 and investigates optimal blood pressure (BP) and preferred treatment substances. Three common archetypes are discussed that hamper the treatment of hypertension in the very elderly. In addition, this paper presents the current recommendations of the NICE 2011, JNC7 2013-update, ESH/ESC 2013, CHEP 2013, JNC8 and ASH/ISH guidelines for elderly patients. Advantages of the six main substance classes, namely diuretics, beta-blockers (BBs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) are discussed. Medical and economic implications of drug administration in the very elderly are presented. Avoidance of treatment-related adverse effects has become increasingly relevant. Current substance classes are equally effective, with similar effects on cardiovascular outcomes. Selection of substances should therefore also be based on collateral advantages of drugs that extend beyond BP reduction. The combination of ACEIs and diuretics appears to be favorable in managing systolic/diastolic hypertension. Diuretics are a preferred and cheap combination drug, and the combination with CCBs is recommended for patients with isolated systolic hypertension. ACEIs and CCBs are favorable for patients with dementia, while CCBs and ARBs imply substantial cost savings due to high adherence. PMID:24711696

  18. Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain.

    PubMed

    Lazarczyk, Maciej J; Kemmler, Julia E; Eyford, Brett A; Short, Jennifer A; Varghese, Merina; Sowa, Allison; Dickstein, Daniel R; Yuk, Frank J; Puri, Rishi; Biron, Kaan E; Leist, Marcel; Jefferies, Wilfred A; Dickstein, Dara L

    2016-01-01

    Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity, and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density, and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function. PMID:27229916

  19. Localisation of deformations of the midfacial complex in subjects with class III malocclusions employing thin-plate spline analysis

    PubMed Central

    SINGH, G. D.; McNAMARA JR, J. A.; LOZANOFF, S.

    1997-01-01

    This study determines deformations of the midface that contribute to a class III appearance, employing thin-plate spline analysis. A total of 135 lateral cephalographs of prepubertal children of European-American descent with either class III malocclusions or a class I molar occlusion were compared. The cephalographs were traced and checked, and 7 homologous landmarks of the midface were identified and digitised. The data sets were scaled to an equivalent size and subjected to Procrustes analysis. These statistical tests indicated significant differences (P<0.05) between the averaged class I and class III morphologies. Thin-plate spline analysis indicated that both affine and nonaffine transformations contribute towards the total spline for the averaged midfacial configuration. For nonaffine transformations, partial warp 3 had the highest magnitude, indicating the large scale deformations of the midfacial configuration. These deformations affected the palatal landmarks, and were associated with compression of the midfacial complex in the anteroposterior plane predominantly. Partial warp 4 produced some vertical compression of the posterior aspect of the midfacial complex whereas partial warps 1 and 2 indicated localised shape changes of the maxillary alveolus region. Large spatial-scale deformations therefore affect the midfacial complex in an anteroposterior axis, in combination with vertical compression and localised distortions. These deformations may represent a developmental diminution of the palatal complex anteroposteriorly that, allied with vertical shortening of midfacial height posteriorly, results in class III malocclusions with a retrusive midfacial profile. PMID:9449078

  20. Multimodal representation contributes to the complex development of science literacy in a college biology class

    NASA Astrophysics Data System (ADS)

    Bennett, William Drew

    educators are communicating ideas and concepts to their audience with more than simple text. A focused holistic rubric was designed in this study to score how well students in this class were able to incorporate aspects of multimodality into their writing assignments. Using these scores and factors within the rubric (ex. Number of original modes created) they were correlated with classroom performance scores to determine the strength and direction of the relationship. Classroom observations of lectures and discussion sections along with personal interviews with students and teaching assistants aided the interpretation of the results. The results from the study were surprisingly complex to interpret given the background of literature which suggested a strong relationship between multimodal representations and science learning (Lemke, 2000). There were significant positive correlations between student multimodal representations and quiz scores but not exam scores. This study was also confounded by significant differences between sections at the beginning of the study which may have led to learning effects later. The dissimilarity between the tasks of writing during their homework and working on exams may be the reason for no significant correlations with exams. The power to interpret these results was limited by the number of the participants, the number of modal experiences by the students, and the operationalization of multimodal knowledge through the holistic rubric. These results do show that a relationship does exist between the similar tasks within science writing and quizzes. Students may also gain derived science literacy benefits from modal experiences on distal tasks in exams as well. This study shows that there is still much more research to be known about the interconnectedness of multimodal representational knowledge and use to the development of science literacy.

  1. A versatile class of prototype dynamical systems for complex bifurcation cascades of limit cycles

    PubMed Central

    Sándor, Bulcsú; Gros, Claudius

    2015-01-01

    A general class of prototype dynamical systems is introduced, which allows to study the generation of complex bifurcation cascades of limit cycles, including bifurcations breaking spontaneously a symmetry of the system, period doubling and homoclinic bifurcations, and transitions to chaos induced by sequences of limit cycle bifurcations. The prototype systems are adaptive, with friction forces f(V(x)) being functionally dependent exclusively on the mechanical potential V(x), characterized in turn by a finite number of local minima. We discuss several low-dimensional systems, with friction forces f(V) which are linear, quadratic or cubic polynomials in the potential V. We point out that the zeros of f(V) regulate both the relative importance of energy uptake and dissipation respectively, serving at the same time as bifurcation parameters, hence allowing for an intuitive interpretation of the overall dynamical behavior. Starting from simple Hopf- and homoclinic bifurcations, complex sequences of limit cycle bifurcations are observed when the energy uptake gains progressively in importance. PMID:26198731

  2. Engagement of major histocompatibility complex class I and class II molecules up-regulates intercellular adhesion of human B cells via a CD11/CD18-independent mechanism.

    PubMed

    Alcover, A; Juillard, V; Acuto, O

    1992-02-01

    We have studied the role of major histocompatibility complex (MHC) molecules in the regulation of intercellular adhesion of human B cells. We found that molecules able to bind to MHC class II molecules, such as monoclonal antibodies or staphylococcal enterotoxins, induced rapid and sustained homotypic adhesion of Epstein-Barr virus (EBV)-transformed B cell lines as well as peripheral blood B lymphocytes. Moreover, anti-MHC class I monoclonal antibodies also stimulated intercellular adherence. Adhesion induced upon MHC engagement was faster and stronger than that triggered by phorbol esters. It needed active metabolism, but divalent cations were not required. Monoclonal antibodies directed against LFA-1 (CD11a/CD18) or its ligand ICAM-1 (CD54) did not inhibit MHC class II-induced homotypic adhesion of various EBV-transformed B cell lines, nor of a variant of the B cell line Raji expressing very low LFA-1 surface levels. Moreover, EBV-transformed B cells from a severe lymphocyte adhesion deficiency patient, lacking surface CD11/CD18, also aggregated in response to anti-MHC class I or class II monoclonal antibodies. Together these data indicate that engagement of MHC molecules may transduce signals to B cells resulting in up-regulation of intercellular adhesion, via an LFA-1-independent mechanism. This may play a role in the stabilization of T cell/antigen-presenting cell conjugates at the moment of antigen recognition.

  3. Class 1 integrons and antibiotic resistance of clinical Acinetobacter calcoaceticus-baumannii complex in Poznań, Poland.

    PubMed

    Koczura, Ryszard; Przyszlakowska, Beata; Mokracka, Joanna; Kaznowski, Adam

    2014-09-01

    Sixty-three clinical isolates of Acinetobacter calcoaceticus-baumannii complex were analyzed for the presence of integrons and antimicrobial resistance. Class 1 integrons were detected in 40 (63.5 %) isolates. None of them had class 2 or class 3 integrons. The majority of the integrons contained aacC1-orfA-orfB-aadA1 gene cassette array. The presence of integrons was associated with the increased frequency of resistance to 12 of 15 antimicrobials tested, multi-drug resistance phenotype, and the overall resistance ranges of the strains.

  4. Structures of Staphylococcus aureus peptide deformylase in complex with two classes of new inhibitors.

    PubMed

    Lee, Sang Jae; Lee, Seung-Jae; Lee, Seung Kyu; Yoon, Hye-Jin; Lee, Hyung Ho; Kim, Kyeong Kyu; Lee, Bong Jin; Lee, Byung Il; Suh, Se Won

    2012-07-01

    Peptide deformylase (PDF) catalyzes the removal of the formyl group from the N-terminal methionine residue in newly synthesized polypeptides, which is an essential process in bacteria. Four new inhibitors of PDF that belong to two different classes, hydroxamate/pseudopeptide compounds [PMT387 (7a) and PMT497] and reverse-hydroxamate/nonpeptide compounds [PMT1039 (15e) and PMT1067], have been developed. These compounds inhibited the growth of several pathogens involved in respiratory-tract infections, such as Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, and leading nosocomial pathogens such as Staphylococcus aureus and Klebsiella pneumoniae with a minimum inhibitory concentration (MIC) in the range 0.1-0.8 mg ml(-1). Interestingly, the reverse-hydroxamate/nonpeptide compounds showed a 250-fold higher antimicrobial activity towards S. aureus, although the four compounds showed similar K(i) values against S. aureus PDF enzymes, with K(i) values in the 11-85 nM range. To provide a structural basis for the discovery of additional PDF inhibitors, the crystal structures of S. aureus PDF in complex with the four inhibitors were determined at resolutions of 1.90-2.30 Å. The inhibitor-bound structures displayed distinct deviations depending on the inhibitor class. The distance between the Zn(2+) ion and the carbonyl O atom of the hydroxamate inhibitors (or the hydroxyl O atom of the reverse-hydroxamate inhibitors) appears to be correlated to S. aureus inhibition activity. The structural information reported in this study should aid in the discovery of new PDF inhibitors that can be used as novel antibacterial drugs. PMID:22751663

  5. Specificity of CTL interactions with peptide-MHC class I tetrameric complexes is temperature dependent.

    PubMed

    Whelan, J A; Dunbar, P R; Price, D A; Purbhoo, M A; Lechner, F; Ogg, G S; Griffiths, G; Phillips, R E; Cerundolo, V; Sewell, A K

    1999-10-15

    Tetrameric peptide-MHC class I complexes ("tetramers") are proving invaluable as reagents for characterizing immune responses involving CTLs. However, because the TCR can exhibit a degree of promiscuity for binding peptide-MHC class I ligands, there is potential for cross-reactivity. Recent reports showing that the TCR/peptide-MHC interaction is dramatically dependent upon temperature led us to investigate the effects of incubation temperature on tetramer staining. We find that tetramers rapidly stain CTLs with high intensity at 37 degrees C. We examine the fine specificity of tetramer staining using a well-characterized set of natural epitope variants. Peptide variants that elicit little or no functional cellular response from CTLs can stain these cells at 4 degrees C but not at 37 degrees C when incorporated into tetramers. These results suggest that some studies reporting tetramer incubations at 4 degrees C could detect cross-reactive populations of CTLs with minimal avidity for the tetramer peptide, especially in the tetramer-low population. For identifying specific CTLs among polyclonal cell populations such as PBLs, incubation with tetramers at 37 degrees C improves the staining intensity of specific CTLs, resulting in improved separation of tetramer-high CD8+ cells. Confocal microscopy reveals that tetramers incubated at 37 degrees C can be rapidly internalized by specific CTLs into vesicles that overlap with the early endocytic compartment. This TCR-specific internalization suggests that coupling of tetramers or analogues with toxins, which are activated only after receptor internalization, may create immunotoxins capable of killing CTLs of single specificities.

  6. Cooperativity between the J and S elements of class II major histocompatibility complex genes as enhancers in normal and class II- negative patient and mutant B cell lines

    PubMed Central

    1995-01-01

    The class II major histocompatibility complex genes all contain in their proximal promoters three cis-elements called S, X, and Y that are conserved in both sequence and position, and a fourth element, J, conserved in sequence but not in position. J, X, and Y and, to some extent, S, have been shown to be functionally important in regulation of expression of these genes. In the present study, a protein factor that binds cooperatively to the S plus J elements of the promoter of the class II major histocompatibility complex gene DPA has been detected. Moreover, functional cooperativity between S and J in activation of the enhancerless -40 interferon-beta (-40 IFN-beta) promoter has been demonstrated. Finally, the latter assay appears to subdivide complementation group A of class II negative human B cell lines that includes both mutants generated in vitro and cells from patients with the bare lymphocyte syndrome (type II). In three of these cell lines, the enhancerless -40 IFN-beta promoter containing the S plus J elements was functionally active, while in the others it was inactive. PMID:7790817

  7. Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris

    SciTech Connect

    Ahmed, A.R. Center for Blood Research, Boston, MA American Red Cross Blood Services-Northeast Region, Dedham, MA ); Wagner, R.; Khatri, K.; Notani, G.; Awdeh, Z.; Alper, C.A. ); Yunis, E.J. American Red Cross Blood Services-Northeast Region, Dedham, MA )

    1991-06-01

    Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype (HLA-B38, SC21, DR4, DQw8) or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) halotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 amd has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8-or the DRw14, DQw5-linked susceptibility genes.

  8. Complex relationship between mismatch repair proteins and MBD4 during immunoglobulin class switch recombination.

    PubMed

    Grigera, Fernando; Bellacosa, Alfonso; Kenter, Amy L

    2013-01-01

    Mismatch repair (MMR) safeguards against genomic instability and is required for efficient Ig class switch recombination (CSR). Methyl CpG binding domain protein 4 (MBD4) binds to MutL homologue 1 (MLH1) and controls the post-transcriptional level of several MMR proteins, including MutS homologue 2 (MSH2). We show that in WT B cells activated for CSR, MBD4 is induced and interacts with MMR proteins, thereby implying a role for MBD4 in CSR. However, CSR is in the normal range in Mbd4 deficient mice deleted for exons 2-5 despite concomitant reduction of MSH2. We show by comparison in Msh2(+/-) B cells that a two-fold reduction of MSH2 and MBD4 proteins is correlated with impaired CSR. It is therefore surprising that CSR occurs at normal frequencies in the Mbd4 deficient B cells where MSH2 is reduced. We find that a variant Mbd4 transcript spanning exons 1,6-8 is expressed in Mbd4 deficient B cells. This transcript can be ectopically expressed and produces a truncated MBD4 peptide. Thus, the 3' end of the Mbd4 locus is not silent in Mbd4 deficient B cells and may contribute to CSR. Our findings highlight a complex relationship between MBD4 and MMR proteins in B cells and a potential reconsideration of their role in CSR.

  9. Regulation of major histocompatibility complex class II synthesis by interleukin-10

    PubMed Central

    Morel, Anne-Sophie; Coulton, Gary; Londei, Marco

    2002-01-01

    We have shown previously that interleukin-10 (IL-10) blocks the development and T-cell stimulatory capacity of human monocyte-derived dendritic cells, without apparently down-regulating the surface expression of co-stimulatory molecules or human leucocyte antigen (HLA) molecules. In the majority of donors (60%), the cell surface levels of HLA-DR actually increased upon IL-10 treatment. Here we have shown that IL-10 does not regulate HLA-DR transcription as assessed by polymerase chain reation. Epifluorescence microscopy analysis showed that IL-10 primarily increased the intracellular pool of HLA-DR. In fact, IL-10 directly increased HLA-DR protein synthesis. However, IL-10 did not significantly alter the synthesis of invariant chain (Ii), which plays a crucial role in the assembly, transport and loading of newly formed HLA class II molecules, nor the amount of Ii reaching the cell-surface. In contrast, IL-10 increased the amount of HLA-DR-bound Iip33 shortly after the HLA-DR complex assembly. We postulate that, upon IL-10 treatment, immature Ii-associated HLA II molecules can still transit to the cell surface as they do in immature dendritic cells and recycle to the intracellular space, where they accumulate. A higher proportion of Ii-associated HLA-DR, coupled to increased membrane recycling, may contribute to the lower T-cell stimulatory capacity of IL-10-treated dendritic cells. PMID:12047752

  10. Effects of major histocompatibility complex class II knockout on mouse bone mechanical properties during development

    NASA Technical Reports Server (NTRS)

    Simske, Steven J.; Bateman, Ted A.; Smith, Erin E.; Ferguson, Virginia L.; Chapes, Stephen K.

    2002-01-01

    We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls.

  11. Yeast surface display of a noncovalent MHC class II heterodimer complexed with antigenic peptide.

    PubMed

    Boder, Eric T; Bill, Jerome R; Nields, Andrew W; Marrack, Philippa C; Kappler, John W

    2005-11-20

    Microbial protein display technologies have enabled directed molecular evolution of binding and stability properties in numerous protein systems. In particular, dramatic improvements to antibody binding affinity and kinetics have been accomplished using these tools in recent years. Examples of successful application of display technologies to other immunological proteins have been limited to date. Herein, we describe the expression of human class II major histocompatibility complex allele (MHCII) HLA-DR4 on the surface of Saccharomyces cerevisiae as a noncovalently associated heterodimer. The yeast-displayed MHCII is fully native as assessed by binding of conformationally specific monoclonal antibodies; failure of antibodies specific for empty HLA-DR4 to bind yeast-displayed protein indicates antigenic peptide is bound. This report represents the first example of a noncovalent protein dimer displayed on yeast and of successful display of wild-type MHCII. Results further point to the potential for using yeast surface display for engineering and analyzing the antigen binding properties of MHCII.

  12. Persistent Ehrlichia chaffeensis infection occurs in the absence of functional major histocompatibility complex class II genes

    NASA Technical Reports Server (NTRS)

    Ganta, Roman Reddy; Wilkerson, Melinda J.; Cheng, Chuanmin; Rokey, Aaron M.; Chapes, Stephen K.

    2002-01-01

    Human monocytic ehrlichiosis is an emerging tick-borne disease caused by the rickettsia Ehrlichia chaffeensis. We investigated the impact of two genes that control macrophage and T-cell function on murine resistance to E. chaffeensis. Congenic pairs of wild-type and toll-like receptor 4 (tlr4)- or major histocompatibility complex class II (MHC-II)-deficient mice were used for these studies. Wild-type mice cleared the infection within 2 weeks, and the response included macrophage activation and the synthesis of E. chaffeensis-specific Th1-type immunoglobulin G response. The absence of a functional tlr4 gene depressed nitric oxide and interleukin 6 secretion by macrophages and resulted in short-term persistent infections for > or =30 days. In the absence of MHC-II alleles, E. chaffeensis infections persisted throughout the entire 3-month evaluation period. Together, these data suggest that macrophage activation and cell-mediated immunity, orchestrated by CD4(+) T cells, are critical for conferring resistance to E. chaffeensis.

  13. Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity.

    PubMed Central

    Fu, Y; Nathan, D M; Li, F; Li, X; Faustman, D L

    1993-01-01

    Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patients with IDDM, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosis, rheumatoid arthritis, and Sjogren's syndrome. Nondiabetic and non-insulin-dependent diabetes mellitus patients served as controls. MHC class I expression was measured with a conformationally dependent monoclonal antibody, W6/32. Freshly prepared PBLs from the autoimmune diseases studied and the corresponding fresh EBV-transformed B cell lines had decreased MHC class I expression compared with PBLs from normal volunteers and non-insulin-dependent (nonautoimmune) diabetic patients. Only 3 of more than 180 donors without IDDM or other clinically recognized autoimmune disease had persistently decreased MHC class I expression; one patient was treated with immunosuppressive drugs, and subsequent screening of the other two patients revealed high titers of autoantibodies, revealing clinically occult autoimmunity. Patients with nonautoimmune inflammation (osteomyelitis or tuberculosis) had normal MHC class I expression. Autoimmune diseases are characterized by decreased expression of MHC class I on lymphocytes. MHC class I expression may be necessary for self-tolerance, and abnormalities in such expression may lead to autoimmunity. PMID:8486790

  14. Genetic polymorphism of the swine major histocompatibility complex ( SLA) class I genes, SLA-1, -2 and -3.

    PubMed

    Ando, Asako; Kawata, Hisako; Shigenari, Atsuko; Anzai, Tatsuya; Ota, Masao; Katsuyama, Yoshihiko; Sada, Masaharu; Goto, Rieko; Takeshima, Shin-Nosuke; Aida, Yoko; Iwanaga, Takahiro; Fujimura, Nobuyuki; Suzuki, Yoshiyuki; Gojobori, Takashi; Inoko, Hidetoshi

    2003-12-01

    In order to identify and characterize genetic polymorphism of the swine major histocompatibility complex ( Mhc: SLA) class I genes, RT-PCR products of the second and third exons of the three SLA classical class I genes, SLA-1, SLA-2 and SLA-3 were subjected to nucleotide determination. These analyses allowed the identification of four, eight and seven alleles at the SLA-1, SLA-2 and SLA-3 loci, respectively, from three different breeds of miniature swine and one mixed breed. Among them, 12 alleles were novel. Construction of a phylogenetic tree using the nucleotide sequences of those 19 alleles indicated that the SLA-1 and -2 genes are more closely related to each other than to SLA-3. Selective forces operating at single amino acid sites of the SLA class I molecules were analyzed by the Adaptsite Package program. Ten positive selection sites were found at the putative antigen recognition sites (ARSs). Among the 14 positively selected sites observed in the human MHC ( HLA) classical class I molecules, eight corresponding positions in the SLA class I molecules were inferred as positively selected. On the other hand, four amino acids at the putative ARSs were identified as negatively selected in the SLA class I molecules. These results suggest that selective forces operating in the SLA class I molecules are almost similar to those of the HLA class I molecules, although several functional sites for antigen and cytotoxic T-lymphocyte recognition by the SLA class I molecules may be different from those of the HLA class I molecules.

  15. Distribution and origin of bovine major histocompatibility complex class II DQA1 genes in Japan.

    PubMed

    Takeshima, S; Chen, S; Miki, M; Kado, M; Aida, Y

    2008-09-01

    We sequenced the major histocompatibility complex (MHC) class II DQA1 gene in 352 Japanese cattle (95 Japanese Black, 91 Holstein, 102 Japanese Shorthorn and 64 Jersey cattle) using a new sequence-based typing method. In total, 19 bovine MHC (BoLA)-DQA1 alleles, of which two were novel alleles, were detected. The Holstein, Jersey, Japanese Shorthorn and Japanese Black breeds had 13, 12, 10 and 15 alleles, respectively. The dendrogram that was constructed by the neighbor-joining method on the basis of the DQA1 gene allele frequencies of the four Japanese cattle breeds showed that the Holstein and Japanese Black breeds were closest to each other, with Jersey being farther from these two breeds than Japanese Shorthorn. In addition, Wu-Kabat analysis showed that the DQA1 alleles of the Holstein and Japanese Black were the most and least polymorphic, respectively. Phylogenetic analyses indicated that the DQA1 gene of Bovidae such as cattle, sheep, bison and goat were more similar to pig SLA-DQA genes than to human HLA-DQA1 and dog DLA-DQA genes. The cattle, goat, bison, sheep, human and pig DQA1 molecules had similar rates of amino acid sequence polymorphism, but the distribution of their polymorphic residues differed from that in the dog DQA1 protein. However, the Bovidae DQA1 molecule had more polymorphic residues than the human, pig and dog DQA molecules at two regions, namely positions 52-53 and 65-66. This indicates that the Bovidae DQA1 locus is more polymorphic than the DQA loci of other species.

  16. Species specificity and augmentation of responses to class II major histocompatibility complex molecules in human CD4 transgenic mice

    PubMed Central

    1992-01-01

    Murine T cell responses to human class II major histocompatibility complex (MHC) molecules were shown to be a minimum of 20-70-fold lower than responses to allogeneic molecules. Transgenic mice expressing slightly below normal (75-95%) or very high (250-380%) cell surface levels of human CD4 were utilized to determine whether this was due to a species-specific interaction between murine CD4 and class II molecules. Human CD4 was shown to function in signal transduction events in murine T cells based on the ability of anti-human CD4 antibody to synergize with suboptimal doses of anti-murine CD3 antibody in stimulating T cell proliferation. In mice expressing lower levels of human CD4, T cell responses to human class II molecules were enhanced up to threefold, whereas allogeneic responses were unaltered. In mice expressing high levels of human CD4, responses to human class II molecules were enhanced at least 10-fold, whereas allogeneic responses were between one and three times the level of normal responses. The relatively greater enhancement of the response to human class II molecules in both lines argues for a preferential interaction between human CD4 and human class II molecules. In mice expressing lower levels of human CD4, responses to human class II molecules were blocked by antibodies to CD4 of either species, indicating participation by both molecules. In mice expressing high levels of human CD4, responses to both human and murine class II molecules were almost completely blocked with anti-human CD4 antibody, whereas anti-murine CD4 antibody had no effect. However, anti-murine CD4 continued to synergize with anti-CD3 in stimulating T cell proliferation in these mice. Thus, overexpression of human CD4 selectively impaired the ability of murine CD4 to assist in the process of antigen recognition. The ability of human CD4 to support a strong allogeneic response under these conditions indicates that this molecule can interact with murine class II molecules to a

  17. Multimodal Representation Contributes to the Complex Development of Science Literacy in a College Biology Class

    ERIC Educational Resources Information Center

    Bennett, William Drew

    2011-01-01

    This study is an investigation into the science literacy of college genetics students who were given a modified curriculum to address specific teaching and learning problems from a previous class. This study arose out of an interest by the professor and researcher to determine how well students in the class Human Genetics in the 21st Century…

  18. Disruption of hydrogen bonds between major histocompatibility complex class II and the peptide N-terminus is not sufficient to form a human leukocyte antigen-DM receptive state of major histocompatibility complex class II.

    PubMed

    Schulze, Monika-Sarah E D; Anders, Anne-Kathrin; Sethi, Dhruv K; Call, Melissa J

    2013-01-01

    Peptide presentation by MHC class II is of critical importance to the function of CD4+ T cells. HLA-DM resides in the endosomal pathway and edits the peptide repertoire of newly synthesized MHC class II molecules before they are exported to the cell surface. HLA-DM ensures MHC class II molecules bind high affinity peptides by targeting unstable MHC class II:peptide complexes for peptide exchange. Research over the past decade has implicated the peptide N-terminus in modulating the ability of HLA-DM to target a given MHC class II:peptide combination. In particular, attention has been focused on both the hydrogen bonds between MHC class II and peptide, and the occupancy of the P1 anchor pocket. We sought to solve the crystal structure of a HLA-DR1 molecule containing a truncated hemagglutinin peptide missing three N-terminal residues compared to the full-length sequence (residues 306-318) to determine the nature of the MHC class II:peptide species that binds HLA-DM. Here we present structural evidence that HLA-DR1 that is loaded with a peptide truncated to the P1 anchor residue such that it cannot make select hydrogen bonds with the peptide N-terminus, adopts the same conformation as molecules loaded with full-length peptide. HLA-DR1:peptide combinations that were unable to engage up to four key hydrogen bonds were also unable to bind HLA-DM, while those truncated to the P2 residue bound well. These results indicate that the conformational changes in MHC class II molecules that are recognized by HLA-DM occur after disengagement of the P1 anchor residue.

  19. Aldehyde-mannan antigen complexes target the MHC class I antigen-presentation pathway.

    PubMed

    Apostolopoulos, V; Pietersz, G A; Gordon, S; Martinez-Pomares, L; McKenzie, I F

    2000-06-01

    Antigens such as MUC1 coupled to oxidized mannan lead to rapid and efficient MHC class I presentation to CD8+ cells and a preferential T1 response; after reduction there is class II presentation and a T2 immune response. We now show that the selective advantage of the oxidized mannan-MUC1 is due to the presence of aldehydes and not Schiff bases, and that oxidized mannan-MUC1 binds to the mannose and not scavenger receptors and is internalized and presented by MHC class I molecules 1,000 times more efficiently than when reduced. After internalization there is rapid access to the class I pathway via endosomes but not lysosomes, proteasomal processing and transport to the endoplasmic reticulum, Golgi apparatus and cell surface. Aldehydes cause rapid entry into the class I pathway, and can therefore direct the subsequent immune response.

  20. The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem

    SciTech Connect

    Schneider, Kyle D.; Karpen, Mary E.; Bonomo, Robert A.; Leonard, David A.; Powers, Rachel A.

    2010-01-12

    The clinical efficacy of carbapenem antibiotics depends on their resistance to the hydrolytic action of {beta}-lactamase enzymes. The structure of the class D {beta}-lactamase OXA-1 as an acyl complex with the carbapenem doripenem was determined to 1.4 {angstrom} resolution. Unlike most class A and class C carbapenem complexes, the acyl carbonyl oxygen in the OXA-1-doripenem complex is bound in the oxyanion hole. Interestingly, no water molecules were observed in the vicinity of the acyl linkage, providing an explanation for why carbapenems inhibit OXA-1. The side chain amine of K70 remains fully carboxylated in the acyl structure, and the resulting carbamate group forms a hydrogen bond to the alcohol of the 6{alpha}-hydroxyethyl moiety of doripenem. The carboxylate attached to the {beta}-lactam ring of doripenem is stabilized by a salt bridge to K212 and a hydrogen bond with T213, in lieu of the interaction with an arginine side chain found in most other {beta}-lactamase-{beta}-lactam complexes (e.g., R244 in the class A member TEM-1). This novel set of interactions with the carboxylate results in a major shift of the carbapenem's pyrroline ring compared to the structure of the same ring in meropenem bound to OXA-13. Additionally, bond angles of the pyrroline ring suggest that after acylation, doripenem adopts the {Delta}{sup 1} tautomer. These findings provide important insights into the role that carbapenems may have in the inactivation process of class D {beta}-lactamases.

  1. Identification of the class I genes of the mouse major histocompatibility complex by DNA-mediated gene transfer.

    PubMed

    Goodenow, R S; McMillan, M; Nicolson, M; Sher, B T; Eakle, K; Davidson, N; Hood, L

    1982-11-18

    DNA-mediated gene transfer was used to identify cloned class I genes from the major histocompatibility complex of the BALB/c mouse. Three genes encoding the transplantation antigens H-2 Kd, Dd and Ld were identified as well as genes encoding the Qa-2,3 and two TL differentiation antigens. As many as 10 putative novel class I genes were detected by the association of their gene products with beta 2-microglobulin. Alloantiserum prepared to one of the novel antigens was used to demonstrate the expression of the previously undetected antigen on spleen cells of various inbred, congeneic, and recombinant congeneic strains of mice. PMID:6815535

  2. Crystal structures of an archaeal class II DNA photolyase and its complex with UV-damaged duplex DNA

    PubMed Central

    Kiontke, Stephan; Geisselbrecht, Yann; Pokorny, Richard; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver

    2011-01-01

    Class II photolyases ubiquitously occur in plants, animals, prokaryotes and some viruses. Like the distantly related microbial class I photolyases, these enzymes repair UV-induced cyclobutane pyrimidine dimer (CPD) lesions within duplex DNA using blue/near-UV light. Methanosarcina mazei Mm0852 is a class II photolyase of the archaeal order of Methanosarcinales, and is closely related to plant and metazoan counterparts. Mm0852 catalyses light-driven DNA repair and photoreduction, but in contrast to class I enzymes lacks a high degree of binding discrimination between UV-damaged and intact duplex DNA. We solved crystal structures of Mm0852, the first one for a class II photolyase, alone and in complex with CPD lesion-containing duplex DNA. The lesion-binding mode differs from other photolyases by a larger DNA-binding site, and an unrepaired CPD lesion is found flipped into the active site and recognized by a cluster of five water molecules next to the bound 3′-thymine base. Different from other members of the photolyase-cryptochrome family, class II photolyases appear to utilize an unusual, conserved tryptophane dyad as electron transfer pathway to the catalytic FAD cofactor. PMID:21892138

  3. Crystal structures of an archaeal class II DNA photolyase and its complex with UV-damaged duplex DNA.

    PubMed

    Kiontke, Stephan; Geisselbrecht, Yann; Pokorny, Richard; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver

    2011-11-01

    Class II photolyases ubiquitously occur in plants, animals, prokaryotes and some viruses. Like the distantly related microbial class I photolyases, these enzymes repair UV-induced cyclobutane pyrimidine dimer (CPD) lesions within duplex DNA using blue/near-UV light. Methanosarcina mazei Mm0852 is a class II photolyase of the archaeal order of Methanosarcinales, and is closely related to plant and metazoan counterparts. Mm0852 catalyses light-driven DNA repair and photoreduction, but in contrast to class I enzymes lacks a high degree of binding discrimination between UV-damaged and intact duplex DNA. We solved crystal structures of Mm0852, the first one for a class II photolyase, alone and in complex with CPD lesion-containing duplex DNA. The lesion-binding mode differs from other photolyases by a larger DNA-binding site, and an unrepaired CPD lesion is found flipped into the active site and recognized by a cluster of five water molecules next to the bound 3'-thymine base. Different from other members of the photolyase-cryptochrome family, class II photolyases appear to utilize an unusual, conserved tryptophane dyad as electron transfer pathway to the catalytic FAD cofactor. PMID:21892138

  4. Determinant selection of major histocompatibility complex class I- restricted antigenic peptides is explained by class I-peptide affinity and is strongly influenced by nondominant anchor residues

    PubMed Central

    1994-01-01

    The contribution of major histocompatibility complex (MHC) class I- peptide affinity to immunodominance of particular peptide antigens (Ags) in the class I-restricted cytotoxic T lymphocyte (CTL) response is not clearly established. Therefore, we have compared the H-2Kb- restricted binding and presentation of the immunodominant ovalbumin (OVA)257-264 (SIINFEKL) determinant to that of a subdominant OVA determinant OVA55-62 (KVVRFDKL). Immunodominance of OVA257-264 was not attributable to the specific T cell repertoire but correlated instead with more efficient Ag presentation. This enhanced Ag presentation could be accounted for by the higher affinity of Kb/OVA257-264 compared with Kb/OVA55-62 despite the presence of a conserved Kb-binding motif in both peptides. Kinetic binding studies using purified soluble H-2Kb molecules (Kbs) and biosensor techniques indicated that the Kon for association of OVA257-264-C6 and Kbs at 25 degrees C was integral of 10- fold faster (5.9 x 10(3) M-1 s-1 versus 6.5 x 10(2) M-1 s-1), and the Koff approximately twofold slower (9.1 x 10(-6) s-1 versus 1.6 x 10(-5) s-1), than the rate constants for interaction of OVA55-62-C6 and Kbs. The association of these peptides with Kb was significantly influenced by multiple residues at presumed nonanchor sites within the peptide sequence. The contribution of each peptide residue to Kb-binding was dependent upon the sequence context and the summed contributions were not additive. Thus the affinity of MHC class I-peptide binding is a critical factor controlling presentation of peptide Ag and immunodominance in the class I-restricted CTL response. PMID:7523572

  5. Molecular identification, polymorphism, and expression analysis of major histocompatibility complex class IIA and B genes of turbot (Scophthalmus maximus).

    PubMed

    Zhang, Yu-Xi; Chen, Song-Lin

    2006-01-01

    Major histocompatibility complex (MHC) class II has a central role in the adaptive immune system by presenting foreign peptides to the T-cell receptor. The full lengths of MHC class II A and B cDNA were cloned from turbot by homology cloning and rapid amplification of cDNA ends polymerase chain reaction (RACE PCR), and genomic organization, molecular polymorphism, and expression of turbot class IIB gene were examined to study the function of class IIB gene in fish. The deduced amino acid sequence of turbot class II A (GenBank accession no.DQ001730) and turbot class IIB (GenBank accession no. DQ094170) had 69.8%, 67.6%, 65.5%, 59.2%, 54.5%, 52.8%, 46.2%, 46.6%, 28.3%, 28.5%, 22.2% identity and 71.5%, 70.7%, 67.1%, 68.4%, 46.7%, 53.5%, 46.7%, 50.0%, 25.2%, 29.2%, 27.6% identity with those of Japanese flounder, striped sea bass, red sea bream, cichlid, rainbow trout, Atlantic salmon, carp, zebrafish, nurse shark, mouse and human, respectively. Eleven class IIB alleles were identified from three turbot individuals. The amino acid sequence of turbot class IIB designated as Scma-DAB*0101 had 86.9%, 88.6%, 88.6%, 89.4%, 87.8%, 86.9%, 84.1%, 86.5%, 87.3%, 77.1%, and 86.9% identity with those of turbot class IIB 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (Scma-DAB*0201- Scma-DAB*1201), respectively. Six different class IIB alleles observed in a single individual may infer the existence of three loci at least. Semiquantitative reverse transcriptase PCR (RT-PCR) demonstrated that turbot class IIA and B were ubiquitously expressed in normal tissues. Challenge of turbot with pathogenic bacteria, Vibrio anguillarum, resulted in a significant decrease in the expression of MHC class IIB mRNA from 24 h to 48 h after infection in liver and head kidney, and a significant decrease from 24 h to 72 h after infection in spleen, followed by an increase after 96 h, respectively.

  6. The lectin Siglec-G inhibits dendritic cell cross-presentation by impairing MHC class I-peptide complex formation.

    PubMed

    Ding, Yuanyuan; Guo, Zhenhong; Liu, Yiqi; Li, Xia; Zhang, Qian; Xu, Xiongfei; Gu, Yan; Zhang, Yi; Zhao, Dezhi; Cao, Xuetao

    2016-10-01

    CD8α(+) dendritic cells (DCs) are specialized at cross-presenting extracellular antigens on major histocompatibility complex (MHC) class I molecules to initiate cytotoxic T lymphocyte (CTL) responses; however, details of the mechanisms that regulate cross-presentation remain unknown. We found lower expression of the lectin family member Siglec-G in CD8α(+) DCs, and Siglec-G deficient (Siglecg(-/-)) mice generated more antigen-specific CTLs to inhibit intracellular bacterial infection and tumor growth. MHC class I-peptide complexes were more abundant on Siglecg(-/-) CD8α(+) DCs than on Siglecg(+/+) CD8α(+) DCs. Mechanistically, phagosome-expressed Siglec-G recruited the phosphatase SHP-1, which dephosphorylated the NADPH oxidase component p47(phox) and inhibited the activation of NOX2 on phagosomes. This resulted in excessive hydrolysis of exogenous antigens, which led to diminished formation of MHC class I-peptide complexes for cross-presentation. Therefore, Siglec-G inhibited DC cross-presentation by impairing such complex formation, and our results add insight into the regulation of cross-presentation in adaptive immunity. PMID:27548433

  7. Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.

    PubMed

    Harikumar, Kaleeckal G; Augustine, Mary Lou; Lee, Leo T O; Chow, Billy K C; Miller, Laurence J

    2016-08-12

    Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these cross-class complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor. PMID:27330080

  8. Zinc Induces Dimerization of the Class II Major Histocompatibility Complex Molecule That Leads to Cooperative Binding to a Superantigen

    SciTech Connect

    Li,H.; Zhao, Y.; Guo, Y.; Li, Z.; Eislele, L.; Mourad, W.

    2007-01-01

    Dimerization of class II major histocompatibility complex (MHC) plays an important role in the MHC biological function. Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing specific T cell receptor V{beta} elements. Here we have used structural, sedimentation, and surface plasmon resonance detection approaches to investigate the molecular interactions between MAM and the class II MHC molecule HLA-DR1 in the context of a hemagglutinin peptide-(306-318) (HA). Our results revealed that zinc ion can efficiently induce the dimerization of the HLA-DR1/HA complex. Because the crystal structure of the MAM/HLA-DR1/hemagglutinin complex in the presence of EDTA is nearly identical to the structure of the complex crystallized in the presence of zinc ion, Zn{sup 2+} is evidently not directly involved in the binding between MAM and HLA-DR1. Sedimentation and surface plasmon resonance studies further revealed that MAM binds the HLA-DR1/HA complex with high affinity in a 1:1 stoichiometry, in the absence of Zn{sup 2+}. However, in the presence of Zn{sup 2+}, a dimerized MAM/HLA-DR1/HA complex can arise through the Zn{sup 2+}-induced DR1 dimer. In the presence of Zn{sup 2+}, cooperative binding of MAM to the DR1 dimer was also observed.

  9. Boundary value problems for a class of planar complex vector fields

    NASA Astrophysics Data System (ADS)

    Campana, C.; Meziani, A.

    2016-11-01

    This paper deals with a Riemann-Hilbert problem and a Riemann problem for a class of planar elliptic vector fields with degeneracies. Existence of Hölder continuous solutions is established when the associated index is nonnegative.

  10. Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

    PubMed Central

    Ahmed, A R; Wagner, R; Khatri, K; Notani, G; Awdeh, Z; Alper, C A; Yunis, E J

    1991-01-01

    Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes. Images PMID:1675792

  11. Reassociation with beta 2-microglobulin is necessary for Db class I major histocompatibility complex binding of an exogenous influenza peptide.

    PubMed Central

    Rock, K L; Gamble, S; Rothstein, L; Benacerraf, B

    1991-01-01

    A synthetic peptide corresponding to residues 365-380 of the influenza nucleoprotein (NP365-380) has been previously shown to associate with class I major histocompatibility complex-encoded molecules and to stimulate cytotoxic T lymphocytes [Townsend, A. R. M., Rothbard, J., Gotch, F. M., Bahadur, G., Wraith, D. & McMichael, A. J. (1986) Cell 44, 959-968]. We find that intact Db class I heterodimers on the cell surface are unreceptive to binding this antigen. However, NP365-380 readily associates with Db molecules on the plasma membrane in the presence of exogenous beta 2-microglobulin. In addition, there is a second pathway through which this peptide associates with class I molecules that requires energy and de novo protein synthesis. These findings have implications for maintaining the immunological identity of cells and for the use of peptides as vaccines for priming cytolytic T-cell immunity. Images PMID:1986378

  12. Organization and evolution of D region class I genes in the mouse major histocompatibility complex

    PubMed Central

    1986-01-01

    Chromosome walking has been used to study the organization of the class I genes in the D and Qa regions of the MHC of the BALB/c mouse and in the D region of the AKR mouse. Five and eight class I genes are found in the D and Qa regions of the BALB/c mouse, respectively, while the AKR mouse contains only a single class I D region gene that has been identified by transfection as the Dk gene. Restriction map homologies and crosshybridization experiments suggest that the multiple class I genes in the D region of the BALB/c mouse have been generated by unequal crossing-over involving class I genes from the Qa region. The expanded D region of BALB/c and other H-2d haplotype mouse strains appears to be metastable, since evidence for gene contraction in the Dd region has been found in two mutant strains. Thus the D region and also the Qa region class I genes are in a dynamic state, evolving by gene expansion and contraction. PMID:3701254

  13. Coronavirus induction of class I major histocompatibility complex expression in murine astrocytes is virus strain specific

    PubMed Central

    1994-01-01

    Neurotropic strains of mouse hepatitis viruses (MHV) such as MHV-A59 (A59) and MHV-4 (JHMV) cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. They are widely used as models of human demyelinating diseases such as multiple sclerosis (MS), in which immune mechanisms are thought to participate in the development of lesions in the central nervous system (CNS). The effects of MHV infection on target cell functions in the CNS are not well understood, but A59 has been shown to induce the expression of MHC class I molecules in glial cells after in vivo and in vitro infection. Changes in class I expression in infected cells may contribute to the immunopathogenesis of MHV infection in the CNS. In this communication, a large panel of MHV strains was tested for their ability to stimulate class I expression in primary astrocytes in vitro. The data show that the more hepatotropic strains, such as MHV-A59, MHV-1, MHV-2, MHV-3, MHV-D, MHV-K, and MHV-NuU, were potent inducers of class I expression in astrocytes during acute infection, measured by radioimmunoassay. The Kb molecule was preferentially expressed over Db. By contrast, JHMV and several viral strains derived from it did not stimulate the expression of class I molecules. Assays of virus infectivity indicated that the class I-inducing activity did not correlate with the ability of the individual viral strain to replicate in astrocytes. However, exposure of the viruses or the supernatants from infected astrocytes to ultraviolet light abolished the class I-inducing activity, indicating that infectious virus is required for class I expression. These data also suggest that class I expression was induced directly by virus infection, and not by the secretion of a soluble substance into the medium by infected astrocytes. Finally, analyses of A59/JHMV recombinant viral strains suggest that class I-inducing activity resides in one of the A59 structural genes. PMID:8064222

  14. Transfer of cloned human class I major histocompatibility complex genes into HLA mutant human lymphoblastoid cells.

    PubMed Central

    Shimizu, Y; Koller, B; Geraghty, D; Orr, H; Shaw, S; Kavathas, P; DeMars, R

    1986-01-01

    Three new kinds of recombinant DNA constructs were used to transfer cloned human class I HLA genes (A2 and B8) into unique HLA mutant lymphoblastoid cells: pHeBo(x): a class I gene, "x," in plasmid vector pHeBo, which contains a hygromycin resistance gene and Epstein-Barr virus oriP element that sustains extrachromosomal replication; pHPT(x): gene x in a vector with a hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene; pHPTe(x): gene x in a vector with the HPRT gene and oriP element. Cell surface class I antigen expression was strong in transferents made with class I-deficient lymphoblastoid cell line mutants .144 (A-null), .53 (B-null), and .184 (A-null, B-null). Transferents expressing HLA-A2 were recognized specifically by HLA-A2-specific cytotoxic T lymphocytes. When introduced on either of the vectors with the Epstein-Barr virus oriP element, the class I gene replicated extrachromosomally and was lost at rates of 0.2 to 0.3 per cell division. When introduced with vector pHPT (lacking Epstein-Barr virus oriP), the B8 gene was inserted at different chromosomal locations. Introduction of the HLA-B8 gene failed to restore antigen expression by HLA-B-null mutant .174, providing evidence that, unlike mutants exemplified by .53, .144, and .184, some HLA antigen loss mutants are deficient in a trans-acting function needed for class I antigen expression. Of more general interest, the results obtained with HLA class I genes in vectors that replicate extrachromosomally suggest ways of relating genic expression to chromatin structure and function and of attempting to clone functional human centromeres. Images PMID:3023867

  15. Transfer of cloned human class I major histocompatibility complex genes into HLA mutant human lymphoblastoid cells.

    PubMed

    Shimizu, Y; Koller, B; Geraghty, D; Orr, H; Shaw, S; Kavathas, P; DeMars, R

    1986-04-01

    Three new kinds of recombinant DNA constructs were used to transfer cloned human class I HLA genes (A2 and B8) into unique HLA mutant lymphoblastoid cells: pHeBo(x): a class I gene, "x," in plasmid vector pHeBo, which contains a hygromycin resistance gene and Epstein-Barr virus oriP element that sustains extrachromosomal replication; pHPT(x): gene x in a vector with a hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene; pHPTe(x): gene x in a vector with the HPRT gene and oriP element. Cell surface class I antigen expression was strong in transferents made with class I-deficient lymphoblastoid cell line mutants .144 (A-null), .53 (B-null), and .184 (A-null, B-null). Transferents expressing HLA-A2 were recognized specifically by HLA-A2-specific cytotoxic T lymphocytes. When introduced on either of the vectors with the Epstein-Barr virus oriP element, the class I gene replicated extrachromosomally and was lost at rates of 0.2 to 0.3 per cell division. When introduced with vector pHPT (lacking Epstein-Barr virus oriP), the B8 gene was inserted at different chromosomal locations. Introduction of the HLA-B8 gene failed to restore antigen expression by HLA-B-null mutant .174, providing evidence that, unlike mutants exemplified by .53, .144, and .184, some HLA antigen loss mutants are deficient in a trans-acting function needed for class I antigen expression. Of more general interest, the results obtained with HLA class I genes in vectors that replicate extrachromosomally suggest ways of relating genic expression to chromatin structure and function and of attempting to clone functional human centromeres. PMID:3023867

  16. Organization and characteristics of the major histocompatibility complex class II region in the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis)

    PubMed Central

    Ruan, Rui; Ruan, Jue; Wan, Xiao-Ling; Zheng, Yang; Chen, Min-Min; Zheng, Jin-Song; Wang, Ding

    2016-01-01

    Little is known about the major histocompatibility complex (MHC) in the genome of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) (YFP) or other cetaceans. In this study, a high-quality YFP bacterial artificial chromosome (BAC) library was constructed. We then determined the organization and characterization of YFP MHC class II region by screening the BAC library, followed by sequencing and assembly of positive BAC clones. The YFP MHC class II region consists of two segregated contigs (218,725 bp and 328,435 bp respectively) that include only eight expressed MHC class II genes, three pseudo MHC genes and twelve non-MHC genes. The YFP has fewer MHC class II genes than ruminants, showing locus reduction in DRB, DQA, DQB, and loss of DY. In addition, phylogenic and evolutionary analyses indicated that the DRB, DQA and DQB genes might have undergone birth-and-death evolution, whereas the DQB gene might have evolved under positive selection in cetaceans. These findings provide an essential foundation for future work, such as estimating MHC genetic variation in the YFP or other cetaceans. This work is the first report on the MHC class II region in cetaceans and offers valuable information for understanding the evolution of MHC genome in cetaceans. PMID:26932528

  17. Characterization of major histocompatibility complex class I loci of the lark sparrow (Chondestes grammacus) and insights into avian MHC evolution.

    PubMed

    Lyons, Amanda C; Hoostal, Matthew J; Bouzat, Juan L

    2015-08-01

    The major histocompatibilty complex (MHC) has become increasingly important in the study of the immunocapabilities of non-model vertebrates due to its direct involvement in the immune response. The characterization of MHC class I loci in the lark sparrow (Chondestes grammacus) revealed multiple MHC class I loci with elevated genetic diversity at exon 3, evidence of differential selection between the peptide binding region (PBR) and non-PBR, and the presence of multiple pseudogenes with limited divergence. The minimum number of functional MHC class I loci was estimated at four. Sequence analysis revealed d N /d S ratios significantly less than one at non-PBR sites, indicative of negative selection, whereas PBR sites associated with antigen recognition showed ratios greater than 1 but non-significant. GenBank surveys and phylogenetic analyses of previously reported avian MHC class I sequences revealed variable signatures of evolutionary processes acting upon this gene family, including gene duplication and potential concerted evolution. An increase in the number of class I loci across species coincided with an increase in pseudogene prevalence, revealing the importance of gene duplication in the expansion of multigene families and the creation of pseudogenes.

  18. 'You were not born here, so you are classless, you are free!' Social class and cultural complex in analysis.

    PubMed

    Kiehl, Emilija

    2016-09-01

    The unconscious impact of differences in culture and social class is discussed from the perspective of an analyst practising in London whose 'foreign accent' prevents patients from placing her within the social stratifications by which they feel confined. Because she is seen by them as an analyst from both 'inside' and 'outside' the British psycho-social fabric and cultural complex, this opens a space in the transference that enables fuller exploration of the impact of the British social class system on patients' experience of themselves and their world. The paper considers this impact as a trans-generational trauma of living in a society of sharp socio-economic divisions based on material property. This is illustrated with the example of a patient who, at the point of moving towards the career to which he aspired, was unable to separate a sense of personal identity from the social class he so desperately wanted to leave behind and walk the long avenue of individuation. The dearth of literature on the subject of class is considered, and the paper concludes that not enough attention is given to class identification in training. PMID:27530168

  19. Organization and characteristics of the major histocompatibility complex class II region in the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis).

    PubMed

    Ruan, Rui; Ruan, Jue; Wan, Xiao-Ling; Zheng, Yang; Chen, Min-Min; Zheng, Jin-Song; Wang, Ding

    2016-01-01

    Little is known about the major histocompatibility complex (MHC) in the genome of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) (YFP) or other cetaceans. In this study, a high-quality YFP bacterial artificial chromosome (BAC) library was constructed. We then determined the organization and characterization of YFP MHC class II region by screening the BAC library, followed by sequencing and assembly of positive BAC clones. The YFP MHC class II region consists of two segregated contigs (218,725 bp and 328,435 bp respectively) that include only eight expressed MHC class II genes, three pseudo MHC genes and twelve non-MHC genes. The YFP has fewer MHC class II genes than ruminants, showing locus reduction in DRB, DQA, DQB, and loss of DY. In addition, phylogenic and evolutionary analyses indicated that the DRB, DQA and DQB genes might have undergone birth-and-death evolution, whereas the DQB gene might have evolved under positive selection in cetaceans. These findings provide an essential foundation for future work, such as estimating MHC genetic variation in the YFP or other cetaceans. This work is the first report on the MHC class II region in cetaceans and offers valuable information for understanding the evolution of MHC genome in cetaceans. PMID:26932528

  20. Selection and Trans-Species Polymorphism of Major Histocompatibility Complex Class II Genes in the Order Crocodylia

    PubMed Central

    Jaratlerdsiri, Weerachai; Isberg, Sally R.; Higgins, Damien P.; Miles, Lee G.; Gongora, Jaime

    2014-01-01

    Major Histocompatibility Complex (MHC) class II genes encode for molecules that aid in the presentation of antigens to helper T cells. MHC characterisation within and between major vertebrate taxa has shed light on the evolutionary mechanisms shaping the diversity within this genomic region, though little characterisation has been performed within the Order Crocodylia. Here we investigate the extent and effect of selective pressures and trans-species polymorphism on MHC class II α and β evolution among 20 extant species of Crocodylia. Selection detection analyses showed that diversifying selection influenced MHC class II β diversity, whilst diversity within MHC class II α is the result of strong purifying selection. Comparison of translated sequences between species revealed the presence of twelve trans-species polymorphisms, some of which appear to be specific to the genera Crocodylus and Caiman. Phylogenetic reconstruction clustered MHC class II α sequences into two major clades representing the families Crocodilidae and Alligatoridae. However, no further subdivision within these clades was evident and, based on the observation that most MHC class II α sequences shared the same trans-species polymorphisms, it is possible that they correspond to the same gene lineage across species. In contrast, phylogenetic analyses of MHC class II β sequences showed a mixture of subclades containing sequences from Crocodilidae and/or Alligatoridae, illustrating orthologous relationships among those genes. Interestingly, two of the subclades containing sequences from both Crocodilidae and Alligatoridae shared specific trans-species polymorphisms, suggesting that they may belong to ancient lineages pre-dating the divergence of these two families from the common ancestor 85–90 million years ago. The results presented herein provide an immunogenetic resource that may be used to further assess MHC diversity and functionality in Crocodylia. PMID:24503938

  1. Posttranscriptional Inhibition of Class I Major Histocompatibility Complex Presentation on Hepatocytes and Lymphoid Cells in Chronic Woodchuck Hepatitis Virus Infection

    PubMed Central

    Michalak, Tomasz I.; Hodgson, Paul D.; Churchill, Norma D.

    2000-01-01

    Woodchuck hepatitis virus (WHV), similar to human hepatitis B virus, causes acute liver inflammation that can progress to chronic hepatitis and hepatocellular carcinoma. WHV also invades cells of the host lymphatic system, where it persists for life. We report here that acute and chronic hepadnavirus hepatitis is characterized by a profound difference in the expression of class I major histocompatibility complex (MHC) molecules on the surface of infected hepatocytes and, notably, lymphoid cells. While acute WHV infection is accompanied by the enhanced hepatocyte surface presentation of class I MHC antigen and upregulated transcription of the relevant hepatic genes, inhibition of class I antigen display on liver cells is a uniform hallmark of chronic WHV infection. This inhibition in chronic hepatitis occurs despite augmented (as in acute infection) expression of hepatic genes for class I MHC heavy chain, β2-microglobulin, and transporters associated with antigen processing (TAP1 and TAP2). Further, the class I antigen inhibition is not related to the histological severity of hepatocellular injury, the extent of lymphocytic infiltrations, the level of intrahepatic gamma interferon induction, or the hepatic WHV load. Importantly, the antigen expression is also inhibited on organ lymphoid cells of chronically infected hosts. The results obtained in this study demonstrate that the defective presentation of class I MHC molecules on cells supporting persistent WHV replication is due to viral posttranscriptional interference. This event may diminish the susceptibility of infected hepatocytes to virus-specific T-cell-mediated elimination, hinder virus clearance, and deregulate the class I MHC-dependent functions of the host immune system. This multifarious effect could be critical for perpetuation of liver damage and evasion of the antiviral immunological surveillance in chronic infection and therefore could be supportive of hepadnavirus persistence. PMID:10775584

  2. Two-dimensional nuclear magnetic resonance analysis of a labeled peptide bound to a class II major histocompatibility complex molecule.

    PubMed

    Driscoll, P C; Altman, J D; Boniface, J J; Sakaguchi, K; Reay, P A; Omichinski, J G; Appella, E; Davis, M M

    1993-07-20

    The formation of peptide/major histocompatibility complex (MHC) complexes and their subsequent recognition by T cells is a pivotal event in the initiation of an immune response. While X-ray crystal structures are now available for class I MHC/peptide complexes, little detailed structural information is known about the class II MHC equivalent, and there are no solution structure data for either. A 16 amino acid residue moth cytochrome c peptide (residues 88 to 103) was 13C-labeled for two-dimensional isotope-edited NMR analysis. The peptide was labeled either selectively in the methyl groups of alanine residues or uniformly at every carbon position, and bound to unlabeled soluble mouse I-Ek class II MHC molecules. Although alpha-helical in the native cytochrome c protein and with no uniform structure in solution, the peptide is bound to the I-Ek molecule with the alpha-carbon atoms of the 11 C-terminal residues held in the binding groove. This indicates that the class II MHC peptide binding site is somewhat larger than that of class I MHC molecules (> or = 11 amino acid residues versus 8 to 10 amino acid residues), consistent with recent data on eluted peptides. Despite the large size of the complex (approximately 70 kDa), nuclear Overhauser effects are clearly detectable between peptide side-chains and the MHC molecule. Indications of the buried or exposed nature of particular side-chains within the bound peptide are derived from the NMR data and these are used together with information from previous biological studies to propose a crude model of the interaction of the peptide with the groove of the MHC molecule. We find no evidence for a conformational change in the peptide/MHC complex in the spectra at pH 5.0 versus pH 7.0, despite a 40-fold faster on-rate for the peptide at the lower pH value. PMID:8393933

  3. Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations

    PubMed Central

    Jacobson, Samuel G.; McGuigan, David B.; Sumaroka, Alexander; Roman, Alejandro J.; Gruzensky, Michaela L.; Sheplock, Rebecca; Palma, Judy; Schwartz, Sharon B.; Aleman, Tomas S.; Cideciyan, Artur V.

    2016-01-01

    Purpose Previously, patients with RHO mutations and a class A phenotype were found to have severe early-onset loss of rod function, whereas patients with a class B phenotype retained rod function at least in certain retinal regions. Here class B patients were studied at different disease stages to understand the topographic details of the phenotype in preparation for therapies of this regionalized retinopathy. Methods A cohort of patients with RHO mutations and class B phenotype (n = 28; ages 10–80 years) were studied with rod and cone perimetry and optical coherence tomography (OCT). Results At least three components of the phenotype were identified in these cross-sectional studies. Patients could have hemifield dysfunction, pericentral loss of function, or a diffuse rod sensitivity loss across the visual field. Combinations of these different patterns were also found. Colocalized photoreceptor layer thicknesses were in agreement with the psychophysical results. Conclusions These disorders with regional retinal variation of severity require pre-evaluations before enrollment into clinical trials to seek answers to questions about where in the retina would be appropriate to deliver focal treatments, and, for retina-wide treatment strategies, where in the retina should be monitored for therapeutic efficacy (or safety). PMID:27654411

  4. [Supraventricular tachycardia with wide QRS complexes during Vaughan-Williams class I anti-arrhythmic treatment. Diagnostic and therapeutic implications].

    PubMed

    Aouate, P; Frank, R; Fontaine, G; Tonet, J; Tageddine, R; Benassar, A; Turlure, A; Jacquemin, M; Laborde, J P

    1995-12-01

    The authors report 8 cases of regular tachycardia with wide QRS complexes during treatment with Vaughan-Williams class 1 antiarrhythmic drugs. These antiarrhythmics, prescribed to prevent atrial fibrillation (3 patients) and atrial flutter (5 patients), were flecainide in 4 cases, propafenone in 2 cases and cibenzoline and hydroquinidine respectively associated with digitoxine and propranolol. These wide complex tachycardias were regular atrial tachycardias with 1/1 conduction to the ventricle. The action of the drug, more pronounced on intra-atrial conduction velocities than on atrioventricular node refractoriness resulted in transformation of flutter at 300 cycles/min with 2/1 conduction and a ventricular rate of 150 cycles/min to atrial flutter at 210 cycles/min with 1/1 ventricular conduction. This acceleration of the ventricular rate was accompanied by widening of the QRS complex. Using the new ventricular tachycardia criteria recently published by Brugada resulted in a diagnostic error in 7 out of the 8 cases. The recording of a wide QRS complex tachycardia in a patient on class 1 antiarrhythmic therapy for an atrial arrhythmia should alert the physician to 1/1 atrial tachycardia despite morphological electrocardiographic criteria of ventricular tachycardia. The 1/1 atrial tachycardia may be poorly tolerated and require emergency treatment. The preventive association of a drug which slows conduction through the atrioventricular node is not always effective.

  5. Identification and mapping of two divergent, unlinked major histocompatibility complex class II B genes in Xiphophorus fishes.

    PubMed Central

    McConnell, T J; Godwin, U B; Norton, S F; Nairn, R S; Kazianis, S; Morizot, D C

    1998-01-01

    We have isolated two major histocompatibility complex (MHC) class II B genes from the inbred fish strain Xiphophorus maculatus Jp 163 A. We mapped one of these genes, designated here as DXB, to linkage group III, linked to a malic enzyme locus, also syntenic with human and mouse MHC. Comparison of genomic and cDNA clones shows the gene consists of six exons and five introns. The encoded beta1 domain has three amino acids deleted and a cytoplasmic tail nine amino acids longer than in other teleost class II beta chains, more similar to HLA-DRB, clawed frog Xela-F3, and nurse shark Gici-B. Key residues for disulfide bonds, glycosylation, and interaction with alpha chains are conserved. These same features are also present in a swordtail (Xiphophorus helleri) genomic DXB PCR clone. A second type of class II B clone was amplified by PCR from X. maculatus and found to be orthologous to class II genes identified in other fishes. This DAB-like gene is 63% identical to the X. maculatus DXB sequence in the conserved beta2-encoding exon and was mapped to new unassigned linkage group LG U24. The DXB gene, then, represents an unlinked duplicated locus not previously identified in teleosts. PMID:9691047

  6. Unusual association of beta 2-microglobulin with certain class I heavy chains of the murine major histocompatibility complex.

    PubMed Central

    Bushkin, Y; Tung, J S; Pinter, A; Michaelson, J; Boyse, E A

    1986-01-01

    Class I products of the major histocompatibility complex (MHC) comprise a heavy chain of about 45 kDa noncovalently linked to a 12-kDa beta 2-microglobulin (beta 2m) light chain encoded on a different chromosome. We find that class I products of some mouse strains include an additional 62-kDa molecule which on the following evidence consists of a heavy chain linked covalently with beta 2m. Production of the 62-kDa protein invariably accorded with the occurrence of cysteine at position 121 of the heavy chain (Kb,Kbm1,Kbm3,Dd, and Ld). Substitution of arginine at position 121 invariably accorded with absence of the 62-kDa protein (Kbm6,Kbm7,Kbm9,Kd, and Db). On the basis of observed production versus nonproduction of the 62-kDa molecule, predictions are made regarding residue 121 in class I products for which this is not yet known; namely, Kk, Ks, and Dk, which produce the 62-kDa molecule, as compared with Kj, Qa-2, and TL, which do not. Reported differences in immunologic reactivity between Kb mutant strains with Arg-121 in place of Cys-121 imply that the occurrence of 62-kDa class I products in mice of Cys-121 genotype has functional consequences. Images PMID:3510435

  7. Complex MHC Class I Gene Transcription Profiles and Their Functional Impact in Orangutans.

    PubMed

    de Groot, Natasja G; Heijmans, Corrine M C; van der Wiel, Marit K H; Blokhuis, Jeroen H; Mulder, Arend; Guethlein, Lisbeth A; Doxiadis, Gaby G M; Claas, Frans H J; Parham, Peter; Bontrop, Ronald E

    2016-01-15

    MHC haplotypes of humans and the African great ape species have one copy of the MHC-A, -B, and -C genes. In contrast, MHC haplotypes of orangutans, the Asian great ape species, exhibit variation in the number of gene copies. An in-depth analysis of the MHC class I gene repertoire in the two orangutan species, Pongo abelii and Pongo pygmaeus, is presented in this article. This analysis involved Sanger and next-generation sequencing methodologies, revealing diverse and complicated transcription profiles for orangutan MHC-A, -B, and -C. Thirty-five previously unreported MHC class I alleles are described. The data demonstrate that each orangutan MHC haplotype has one copy of the MHC-A gene, and that the MHC-B region has been subject to duplication, giving rise to at least three MHC-B genes. The MHC-B*03 and -B*08 lineages of alleles each account for a separate MHC-B gene. All MHC-B*08 allotypes have the C1-epitope motif recognized by killer cell Ig-like receptor. At least one other MHC-B gene is present, pointing to MHC-B alleles that are not B*03 or B*08. The MHC-C gene is present only on some haplotypes, and each MHC-C allotype has the C1-epitope. The transcription profiles demonstrate that MHC-A alleles are highly transcribed, whereas MHC-C alleles, when present, are transcribed at very low levels. The MHC-B alleles are transcribed to a variable extent and over a wide range. For those orangutan MHC class I allotypes that are detected by human monoclonal anti-HLA class I Abs, the level of cell-surface expression of proteins correlates with the level of transcription of the allele. PMID:26685209

  8. Characterization and 454 pyrosequencing of Major Histocompatibility Complex class I genes in the great tit reveal complexity in a passerine system

    PubMed Central

    2012-01-01

    Background The critical role of Major Histocompatibility Complex (Mhc) genes in disease resistance and their highly polymorphic nature make them exceptional candidates for studies investigating genetic effects on survival, mate choice and conservation. Species that harbor many Mhc loci and high allelic diversity are particularly intriguing as they are potentially under strong selection and studies of such species provide valuable information as to the mechanisms maintaining Mhc diversity. However comprehensive genotyping of complex multilocus systems has been a major challenge to date with the result that little is known about the consequences of this complexity in terms of fitness effects and disease resistance. Results In this study, we genotyped the Mhc class I exon 3 of the great tit (Parus major) from two nest-box breeding populations near Oxford, UK that have been monitored for decades. Characterization of Mhc class I exon 3 was adopted and bidirectional sequencing was carried using the 454 sequencing platform. Full analysis of sequences through a stepwise variant validation procedure allowed reliable typing of more than 800 great tits based on 214,357 reads; from duplicates we estimated the repeatability of typing as 0.94. A total of 862 alleles were detected, and the presence of at least 16 functional loci was shown - the highest number characterized in a wild bird species. Finally, the functional alleles were grouped into 17 supertypes based on their antigen binding affinities. Conclusions We found extreme complexity at the Mhc class I of the great tit both in terms of allelic diversity and gene number. The presence of many functional loci was shown, together with a pseudogene family and putatively non-functional alleles; there was clear evidence that functional alleles were under strong balancing selection. This study is the first step towards an in-depth analysis of this gene complex in this species, which will help understanding how parasite

  9. Transcription specificity of the class Ib genes SLA-6, SLA-7 and SLA-8 of the swine major histocompatibility complex and comparison with class Ia genes.

    PubMed

    Kusza, S; Flori, L; Gao, Y; Teillaud, A; Hu, R; Lemonnier, G; Bosze, Z; Bourneuf, E; Vincent-Naulleau, S; Rogel-Gaillard, C

    2011-10-01

    Our aim was to analyse the transcription levels of the three non-classical class Ib genes SLA-6, SLA-7 and SLA-8 of the swine major histocompatibility complex in various tissues and conditions and to compare them to the transcription levels of classical class Ia genes. Twenty-five adult tissues from two pig breeds, pig renal PK15 cells infected with the Pseudorabies virus, and peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide or a mixture of phorbol myristate acetate and ionomycin were included in our study. Relative transcription was quantified by quantitative real-time PCR. On average, in adult tissues and PBMCs and compared to SLA-6, the transcription level of SLA-Ia genes was 100-1000 times higher, the level of SLA-8 was 10-20 times higher, and that of SLA-7 was five times higher. Thus, SLA-8 is the most transcribed SLA-Ib gene, followed by the SLA-7 and SLA-6 genes. The highest transcription levels of SLA-Ib transcripts were found in the lymphoid organs, followed by the lung and the digestive tract. The tissue variability of expression levels was widest for the SLA-6 gene, with a 1:32 ratio between the lowest and highest levels in contrast to a 1:12 ratio for the SLA-7 and SLA-8 genes and a 1:16 ratio for the SLA-Ia genes. During PK-15 infection and PBMC stimulation, SLA-Ia and SLA-8 genes were downregulated, whereas SLA-6 and SLA-7 were upregulated, downregulated or not significantly modified. Our overall results confirm the tissue-wide transcription of the three SLA-Ib genes and suggest that they have complementary roles.

  10. Stereospecific alignment of the X and Y elements is required for major histocompatibility complex class II DRA promoter function.

    PubMed Central

    Vilen, B J; Cogswell, J P; Ting, J P

    1991-01-01

    The regulatory mechanisms controlling expression of the major histocompatibility complex (MHC) class II genes involve several cis-acting DNA elements, including the X and Y boxes. These two elements are conserved within all murine and human class II genes and are required for accurate and efficient transcription from MHC class II promoters. Interestingly, the distance between the X and Y elements is also evolutionarily conserved at 18 to 20 bp. To investigate the function of the invariant spacing in the human MHC class II gene, HLA-DRA, we constructed a series of spacing mutants which alters the distance between the X and Y elements by integral and half-integral turns of the DNA helix. Transient transfection of the spacing constructs into Raji cells revealed that inserting integral turns of the DNA helix (+20 and +10 bp) did not reduce promoter activity, while inserting or deleting half-integral turns of the DNA helix (+15, +5, and -5 bp) drastically reduced promoter activity. The loss of promoter function in these half-integral turn constructs was due neither to the inability of the X and Y elements to bind proteins nor to improper binding of the X- and Y-box-binding proteins. These data indicate that the X and Y elements must be aligned on the same side of the DNA helix to ensure normal function. This requirement for stereospecific alignment strongly suggests that the X- and Y-box-binding proteins either interact directly or are components of a larger transcription complex which assembles on one face of the DNA double helix. Images PMID:1901941

  11. Endothelial activation by hydrogen peroxide. Selective increases of intercellular adhesion molecule-1 and major histocompatibility complex class I.

    PubMed Central

    Bradley, J. R.; Johnson, D. R.; Pober, J. S.

    1993-01-01

    Products of activated leukocytes may alter vascular endothelial cell (EC) function. For example, ECs respond to leukocyte-derived cytokines, such as tumor necrosis factor (TNF) or interleukin-1, by reversibly altering levels of expression of specific gene products that promote inflammation. In contrast, hydrogen peroxide, a product of TNF-activated neutrophils, can produce irreversible EC injury and death. In this study, we have investigated the effects of subinjurious concentrations of hydrogen peroxide on EC inflammatory functions. Treatment with 50 to 100 mumol/L hydrogen peroxide selectively increases surface expression of intercellular adhesion molecule-1 and major histocompatibility complex class I, but not endothelial leukocyte adhesion molecule-1 (also known as E-selectin), vascular cell adhesion molecule-1, or gp96, a constitutively expressed EC surface protein. Increased major histocompatibility complex class I and intercellular adhesion molecule-1 surface expression is associated with specifically increased messenger RNA levels, suggesting selective endothelial gene activation. Hydrogen peroxide does not activate the transcription factor Nuclear Factor kappa B, an important mediator of TNF-induced gene expression. Co-treatment with hydrogen peroxide inhibits TNF-induced gene expression at 4 hours, an effect which can be attributed to reversible inhibition of TNF binding to EC surface receptors. Hydrogen peroxide also antagonizes the actions of interleukin-1. At 24 hours, TNF and hydrogen peroxide produce, at most, additive increases in intercellular adhesion molecule-1 and major histocompatibility complex class I. These results suggest that subinjurious concentrations of hydrogen peroxide can activate endothelium and that the effects of hydrogen peroxide on ECs differ from those of inflammatory cytokines. Images Figure 3 Figure 4 Figure 5 PMID:8098585

  12. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates

    PubMed Central

    Watson, Peter J.; Millard, Christopher J.; Riley, Andrew M.; Robertson, Naomi S.; Wright, Lyndsey C.; Godage, Himali Y.; Cowley, Shaun M.; Jamieson, Andrew G.; Potter, Barry V. L.; Schwabe, John W. R.

    2016-01-01

    Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation. PMID:27109927

  13. Restriction fragment length polymorphism within the class I gene loci of the equine major histocompatibility complex

    SciTech Connect

    Alexander, A.J.; Bailey, E.; Woodward, J.G.

    1986-03-05

    Fourteen standard bred horses were serotyped as homozygous for 1 of 6 Equine Leukocyte Antigen (ELA) specificities. DNA was purified from peripheral leukocytes and digested with Hind III or Pvu II. Southern blot hybridization analysis was carried out using a /sup 32/P-labeled mouse cDNA probe (PH2IIa) specific for class I MHC genes. Both enzymes generated blots that contained a large number of bands (23 to 30) per horse. Significant polymorphism existed among most fragment sizes, while a dozen highly conserved band sizes suggested the presence of Qa/tla - like genes. Only 2 animals (both W6's) showed identical band patterns. Polymorphism was greatest between horses of different serotypes and was significantly decreased within serotypes. Unique bands were present on both blots for both W1's and W6's and may account for the serologic specificity seen in ELA W1 and W6 horses. This study is consistent with the findings in other higher vertebrates and implies that the MHC of the horse includes a highly polymorphic class I multigene family.

  14. Ruthenium-Vinylidene Complexes: An Efficient Class of Homogeneous Metathesis Catalysts

    NASA Astrophysics Data System (ADS)

    Dragutan, Ileana; Verpoort, Francis; Dragutan, Valerian; Drozdzak, Renata

    Several routes to access ruthenium (Ru)-vinylidene complexes are described, the majority of which employ alkynes and a Ru source as the starting materials. The successful application of Ru-vinylidenes as efficient pre-catalysts for the synthesis of carbocyclic and heterocyclic compounds by ring-closing metathesis (RCM) of αω, -dienes, and in the synthesis of polymers by ring-opening metathesis polymerization (ROMP) of cyclooctene, norbornene, 5-substituted norbornene, and dicyclopentadiene is fully illustrated. Relevant aspects concerning the activity and selectivity of this type of Ru complexes in metathesis reactions are highlighted.

  15. Osmium(VI) complexes as a new class of potential anti-cancer agents.

    PubMed

    Ni, Wen-Xiu; Man, Wai-Lun; Cheung, Myra Ting-Wai; Sun, Raymond Wai-Yin; Shu, Yuan-Lan; Lam, Yun-Wah; Che, Chi-Ming; Lau, Tai-Chu

    2011-02-21

    A nitridoosmium(VI) complex [Os(VI)(N)(sap)(OH(2))Cl] (H(2)sap = N-salicylidene-2-aminophenol) displays prominent in vitro and in vivo anti-cancer properties, induces S- and G2/M-phase arrest and forms a stable adduct with dianionic 5'-guanosine monophosphate.

  16. Role of chain pairing for the production of functional soluble IA major histocompatibility complex class II molecules

    PubMed Central

    1996-01-01

    Structural studies of cellular receptor molecules involved in immune recognition require the production of large quantities of the extracellular domains of these glycoproteins. The murine major histocompatibility complex (MHC) class II-restricted response has been extensively studied by functional means, but the engineering and purification of the native, empty form of the most-studied murine MHC class II molecule, IA, has been difficult to achieve. IA molecules, which are the murine equivalent of human histocompatibility leukocyte antigen-DQ molecules, have a low efficiency of chain pairing, which results in poor transport to the cell surface and in the appearance of mixed isotype pairs. We have engineered soluble IA molecules whose pairing has been forced by the addition of leucine zipper peptide dimers at their COOH-terminus. The molecules are secreted "empty" into the extracellular medium and can be loaded with single peptide after purification. These IA molecules have been expressed in milligram quantity for crystallization as well as for activation of T cells and measurement of MHC class II-T cell receptor interactions. PMID:8642319

  17. Dissociation of β2-microglobulin determines the surface quality control of major histocompatibility complex class I molecules.

    PubMed

    Montealegre, Sebastián; Venugopalan, Vaishnavi; Fritzsche, Susanne; Kulicke, Corinna; Hein, Zeynep; Springer, Sebastian

    2015-07-01

    Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2K(b) class I proteins from the cell surface. We find that the binding of their light chain, β2-microglobulin (β2m), protects them from endocytic destruction. Thus, the extended survival of suboptimally loaded K(b) molecules at 25°C is attributed to decreased dissociation of β2m. Because all forms of K(b) are constantly internalized but little β2m-receptive heavy chain is present at the cell surface, it is likely that β2m dissociation and recognition of the heavy chain for lysosomal degradation take place in an endocytic compartment.

  18. Major histocompatibility complex class II antigens are required for both cytokine production and proliferation induced by mercuric chloride in vitro.

    PubMed

    Hu, H; Möller, G; Abedi-Valugerdi, M

    1997-10-01

    Autoimmune diseases induced by mercuric chloride are genetically determined, at least one gene being major histocompatibility complex (MHC)-linked. Previously, we showed that in vitro mercury stimulation induced a high proliferative response in lymphocytes from susceptible mice (high-responders) and that the proliferative response could be restored in lymphocytes from low-responders by pretreating the cells with mercury. We also found that the continuous presence of mercury induced IL-2 and IFN-gamma production, while pretreatment with mercury induced IL-4 production. In this study, we showed that anti-MHC class II monoclonal antibodies blocked both the mercury-induced proliferative responses in lymphocytes from high-responders and the restored proliferative responses in low-responders. In addition, anti-MHC class II antibodies also inhibited the mercury-induced IL-2, IFN-gamma and IL-4 cytokine production in vitro. The results demonstrate that MHC class II antigens directly participate in mercury-induced cytokine production and cell activation, and are required at the onset of the initiation.

  19. Expression of bovine non-classical major histocompatibility complex class 1 proteins in mouse P815 and human K562 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-class...

  20. Domain structures and molecular evolution of class I and class II major histocompatibility gene complex (MHC) products deduced from amino acid and nucleotide sequence homologies

    NASA Astrophysics Data System (ADS)

    Ohnishi, Koji

    1984-12-01

    Domain structures of class I and class II MHC products were analyzed from a viewpoint of amino acid and nucleotide sequence homologies. Alignment statistics revealed that class I (transplantation) antigen H chains consist of four mutually homologous domains, and that class II (HLA-DR) antigen β and α chains are both composed of three mutually homologous ones. The N-terminal three and two domains of class I and class II (both β and α) gene products, respectively, all of which being ˜90 residues long, were concluded to be homologous to β2-microglobulin (β2M). The membraneembedded C-terminal shorter domains of these MHC products were also found to be homologous to one another and to the third domain of class I H chains. Class I H chains were found to be more closely related to class II α chains than to class II β chains. Based on these findings, an exon duplication history from a common ancestral gene encoding a β2M-like primodial protein of one-domain-length up to the contemporary MHC products was proposed.

  1. Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules

    NASA Technical Reports Server (NTRS)

    Chapes, S. K.; Hoynowski, S. M.; Woods, K. M.; Armstrong, J. W.; Beharka, A. A.; Iandolo, J. J.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines.

  2. Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules.

    PubMed Central

    Chapes, S K; Hoynowski, S M; Woods, K M; Armstrong, J W; Beharka, A A; Iandolo, J J

    1993-01-01

    We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines. PMID:8359928

  3. Unusual association of. beta. /sub 2/-microglobulin with certain class I heavy chains of the murine major histocompatibility complex

    SciTech Connect

    Bushkin, Y.; Tung, J.S.; Pinter, A.; Michaelson, J.; Boyse, E.A.

    1986-01-01

    Class I products of the major histocompatibility complex (MHC) comprise a heavy chain of about 45 kDa noncovalently linked to a 12-kDa ..beta../sub 2/-microglobulin (..beta../sub 2/m) light chain encoded on a different chromosome. The authors find that class I products of some mouse strains include an additional 62-kDa molecule which on the following evidence consists of a heavy chain linked covalently with ..beta../sub 2/m. Production of the 62-kDa protein invariably accorded with the occurrence of cysteine at position 121 of the heavy chain (K/sup b/, K/sup bm3/, D/sup d/, and L/sup d/). Substitution of arginine at position 121 invariably accorded with absence of the 62-kDa protein (K/sup bm6/, K/sup bm7/, K/sup bm9/, K/sup d/, and D/sup b/). On the basis of observed production versus nonproduction of the 62-kDa molecule, predictions are made regarding residue 121 in class I products for which this is not yet known; namely, K/sup k/, K/sup s/, and D/sup k/, which produce the 62-kDa molecule, as compared with K/sup j/, Qa-2, and TL, which do not. Reported differences in immunologic reactivity between K/sup b/ mutant strains with Arg-121 in place of Cys-121 imply that the occurrence of 62-kDa class I products in mice of Cys-121 genotype has functional consequences. Lymph node cells were labelled with (/sup 35/S)cysteine and Na/sup 125/I.

  4. Regulation of the Tumor-Suppressor Function of the Class III Phosphatidylinositol 3-Kinase Complex by Ubiquitin and SUMO

    PubMed Central

    Reidick, Christina; El Magraoui, Fouzi; Meyer, Helmut E.; Stenmark, Harald; Platta, Harald W.

    2014-01-01

    The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept. PMID:25545884

  5. Pan-Specific Prediction of Peptide-MHC Class I Complex Stability, a Correlate of T Cell Immunogenicity.

    PubMed

    Rasmussen, Michael; Fenoy, Emilio; Harndahl, Mikkel; Kristensen, Anne Bregnballe; Nielsen, Ida Kallehauge; Nielsen, Morten; Buus, Søren

    2016-08-15

    Binding of peptides to MHC class I (MHC-I) molecules is the most selective event in the processing and presentation of Ags to CTL, and insights into the mechanisms that govern peptide-MHC-I binding should facilitate our understanding of CTL biology. Peptide-MHC-I interactions have traditionally been quantified by the strength of the interaction, that is, the binding affinity, yet it has been shown that the stability of the peptide-MHC-I complex is a better correlate of immunogenicity compared with binding affinity. In this study, we have experimentally analyzed peptide-MHC-I complex stability of a large panel of human MHC-I allotypes and generated a body of data sufficient to develop a neural network-based pan-specific predictor of peptide-MHC-I complex stability. Integrating the neural network predictors of peptide-MHC-I complex stability with state-of-the-art predictors of peptide-MHC-I binding is shown to significantly improve the prediction of CTL epitopes. The method is publicly available at http://www.cbs.dtu.dk/services/NetMHCstabpan. PMID:27402703

  6. New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications.

    PubMed

    Dai, Lixiong; Lo, Wai-Sum; Coates, Ian D; Pal, Robert; Law, Ga-Lai

    2016-09-01

    High glum values of +0.30 (ΔJ = 1, 591 nm, in DMSO) and -0.23 (ΔJ = 1, 589 nm, in H2O) were recorded in our series of newly designed macrocyclic europium(III) complexes. A sterically locking approach involving a bidentate chromophore is adopted to control the formation of one stereoisomer, giving rise to extreme rigidity, high stability, and high emission intensity. The combination of a chiral substituent on a macrocyclic chelate for lanthanide ions opens up new perspectives for the further development of circulary polarized luminescent chiral tags in optical and bioapplications. PMID:27537354

  7. Evolutionary history of black grouse major histocompatibility complex class IIB genes revealed through single locus sequence-based genotyping

    PubMed Central

    2013-01-01

    Background Gene duplications are frequently observed in the Major Histocompatibility Complex (MHC) of many species, and as a consequence loci belonging to the same MHC class are often too similar to tell apart. In birds, single locus genotyping of MHC genes has proven difficult due to concerted evolution homogenizing sequences at different loci. But studies on evolutionary history, mode of selection and heterozygosity correlations on the MHC cannot be performed before it is possible to analyse duplicated genes separately. In this study we investigate the architecture and evolution of the MHC class IIB genes in black grouse. We developed a sequence-based genotyping method for separate amplification of the two black grouse MHC class IIB genes BLB1 and BLB2. Based on this approach we are able to study differences in structure and selection between the two genes in black grouse and relate these results to the chicken MHC structure and organization. Results Sequences were obtained from 12 individuals and separated into alleles using the software PHASE. We compared nucleotide diversity measures and employed selection tests for BLB1 and BLB2 to explore their modes of selection. Both BLB1 and BLB2 are transcribed and display classic characteristics of balancing selection as predicted for expressed MHC class IIB genes. We found evidence for both intra- and interlocus recombination or gene conversion, as well as indication for positive but differential selection at both loci. Moreover, the two loci appear to be linked. Phylogenetic analyses revealed orthology of the black grouse MHC class IIB genes to the respective BLB loci in chicken. Conclusions The results indicate that the duplication of the BLB gene occurred before the species divergence into black grouse, chicken and pheasant. Further, we conclude that BLB1 and BLB2 in black grouse are subjected to homogenizing concerted evolution due to interlocus genetic exchange after species divergence. The loci are in linkage

  8. The great diversity of major histocompatibility complex class II genes in Philippine native cattle.

    PubMed

    Takeshima, S N; Miyasaka, T; Polat, M; Kikuya, M; Matsumoto, Y; Mingala, C N; Villanueva, M A; Salces, A J; Onuma, M; Aida, Y

    2014-12-01

    Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle. PMID:25606401

  9. The great diversity of major histocompatibility complex class II genes in Philippine native cattle.

    PubMed

    Takeshima, S N; Miyasaka, T; Polat, M; Kikuya, M; Matsumoto, Y; Mingala, C N; Villanueva, M A; Salces, A J; Onuma, M; Aida, Y

    2014-12-01

    Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle.

  10. The great diversity of major histocompatibility complex class II genes in Philippine native cattle

    PubMed Central

    Takeshima, S.N.; Miyasaka, T.; Polat, M.; Kikuya, M.; Matsumoto, Y.; Mingala, C.N.; Villanueva, M.A.; Salces, A.J.; Onuma, M.; Aida, Y.

    2014-01-01

    Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle. PMID:25606401

  11. Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities.

    PubMed

    Lühder, F; Katz, J; Benoist, C; Mathis, D

    1998-02-01

    Insulin-dependent diabetes is heavily influenced by genes encoded within the major histocompatibility complex (MHC), positively by some class II alleles and negatively by others. We have explored the mechanism of MHC class II-mediated protection from diabetes using a mouse model carrying the rearranged T cell receptor (TCR) transgenes from a diabetogenic T cell clone derived from a nonobese diabetic mouse. BDC2.5 TCR transgenics with C57Bl/6 background genes and two doses of the H-2(g7) allele exhibited strong insulitis at approximately 3 wk of age and most developed diabetes a few weeks later. When one of the H-2(g7) alleles was replaced by H-2(b), insulitis was still severe and only slightly delayed, but diabetes was markedly inhibited in both its penetrance and time of onset. The protective effect was mediated by the Abetab gene, and did not merely reflect haplozygosity of the Abetag7 gene. The only differences we observed in the T cell compartments of g7/g7 and g7/b mice were a decrease in CD4(+) cells displaying the transgene-encoded TCR and an increase in cells expressing endogenously encoded TCR alpha-chains. When the synthesis of endogenously encoded alpha-chains was prevented, the g7/b animals were no longer protected from diabetes. g7/b mice did not have a general defect in the production of Ag7-restricted T cells, and antigen-presenting cells from g7/b animals were as effective as those from g7/g7 mice in stimulating Ag7-restricted T cell hybridomas. These results argue against mechanisms of protection involving clonal deletion or anergization of diabetogenic T cells, or one depending on capture of potentially pathogenic Ag7-restricted epitopes by Ab molecules. Rather, they support a mechanism based on MHC class II-mediated positive selection of T cells expressing additional specificities. PMID:9449718

  12. Selection, trans-species polymorphism, and locus identification of major histocompatibility complex class IIβ alleles of New World ranid frogs

    USGS Publications Warehouse

    Kiemnec-Tyburczy, Karen M.; Richmond, Jonathan Q.; Savage, Anna E.; Zamudio, Kelly R.

    2010-01-01

    Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II ??1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class II?? exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class II?? loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the ??1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations. ?? 2010 Springer-Verlag.

  13. Robust H ∞ Filtering for a Class of Complex Networks with Stochastic Packet Dropouts and Time Delays

    PubMed Central

    Lyu, Ming; Guo, Pengfei; Bo, Yuming

    2014-01-01

    The robust H ∞ filtering problem is investigated for a class of complex network systems which has stochastic packet dropouts and time delays, combined with disturbance inputs. The packet dropout phenomenon occurs in a random way and the occurrence probability for each measurement output node is governed by an individual random variable. Besides, the time delay phenomenon is assumed to occur in a nonlinear vector-valued function. We aim to design a filter such that the estimation error converges to zero exponentially in the mean square, while the disturbance rejection attenuation is constrained to a given level by means of the H ∞ performance index. By constructing the proper Lyapunov-Krasovskii functional, we acquire sufficient conditions to guarantee the stability of the state detection observer for the discrete systems, and the observer gain is also derived by solving linear matrix inequalities. Finally, an illustrative example is provided to show the usefulness and effectiveness of the proposed design method. PMID:24987738

  14. New horizons in mouse immunoinformatics: reliable in silico prediction of mouse class I histocompatibility major complex peptide binding affinity.

    PubMed

    Hattotuwagama, Channa K; Guan, Pingping; Doytchinova, Irini A; Flower, Darren R

    2004-11-21

    Quantitative structure-activity relationship (QSAR) analysis is a main cornerstone of modern informatic disciplines. Predictive computational models, based on QSAR technology, of peptide-major histocompatibility complex (MHC) binding affinity have now become a vital component of modern day computational immunovaccinology. Historically, such approaches have been built around semi-qualitative, classification methods, but these are now giving way to quantitative regression methods. The additive method, an established immunoinformatics technique for the quantitative prediction of peptide-protein affinity, was used here to identify the sequence dependence of peptide binding specificity for three mouse class I MHC alleles: H2-D(b), H2-K(b) and H2-K(k). As we show, in terms of reliability the resulting models represent a significant advance on existing methods. They can be used for the accurate prediction of T-cell epitopes and are freely available online ( http://www.jenner.ac.uk/MHCPred). PMID:15534705

  15. Variation in positively selected major histocompatibility complex class I loci in rufous-collared sparrows (Zonotrichia capensis).

    PubMed

    Jones, Matthew R; Cheviron, Zachary A; Carling, Matthew D

    2014-12-01

    The major histocompatibility complex (MHC) is a highly variable family of genes involved in parasite recognition and the initiation of adaptive immune system responses. Variation in MHC loci is maintained primarily through parasite-mediated selection or disassortative mate choice. To characterize MHC diversity of rufous-collared sparrows (Zonotrichia capensis), an abundant South American passerine, we examined allelic and nucleotide variation in MHC class I exon 3 using pyrosequencing. Exon 3 comprises a substantial portion of the peptide-binding region (PBR) of class I MHC and thus plays an important role in intracellular pathogen defense. We identified 98 putatively functional alleles that produce 56 unique protein sequences across at least 6 paralogous loci. Allelic diversity per individual and exon-wide nucleotide diversity were relatively low; however, we found specific amino acid positions with high nucleotide diversity and signatures of positive selection (elevated d N /d S ) that may correspond to the PBR. Based on the variation in physicochemical properties of amino acids at these "positively selected sites," we identified ten functional MHC supertypes. Spatial variation in nucleotide diversity and the number of MHC alleles, proteins, and supertypes per individual suggests that environmental heterogeneity may affect patterns of MHC diversity. Furthermore, populations with high MHC diversity have higher prevalence of avian malaria, consistent with parasite-mediated selection on MHC. Together, these results provide a framework for subsequent investigations of selective agents acting on MHC in Z. capensis. PMID:25186067

  16. Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression

    PubMed Central

    Benedictus, Lindert; Luteijn, Rutger D.; Otten, Henny; Jan Lebbink, Robert; van Kooten, Peter J. S.; Wiertz, Emmanuel J. H. J.; Rutten, Victor P. M. G.; Koets, Ad P.

    2015-01-01

    Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens inducing BNP-associated alloantibodies in the dam. In this study the specificity of BNP alloantibodies was assessed and was linked to the pathology of BNP. We demonstrated that Major Histocompatibility Complex class I (MHC I) and Very Late Antigen-3, an integrin α3/β1 heterodimer, were the major targets of BNP alloantibodies. However, alloantibody binding to various bovine cell types correlated with MHC I expression, rather than integrin β1 or α3 expression. Likewise, alloantibody-dependent complement-mediated cell lysis correlated strongly with MHC I expression. Examination of several tissues of third trimester bovine foetuses revealed that cells, shown to be affected in calves with BNP, were characterized by high MHC class I expression and high levels of alloantibody binding. We conclude that in spite of the heterogeneous specificity of BNP associated maternal alloantibodies, MHC I-specific antibodies mediate the pathogenicity of BNP in the calf and that cells with high MHC I expression were preferentially affected in BNP. PMID:26235972

  17. Persistent measles virus infection enhances major histocompatibility complex class I expression and immunogenicity of murine neuroblastoma cells.

    PubMed

    Gopas, J; Itzhaky, D; Segev, Y; Salzberg, S; Trink, B; Isakov, N; Rager-Zisman, B

    1992-01-01

    The effect of persistent measles virus infection on the expression of major histocompatibility complex (MHC) class I antigens was studied. Mouse neuroblastoma cells C1300, clone NS20Y, were persistently infected with the Edmonston strain of measles virus. The persistently infected cell line, NS20Y/MS, expressed augmented levels of both H-2Kk and H-2Dd MHC class I glycoproteins. Activation of two interferon(IFN)-induced enzymes, known to be part of the IFN system: (2'-5')oligoadenylate synthetase and double-stranded-RNA-activated protein kinase, was detected. Measles-virus-infected cells elicited cytotoxic T lymphocytes that recognized and lysed virus-infected and uninfected neuroblastoma cells in an H-2-restricted fashion. Furthermore, immunization of mice with persistently infected cells conferred resistance to tumor growth after challenge with the highly malignant NS20Y cells. The rationale for using measles virus for immunotherapy is that most patients develop lifelong immunity after recovery or vaccination from this infection. Patients developing cancer are likely to have memory cells. A secondary response induced by measles-virus-infected cells may therefore induce an efficient immune response against non-infected tumour cells.

  18. Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression.

    PubMed

    Benedictus, Lindert; Luteijn, Rutger D; Otten, Henny; Lebbink, Robert Jan; van Kooten, Peter J S; Wiertz, Emmanuel J H J; Rutten, Victor P M G; Koets, Ad P

    2015-01-01

    Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens inducing BNP-associated alloantibodies in the dam. In this study the specificity of BNP alloantibodies was assessed and was linked to the pathology of BNP. We demonstrated that Major Histocompatibility Complex class I (MHC I) and Very Late Antigen-3, an integrin α3/β1 heterodimer, were the major targets of BNP alloantibodies. However, alloantibody binding to various bovine cell types correlated with MHC I expression, rather than integrin β1 or α3 expression. Likewise, alloantibody-dependent complement-mediated cell lysis correlated strongly with MHC I expression. Examination of several tissues of third trimester bovine foetuses revealed that cells, shown to be affected in calves with BNP, were characterized by high MHC class I expression and high levels of alloantibody binding. We conclude that in spite of the heterogeneous specificity of BNP associated maternal alloantibodies, MHC I-specific antibodies mediate the pathogenicity of BNP in the calf and that cells with high MHC I expression were preferentially affected in BNP. PMID:26235972

  19. The HOPS/class C Vps complex tethers membranes by binding to one Rab GTPase in each apposed membrane

    PubMed Central

    Ho, Ruoya; Stroupe, Christopher

    2015-01-01

    Many Rab GTPase effectors are membrane-tethering factors, that is, they physically link two apposed membranes before intracellular membrane fusion. In this study, we investigate the distinct binding factors needed on apposed membranes for Rab effector–dependent tethering. We show that the homotypic fusion and protein-sorting/class C vacuole protein-sorting (HOPS/class C Vps) complex can tether low-curvature membranes, that is, liposomes with a diameter of ∼100 nm, only when the yeast vacuolar Rab GTPase Ypt7p is present in both tethered membranes. When HOPS is phosphorylated by the vacuolar casein kinase I, Yck3p, tethering only takes place when GTP-bound Ypt7p is present in both tethered membranes. When HOPS is not phosphorylated, however, its tethering activity shows little specificity for the nucleotide-binding state of Ypt7p. These results suggest a model for HOPS-mediated tethering in which HOPS tethers membranes by binding to Ypt7p in each of the two tethered membranes. Moreover, because vacuole-associated HOPS is presumably phosphorylated by Yck3p, our results suggest that nucleotide exchange of Ypt7p on multivesicular bodies (MVBs)/late endosomes must take place before HOPS can mediate tethering at vacuoles. PMID:25995379

  20. The HOPS/class C Vps complex tethers membranes by binding to one Rab GTPase in each apposed membrane.

    PubMed

    Ho, Ruoya; Stroupe, Christopher

    2015-07-15

    Many Rab GTPase effectors are membrane-tethering factors, that is, they physically link two apposed membranes before intracellular membrane fusion. In this study, we investigate the distinct binding factors needed on apposed membranes for Rab effector-dependent tethering. We show that the homotypic fusion and protein-sorting/class C vacuole protein-sorting (HOPS/class C Vps) complex can tether low-curvature membranes, that is, liposomes with a diameter of ∼100 nm, only when the yeast vacuolar Rab GTPase Ypt7p is present in both tethered membranes. When HOPS is phosphorylated by the vacuolar casein kinase I, Yck3p, tethering only takes place when GTP-bound Ypt7p is present in both tethered membranes. When HOPS is not phosphorylated, however, its tethering activity shows little specificity for the nucleotide-binding state of Ypt7p. These results suggest a model for HOPS-mediated tethering in which HOPS tethers membranes by binding to Ypt7p in each of the two tethered membranes. Moreover, because vacuole-associated HOPS is presumably phosphorylated by Yck3p, our results suggest that nucleotide exchange of Ypt7p on multivesicular bodies (MVBs)/late endosomes must take place before HOPS can mediate tethering at vacuoles.

  1. cDNA cloning and genetic polymorphism of the swine major histocompatibility complex (SLA) class II DMA gene.

    PubMed

    Ando, A; Kawata, H; Murakami, T; Shigenari, A; Shiina, T; Sada, M; Tsuji, T; Toriu, A; Nakanishi, Y; Mitsuhashi, T; Sekikawa, K; Inoko, H

    2001-04-01

    cDNA clones corresponding to the swine histocompatibility complex (SLA: swine leucocyte antigen)-DM alpha chain were isolated using the polymerase chain reaction (PCR) products from the third exon in the human HLA-DMA gene as a probe. Amino acid comparative analysis revealed that these clones were more closely related to the bovine and human DMA genes than to the other swine class II genes alpha chain genes, DRA, DQA and DOA. These results suggest that the SLA-DMA gene is expressed and may function, like HLA-DM, as an important modulator in class II restricted antigen processing in swine. Furthermore, based on the sequences and PCR-restriction fragment length polymorphism (PCR-RFLP) patterns in the SLA-DMA gene, no allelic variation was recognized in the second exon, but five allelic variations were recognized in the third exon in five different breeds of swine. These DMA alleles were defined by variation at four nucleotide positions. Two of these alleles resulted in an amino acid substitution. These results suggest that SLA-DMA has little polymorphism as observed in HLA-DMA and mouse H2-Ma.

  2. Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression

    PubMed Central

    Tasaka-Fujita, Megumi; Sugiyama, Nao; Kang, Wonseok; Masaski, Takahiro; Murayama, Asako; Yamada, Norie; Sugiyama, Ryuichi; Tsukuda, Senko; Watashi, Koichi; Asahina, Yasuhiro; Sakamoto, Naoya; Wakita, Takaji; Shin, Eui-Cheol; Kato, Takanobu

    2015-01-01

    Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV. PMID:26365522

  3. An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex

    PubMed Central

    Kracker, Sven; Di Virgilio, Michela; Schwartzentruber, Jeremy; Cuenin, Cyrille; Forveille, Monique; Deau, Marie-Céline; McBride, Kevin M.; Majewski, Jacek; Gazumyan, Anna; Seneviratne, Suranjith; Grimbacher, Bodo; Kutukculer, Necil; Herceg, Zdenko; Cavazzana, Marina; Jabado, Nada; Nussenzweig, Michel C.; Fischer, Alain; Durandy, Anne

    2015-01-01

    Background Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. Objective This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). Methods Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. Results We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. Conclusion INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis. PMID:25312759

  4. The HOPS/Class C Vps Complex Tethers High-Curvature Membranes via a Direct Protein-Membrane Interaction.

    PubMed

    Ho, Ruoya; Stroupe, Christopher

    2016-10-01

    Membrane tethering is a physical association of two membranes before their fusion. Many membrane tethering factors have been identified, but the interactions that mediate inter-membrane associations remain largely a matter of conjecture. Previously, we reported that the homotypic fusion and protein sorting/Class C vacuolar protein sorting (HOPS/Class C Vps) complex, which has two binding sites for the yeast vacuolar Rab GTPase Ypt7p, can tether two low-curvature liposomes when both membranes bear Ypt7p. Here, we show that HOPS tethers highly curved liposomes to Ypt7p-bearing low-curvature liposomes even when the high-curvature liposomes are protein-free. Phosphorylation of the curvature-sensing amphipathic lipid-packing sensor (ALPS) motif from the Vps41p HOPS subunit abrogates tethering of high-curvature liposomes. A HOPS complex without its Vps39p subunit, which contains one of the Ypt7p binding sites in HOPS, lacks tethering activity, though it binds high-curvature liposomes and Ypt7p-bearing low-curvature liposomes. Thus, HOPS tethers highly curved membranes via a direct protein-membrane interaction. Such high-curvature membranes are found at the sites of vacuole tethering and fusion. There, vacuole membranes bend sharply, generating large areas of vacuole-vacuole contact. We propose that HOPS localizes via the Vps41p ALPS motif to these high-curvature regions. There, HOPS binds via Vps39p to Ypt7p in an apposed vacuole membrane. PMID:27307091

  5. Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca)

    PubMed Central

    Zhu, Liang; Ruan, Xiang-Dong; Ge, Yun-Fa; Wan, Qiu-Hong; Fang, Sheng-Guo

    2007-01-01

    Background The giant panda (Ailuropoda melanoleuca) is one of the most endangered animals due to habitat fragmentation and loss. Although the captive breeding program for this species is now nearly two decades old, researches on the genetic background of such captive populations, especially on adaptive molecular polymorphism of major histocompatibility complex (MHC), are still limited. In this study, we characterized adaptive variation of the giant panda's MHC DQA gene by PCR amplification of its antigen-recognizing region (i.e. the exon 2) and subsequent single-strand conformational polymorphism (SSCP) and sequence analyses. Results The results revealed a low level of DQA exon 2 diversity in this rare animal, presenting 6 alleles from 61 giant panda individuals. The observed polymorphism was restricted to 9 amino acid substitutions, all of which occurred at and adjacent to positions forming the functionally important antigen-binding sites. All the samples were in Hardy-Weinberg proportions. A significantly higher rate of non-synonymous than synonymous substitutions at the antigen-binding sites indicated positive selection for diversity in the locus. Conclusion The DQA allelic diversity of giant pandas was low relative to other vertebrates. Nonetheless, the pandas exhibited more alleles in DQA than those in DRB, suggesting the alpha chain genes would play a leading role when coping with certain pathogens and thus should be included in conservation genetic investigation. The microsatellite and MHC loci might predict long-term persistence potential and short-term survival ability, respectively. Consequently, it is recommended to utilize multiple suites of microsatellite markers and multiple MHC loci to detect overall genetic variation in order to design unbiased conservation strategies. PMID:17555583

  6. Major histocompatibility complex class I evolution in songbirds: universal primers, rapid evolution and base compositional shifts in exon 3

    PubMed Central

    Alcaide, Miguel; Liu, Mark

    2013-01-01

    Genes of the Major Histocompatibility Complex (MHC) have become an important marker for the investigation of adaptive genetic variation in vertebrates because of their critical role in pathogen resistance. However, despite significant advances in the last few years the characterization of MHC variation in non-model species still remains a challenging task due to the redundancy and high variation of this gene complex. Here we report the utility of a single pair of primers for the cross-amplification of the third exon of MHC class I genes, which encodes the more polymorphic half of the peptide-binding region (PBR), in oscine passerines (songbirds; Aves: Passeriformes), a group especially challenging for MHC characterization due to the presence of large and complex MHC multigene families. In our survey, although the primers failed to amplify exon 3 from two suboscine passerine birds, they amplified exon 3 of multiple MHC class I genes in all 16 species of oscine songbirds tested, yielding a total of 120 sequences. The 16 songbird species belong to 14 different families, primarily within the Passerida, but also in the Corvida. Using a conservative approach based on the analysis of cloned amplicons (n = 16) from each species, we found between 3 and 10 MHC sequences per individual. Each allele repertoire was highly divergent, with the overall number of polymorphic sites per species ranging from 33 to 108 (out of 264 sites) and the average number of nucleotide differences between alleles ranging from 14.67 to 43.67. Our survey in songbirds allowed us to compare macroevolutionary dynamics of exon 3 between songbirds and non-passerine birds. We found compelling evidence of positive selection acting specifically upon peptide-binding codons across birds, and we estimate the strength of diversifying selection in songbirds to be about twice that in non-passerines. Analysis using comparative methods suggest weaker evidence for a higher GC content in the 3rd codon position of

  7. Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors*

    PubMed Central

    Deng, Lu; Cho, Sangwoo; Malchiodi, Emilio L.; Kerzic, Melissa C.; Dam, Julie; Mariuzza, Roy A.

    2008-01-01

    Natural killer (NK) cells play a vital role in the detection and destruction of virally infected and tumor cells during innate immune responses. The highly polymorphic Ly49 family of NK receptors regulates NK cell function by sensing major histocompatibility complex class I (MHC-I) molecules on target cells. Despite the determination of two Ly49-MHC-I complex structures, the molecular features of Ly49 receptors that confer specificity for particular MHC-I alleles have not been identified. To understand the functional architecture of Ly49-binding sites, we determined the crystal structures of Ly49C and Ly49G and completed refinement of the Ly49C-H-2Kb complex. This information, combined with mutational analysis of Ly49A, permitted a structure-based classification of Ly49s that we used to dissect the binding site into three distinct regions, each having different roles in MHC recognition. One region, located at the center of the binding site, has a similar structure across the Ly49 family and mediates conserved interactions with MHC-I that contribute most to binding. However, the preference of individual Ly49s for particular MHC-I molecules is governed by two regions that flank the central region and are structurally more variable. One of the flanking regions divides Ly49s into those that recognize both H-2D and H-2K versus only H-2D ligands, whereas the other discriminates among H-2D or H-2K alleles. The modular design of Ly49-binding sites provides a framework for predicting the MHC-binding specificity of Ly49s that have not been characterized experimentally. PMID:18426793

  8. Molecular Architecture of the Major Histocompatibility Complex Class I-Binding Site of Ly49 Natural Killer Cell Receptors

    SciTech Connect

    Deng,L.; Cho, S.; Malchiodi, E.; Kerzic, M.; Dam, J.; Mariuzza, R.

    2008-01-01

    Natural killer (NK) cells play a vital role in the detection and destruction of virally infected and tumor cells during innate immune responses. The highly polymorphic Ly49 family of NK receptors regulates NK cell function by sensing major histocompatibility complex class I (MHC-I) molecules on target cells. Despite the determination of two Ly49-MHC-I complex structures, the molecular features of Ly49 receptors that confer specificity for particular MHC-I alleles have not been identified. To understand the functional architecture of Ly49-binding sites, we determined the crystal structures of Ly49C and Ly49G and completed refinement of the Ly49C-H-2Kb complex. This information, combined with mutational analysis of Ly49A, permitted a structure-based classification of Ly49s that we used to dissect the binding site into three distinct regions, each having different roles in MHC recognition. One region, located at the center of the binding site, has a similar structure across the Ly49 family and mediates conserved interactions with MHC-I that contribute most to binding. However, the preference of individual Ly49s for particular MHC-I molecules is governed by two regions that flank the central region and are structurally more variable. One of the flanking regions divides Ly49s into those that recognize both H-2D and H-2K versus only H-2D ligands, whereas the other discriminates among H-2D or H-2K alleles. The modular design of Ly49-binding sites provides a framework for predicting the MHC-binding specificity of Ly49s that have not been characterized experimentally.

  9. The MHC class II ligand lymphocyte activation gene-3 is co-distributed with CD8 and CD3-TCR molecules after their engagement by mAb or peptide-MHC class I complexes.

    PubMed

    Hannier, S; Triebel, F

    1999-11-01

    Previous studies indicated that signaling through lymphocyte activation gene-3 (LAG-3), a MHC class II ligand, induced by multivalent anti-receptor antibodies led to unresponsiveness to TCR stimulation. Here, lateral distribution of the LAG-3 molecules and its topological relationship (mutual proximity) to the TCR, CD8, CD4, and MHC class I and II molecules were studied in the plasma membrane of activated human T cells in co-capping experiments and conventional fluorescence microscopy. Following TCR engagement by either TCR-specific mAb or MHC-peptide complex recognition in T-B cell conjugates, LAG-3 was found to be specifically associated with the CD3-TCR complex. Similarly, following CD8 engagement LAG-3 and CD8 were co-distributed on the cell surface while only a low percentage of CD4-capped cells displayed LAG-3 co-caps. In addition, LAG-3 was found to be associated with MHC class II (i.e. DR, DP and DQ) and partially with MHC class I molecules. The supramolecular assemblies described here between LAG-3, CD3, CD8 and MHC class II molecules may result from an organization in raft microdomains, a phenomenon known to regulate early events of T cell activation.

  10. Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface.

    PubMed

    Wooldridge, Linda; van den Berg, Hugo A; Glick, Meir; Gostick, Emma; Laugel, Bruno; Hutchinson, Sarah L; Milicic, Anita; Brenchley, Jason M; Douek, Daniel C; Price, David A; Sewell, Andrew K

    2005-07-29

    The off-rate (k(off)) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of >1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity.

  11. Trophoblast Major Histocompatibility Complex Class I Expression Is Associated with Immune-Mediated Rejection of Bovine Fetuses Produced by Cloning.

    PubMed

    Rutigliano, Heloisa M; Thomas, Aaron J; Wilhelm, Amanda; Sessions, Benjamin R; Hicks, Brady A; Schlafer, Donald H; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Trophoblast cells from bovine somatic cell nuclear transfer (SCNT) conceptuses express major histocompatibility complex class I (MHC-I) proteins early in gestation, and this may be one cause of the significant first-trimester embryonic mortality observed in these pregnancies. MHC-I homozygous-compatible (n = 9), homozygous-incompatible (n = 8), and heterozygous-incompatible (n = 5) SCNT pregnancies were established. The control group consisted of eight pregnancies produced by artificial insemination. Uterine and placental samples were collected on Day 35 ± 1 of pregnancy, and expression of MHC-I, leukocyte markers, and cytokines were examined by immunohistochemistry. Trophoblast cells from all SCNT pregnancies expressed MHC-I, while trophoblast cells from age-matched control pregnancies were negative for MHC-I expression. Expression of MHC-I antigens by trophoblast cells from SCNT pregnancies was associated with lymphocytic infiltration in the endometrium. Furthermore, MHC-I-incompatible conceptuses, particularly the heterozygous-incompatible ones, induced a more pronounced lymphocytic infiltration than MHC-I-compatible conceptuses. Cells expressing cluster of differentiation (CD) 3, gamma/deltaTCR, and MHC-II were increased in the endometrium of SCNT pregnancies compared to the control group. CD4(+) lymphocytes were increased in MHC-I-incompatible pregnancies compared to MHC-I-compatible and control pregnancies. CD8(+), FOXP3(+), and natural killer cells were increased in MHC-I heterozygous-incompatible SCNT pregnancies compared to homozygous SCNT and control pregnancies.

  12. Genetic variation of the major histocompatibility complex (MHC class II B gene) in the threatened Hume's pheasant, Syrmaticus humiae.

    PubMed

    Chen, Weicai; Bei, Yongjian; Li, Hanhua

    2015-01-01

    Major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates and encode molecules that play a crucial role in pathogen resistance. As a result of their diversity, they have received much attention in the fields of evolutionary and conservation biology. Here, we described the genetic variation of MHC class II B (MHCIIB) exon 2 in a wild population of Hume's pheasant (Syrmaticus humiae), which has suffered a dramatic decline in population over the last three decades across its ranges in the face of heavy exploitation and habitat loss. Twenty-four distinct alleles were found in 73 S. humiae specimens. We found seven shared alleles among four geographical groups as well as six rare MHCIIB alleles. Most individuals displayed between one to five alleles, suggesting that there are at least three MHCIIB loci of the Hume's pheasant. The dN ⁄ dS ratio at putative antigen-binding sites (ABS) was significantly greater than one, indicating balancing selection is acting on MHCIIB exon 2. Additionally, recombination and gene conversion contributed to generating MHCIIB diversity in the Hume's pheasant. One to three recombination events and seventy-five significant gene conversion events were observed within the Hume's pheasant MHCIIB loci. The phylogenetic tree and network analysis revealed that the Hume's pheasant alleles do not cluster together, but are scattered through the tree or network indicating a trans-species evolutionary mode. These findings revealed the evolution of the Hume's pheasant MHC after suffering extreme habitat fragmentation.

  13. Vaccine-induced antibodies linked to bovine neonatal pancytopenia (BNP) recognize cattle major histocompatibility complex class I (MHC I).

    PubMed

    Deutskens, Fabian; Lamp, Benjamin; Riedel, Christiane M; Wentz, Eveline; Lochnit, Günter; Doll, Klaus; Thiel, Heinz-Jürgen; Rümenapf, Till

    2011-01-01

    A mysterious disease affecting calves, named bovine neonatal pancytopenia (BNP), emerged in 2007 in several European countries. Epidemiological studies revealed a connection between BNP and vaccination with an inactivated vaccine against bovine virus diarrhea (BVD). Alloantibodies reacting with blood leukocytes of calves were detected in serum and colostrum of dams, which have given birth to calves affected by BNP. To understand the linkage between vaccination and the development of alloantibodies, we determined the antigens reacting with these alloantibodies. Immunoprecipitation of surface proteins from bovine leukocytes and kidney cells using sera from dams with a confirmed case of BNP in their gestation history reacted with two dominant protein species of 44 and 12 kDa. These proteins were not detected by sera from dams, free of BVDV and not vaccinated against BVD, and from sera of animals vaccinated with a different inactivated BVD vaccine. The 44 kDa protein was identified by mass spectrometry analysis as MHC I, the other as β-2-microglobulin. The presence of major histocompatibility complex class I (MHC I) in the vaccine was confirmed by Western blot using a MHC I specific monoclonal antibody. A model of BNP pathogenesis is proposed. PMID:21878124

  14. Cross-linking staphylococcal enterotoxin A bound to major histocompatibility complex class I is required for TNF-alpha secretion

    NASA Technical Reports Server (NTRS)

    Wright, A. D.; Chapes, S. K.

    1999-01-01

    The mechanism of how superantigens function to activate cells has been linked to their ability to bind and cross-link the major histocompatibility complex class II (MHCII) molecule. Cells that lack the MHCII molecule also respond to superantigens, however, with much less efficiency. Therefore, the purpose of this study was to confirm that staphylococcal enterotoxin A (SEA) could bind the MHCI molecule and to test the hypothesis that cross-linking SEA bound to MHCII-deficient macrophages would induce a more robust cytokine response than without cross-linking. We used a capture enzyme-linked immunosorbent assay and an immunprecipitation assay to directly demonstrate that MHCI molecules bind SEA. Directly cross-linking MHCI using monoclonal antibodies or cross-linking bound SEA with an anti-SEA antibody or biotinylated SEA with avidin increased TNF-alpha and IL-6 secretion by MHCII(-/-) macrophages. The induction of a vigorous macrophage cytokine response by SEA/anti-SEA cross-linking of MHCI offers a mechanism to explain how MHCI could play an important role in superantigen-mediated pathogenesis. Copyright 1999 Academic Press.

  15. Transgenic mice with enhanced neuronal major histocompatibility complex class I expression recover locomotor function better after spinal cord injury.

    PubMed

    Joseph, M Selvan; Bilousova, Tina; Zdunowski, Sharon; Wu, Zhongqi-Phyllis; Middleton, Blake; Boudzinskaia, Maia; Wong, Bonnie; Ali, Noore; Zhong, Hui; Yong, Jing; Washburn, Lorraine; Escande-Beillard, Nathalie; Dang, Hoa; Edgerton, V Reggie; Tillakaratne, Niranjala J K; Kaufman, Daniel L

    2011-03-01

    Mice that are deficient in classical major histocompatibility complex class I (MHCI) have abnormalities in synaptic plasticity and neurodevelopment and have more extensive loss of synapses and reduced axon regeneration after sciatic nerve transection, suggesting that MHCI participates in maintaining synapses and axon regeneration. Little is known about the biological consequences of up-regulating MHCI's expression on neurons. To understand MHCI's neurobiological activity better, and in particular its role in neurorepair after injury, we have studied neurorepair in a transgenic mouse model in which classical MHCI expression is up-regulated only on neurons. Using a well-established spinal cord injury (SCI) model, we observed that transgenic mice with elevated neuronal MHCI expression had significantly better recovery of locomotor abilities after SCI than wild-type mice. Although previous studies have implicated inflammation as both deleterious and beneficial for recovery after SCI, our results point directly to enhanced neuronal MHCI expression as a beneficial factor for promoting recovery of locomotor function after SCI.

  16. Enhanced expression of class I major histocompatibility complex gene (Dk) products on immunogenic variants of a spontaneous murine carcinoma.

    PubMed

    Carlow, D A; Kerbel, R S; Feltis, J T; Elliott, B E

    1985-08-01

    Both immunogenic and nonimmunogenic variant clones were isolated from a recently obtained spontaneous murine adenocarcinoma after treatment (xenogenization) with either the mutagen ethyl methanesulfonate or the DNA hypomethylating agent, and "gene activator," 5-azacytidine. Clonal analysis of the untreated tumor population confirmed that immunogenic variants arose as a consequence of the xenogenization protocol. At a dose of 10(6) cells per mouse, nonimmunogenic variants, like the parental tumor line, grew progressively in normal syngeneic recipients. In contrast, immunogenic variants were rejected in normal syngeneic mice and grew progressively only in T-cell-deficient nude mice. Serologic analysis of the respective clonal variants revealed that immunogenic variants expressed substantially elevated (fourfold to tenfold) levels of class I H-2Dk antigen relative to parental or nonimmunogenic cell lines. Two variants exhibiting marginal immunogenicity expressed high and low levels of major histocompatibility complex (MHC) antigen, respectively suggesting that elevated MHC expression, although possibly a contributing factor, did not account for the immunogenic phenotype in all cases. Finally, the immunogenic phenotype of two variants decayed with time in culture. Clones in the process of reversion lost their elevated Dk gene expression and became progressively more tumorigenic in normal syngeneic mice. Together, these data are consistent with a hypothesis that elevated MHC expression can contribute to the immunogenic phenotype of originally low MHC-expressing tumors and that the reduced level of MHC observed in certain clinical cancers may have significant implications with regard to immunologic aspects of the tumor-host relationship.

  17. Trophoblast Major Histocompatibility Complex Class I Expression Is Associated with Immune-Mediated Rejection of Bovine Fetuses Produced by Cloning.

    PubMed

    Rutigliano, Heloisa M; Thomas, Aaron J; Wilhelm, Amanda; Sessions, Benjamin R; Hicks, Brady A; Schlafer, Donald H; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Trophoblast cells from bovine somatic cell nuclear transfer (SCNT) conceptuses express major histocompatibility complex class I (MHC-I) proteins early in gestation, and this may be one cause of the significant first-trimester embryonic mortality observed in these pregnancies. MHC-I homozygous-compatible (n = 9), homozygous-incompatible (n = 8), and heterozygous-incompatible (n = 5) SCNT pregnancies were established. The control group consisted of eight pregnancies produced by artificial insemination. Uterine and placental samples were collected on Day 35 ± 1 of pregnancy, and expression of MHC-I, leukocyte markers, and cytokines were examined by immunohistochemistry. Trophoblast cells from all SCNT pregnancies expressed MHC-I, while trophoblast cells from age-matched control pregnancies were negative for MHC-I expression. Expression of MHC-I antigens by trophoblast cells from SCNT pregnancies was associated with lymphocytic infiltration in the endometrium. Furthermore, MHC-I-incompatible conceptuses, particularly the heterozygous-incompatible ones, induced a more pronounced lymphocytic infiltration than MHC-I-compatible conceptuses. Cells expressing cluster of differentiation (CD) 3, gamma/deltaTCR, and MHC-II were increased in the endometrium of SCNT pregnancies compared to the control group. CD4(+) lymphocytes were increased in MHC-I-incompatible pregnancies compared to MHC-I-compatible and control pregnancies. CD8(+), FOXP3(+), and natural killer cells were increased in MHC-I heterozygous-incompatible SCNT pregnancies compared to homozygous SCNT and control pregnancies. PMID:27385783

  18. In situ detection of autoreactive CD4 T cells in brain and heart using major histocompatibility complex class II dextramers.

    PubMed

    Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Jia, Ting; Elowsky, Christian; Li, Qingsheng; Zhou, You; Reddy, Jay

    2014-01-01

    This report demonstrates the use of major histocompatibility complex (MHC) class II dextramers for detection of autoreactive CD4 T cells in situ in myelin proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice and cardiac myosin heavy chain-α (Myhc) 334-352-induced experimental autoimmune myocarditis (EAM) in A/J mice. Two sets of cocktails of dextramer reagents were used, where dextramers(+) cells were analyzed by laser scanning confocal microscope (LSCM): EAE, IA(s)/PLP 139-151 dextramers (specific)/anti-CD4 and IA(s)/Theiler's murine encephalomyelitis virus (TMEV) 70-86 dextramers (control)/anti-CD4; and EAM, IA(k)/Myhc 334-352 dextramers/anti-CD4 and IA(k)/bovine ribonuclease (RNase) 43-56 dextramers (control)/anti-CD4. LSCM analysis of brain sections obtained from EAE mice showed the presence of cells positive for CD4 and PLP 139-151 dextramers, but not TMEV 70-86 dextramers suggesting that the staining obtained with PLP 139-151 dextramers was specific. Likewise, heart sections prepared from EAM mice also revealed the presence of Myhc 334-352, but not RNase 43-56-dextramer(+) cells as expected. Further, a comprehensive method has also been devised to quantitatively analyze the frequencies of antigen-specific CD4 T cells in the 'Z' serial images. PMID:25145797

  19. Constraints within major histocompatibility complex class I restricted peptides: Presentation and consequences for T-cell recognition

    SciTech Connect

    Theodossis, Alex; Guillonneau, Carole; Welland, Andrew; Ely, Lauren K.; Clements, Craig S.; Williamson, Nicholas A.; Webb, Andrew I.; Wilce, Jacqueline A.; Mulder, Roger J.; Dunstone, Michelle A.; Doherty, Peter C.; McCluskey, James; Purcell, Anthony W.; Turner, Stephen J.; Rossjohn, Jamie

    2010-03-24

    Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered to function as a series of 'independent pegs' that either anchor the peptide (p) to the MHC-I and/or interact with the spectrum of {alpha}{beta}-T-cell receptors (TCRs) specific for the pMHC-I epitope in question. Mining of the extensive pMHC-I structural database established that many self- and viral peptides show extensive and direct interresidue interactions, an unexpected finding that has led us to the idea of 'constrained' peptides. Mutational analysis of two constrained peptides (the HLA B44 restricted self-peptide (B44DP{alpha}-EEFGRAFSF)) and an H2-D{sup b} restricted influenza peptide (D{sup b}PA, SSLENFRAYV) demonstrated that the conformation of the prominently exposed arginine in both peptides was governed by interactions with MHC-I-orientated flanking residues from the peptide itself. Using reverse genetics in a murine influenza model, we revealed that mutation of an MHC-I-orientated residue (SSLENFRAYV {yields} SSLENARAYV) within the constrained PA peptide resulted in a diminished cytotoxic T lymphocyte (CTL) response and the recruitment of a limited pMHC-I specific TCR repertoire. Interactions between individual peptide positions can thus impose fine control on the conformation of pMHC-I epitopes, whereas the perturbation of such constraints can lead to a previously unappreciated mechanism of viral escape.

  20. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis.

    PubMed

    Song, SungWon; Miranda, Carlos J; Braun, Lyndsey; Meyer, Kathrin; Frakes, Ashley E; Ferraiuolo, Laura; Likhite, Shibi; Bevan, Adam K; Foust, Kevin D; McConnell, Michael J; Walker, Christopher M; Kaspar, Brian K

    2016-04-01

    Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity. PMID:26928464

  1. Characterization of class II β chain major histocompatibility complex genes in a family of Hawaiian honeycreepers: 'amakihi (Hemignathus virens).

    PubMed

    Jarvi, Susan I; Bianchi, Kiara R; Farias, Margaret Em; Txakeeyang, Ann; McFarland, Thomas; Belcaid, Mahdi; Asano, Ashley

    2016-07-01

    Hawaiian honeycreepers (Drepanidinae) have evolved in the absence of mosquitoes for over five million years. Through human activity, mosquitoes were introduced to the Hawaiian archipelago less than 200 years ago. Mosquito-vectored diseases such as avian malaria caused by Plasmodium relictum and Avipoxviruses have greatly impacted these vulnerable species. Susceptibility to these diseases is variable among and within species. Due to their function in adaptive immunity, the role of major histocompatibility complex genes (Mhc) in disease susceptibility is under investigation. In this study, we evaluate gene organization and levels of diversity of Mhc class II β chain genes (exon 2) in a captive-reared family of Hawaii 'amakihi (Hemignathus virens). A total of 233 sequences (173 bp) were obtained by PCR+1 amplification and cloning, and 5720 sequences were generated by Roche 454 pyrosequencing. We report a total of 17 alleles originating from a minimum of 14 distinct loci. We detected three linkage groups that appear to represent three distinct haplotypes. Phylogenetic analysis revealed one variable cluster resembling classical Mhc sequences (DAB) and one highly conserved, low variability cluster resembling non-classical Mhc sequences (DBB). High net evolutionary divergence values between DAB and DBB resemble that seen between chicken BLB system and YLB system genes. High amino acid identity among non-classical alleles from 12 species of passerines (DBB) and four species of Galliformes (YLB) was found, suggesting that these non-classical passerine sequences may be related to the Galliforme YLB sequences. PMID:26971289

  2. Major histocompatibility complex class I genes in murine fibrosarcoma IC9 are down regulated at the level of the chromatin structure.

    PubMed Central

    Maschek, U; Pülm, W; Segal, S; Hämmerling, G J

    1989-01-01

    The fibrosarcoma IC9 is deficient in the expression of the major histocompatibility complex class I genes Kb, Kk, and Dk and expresses only the Db molecule. Because class I deficiency may enable tumor cells to escape the immune response by cytotoxic T lymphocytes, we investigated why the class I genes are not expressed. Expression of the silent class I genes could not be induced, but all known DNA-binding factors specific for class I genes could be detected in nuclear extracts of IC9 cells. After cloning of the silent Kb gene from the IC9 cells and subsequent transfection of this cloned Kb gene into LTK- and IC9 cells, normal Kb antigens were expressed on the cell surface of both cell lines. Digestion of the chromatin of IC9 cells with micrococcal nuclease and DNase I showed a decreased nuclease sensitivity of the silent class I genes in comparison with active genes and the absence of DNase I hypersensitive sites in the promoter region of the silent Dk gene. These findings demonstrate that class I expression is turned off by a cis-acting regulatory mechanism at the level of the chromatin structure. Images PMID:2506438

  3. Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation

    PubMed Central

    1992-01-01

    Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide- specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide- specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo. PMID:1569402

  4. Major histocompatibility complex class I expression on neurons in subacute sclerosing panencephalitis and experimental subacute measles encephalitis

    SciTech Connect

    Gogate, N.; Yamabe, Toshio; Verma, L.; Dhib-Jalbut, S.

    1996-04-01

    Lack of major histocompatibility class I antigens on neurons has been implicated as a possible mechanism for viral persistence in the brain since these antigens are required for cytotoxic T-lymphocyte recognition of infected cells. In subacute sclerosing panencephalitis (SSPE), measles virus (MV) persists in neurons, resulting in a fatal chronic infection. MHC class I mRNA expression was examined in formalin-fixed brain tissue from 6 SSPE patients by in situ hybridization. In addition MHC class I protein expression in MV-infected neurons was examined in experimental Subacute Measles Encephalitis (SME) by double immunohistochemistry. MHC class I mRNA expression was found to be upregulated in SSPE tissues studied, and in 5 out of 6 cases the expression was definitively seen on neurons. The percentage of neurons expressing MHC class I mRNA ranged between 20 to 84% in infected areas. There was no correlation between the degree of infection and expression of MHC class I molecules on neurons. Importantly, the number of neurons co-expressing MHC class I and MV antigens was markedly low, varying between 2 to 8%. Similar results were obtained in SME where 20 to 30% of the neurons expressed MHC class I but < 8% co-expressed MHC class I and MV antigens. Perivascular infiltrating cells in the infected regions in SME expressed IFN{gamma} immunoreactivity. The results suggest that MV may not be directly involved in the induction of MHC class I on neurons and that cytokines such as IFN{gamma} may play an important role. Furthermore, the paucity of neurons co-expressing MHC class I and MV antigens in SSPE and SME suggests that such cells are either rapidly cleared by cytotoxic T lymphocytes (CTL), or, alternatively, lack of co-expression of MHC class I on MV infected neurons favors MV persistence in these cells by escaping CTL recognition. 33 refs., 3 figs., 3 tabs.

  5. Genetic Variation on the BAT1-NFKBIL1-LTA Region of Major Histocompatibility Complex Class III Associates with Periodontitis

    PubMed Central

    Marchesani, Marja; Vlachopoulou, Efthymia; Mäntylä, Päivi; Paju, Susanna; Buhlin, Kåre; Suominen, Anna L.; Contreras, Johanna; Knuuttila, Matti; Hernandez, Marcela; Huumonen, Sisko; Nieminen, Markku S.; Perola, Markus; Sinisalo, Juha; Lokki, Marja-Liisa; Pussinen, Pirkko J.

    2014-01-01

    Periodontitis is a chronic inflammatory disease with a multifactorial etiology. We investigated whether human major histocompatibility complex (MHC) polymorphisms (6p21.3) are associated with periodontal parameters. Parogene 1 population samples (n = 169) were analyzed with 13,245 single nucleotide polymorphisms (SNPs) of the MHC region. Eighteen selected SNPs (P ≤ 0.001) were replicated in Parogene 2 population samples (n = 339) and the Health 2000 Survey (n = 1,420). All subjects had a detailed clinical and radiographic oral health examination. Serum lymphotoxin-α (LTA) concentrations were measured in the Parogene populations, and the protein was detected in inflamed periodontal tissue. In the Parogene 1 population, 10 SNPs were associated with periodontal parameters. The strongest associations emerged from the parameters bleeding on probing (BOP) and a probing pocket depth (PPD) of ≥6 mm with the genes BAT1, NFKBIL1, and LTA. Six SNPs, rs11796, rs3130059, rs2239527, rs2071591, rs909253, and rs1041981 (r2, ≥0.92), constituted a risk haplotype. In the Parogene 1 population, the haplotype had the strongest association with the parameter BOP, a PPD of ≥6 mm, and severe periodontitis with odds ratios (95% confidence intervals) of 2.63 (2.21 to 3.20), 2.90 (2.37 to 3.52), and 3.10 (1.63 to 5.98), respectively. These results were replicated in the other two populations. High serum LTA concentrations in the Parogene population were associated with the periodontitis risk alleles of the LTA SNPs (rs909253 and rs1041981) of the haplotype. In addition, the protein was expressed in inflamed gingival connective tissue. We identified a novel BAT1-NFKBIL1-LTA haplotype as a significant contributor to the risk of periodontitis. The genetic polymorphisms in the MHC class III region may be functionally important in periodontitis susceptibility. PMID:24566624

  6. Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

    NASA Technical Reports Server (NTRS)

    Stewart, Patricia W.; Chapes, Stephen K.

    2003-01-01

    Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

  7. Human class II major histocompatibility complex gene transfer into murine neuroblastoma leads to loss of tumorigenicity, immunity against subsequent tumor challenge, and elimination of microscopic preestablished tumors.

    PubMed

    Hock, R A; Reynolds, B D; Tucker-McClung, C L; Kwok, W W

    1995-01-01

    Immunological recognition of transformed cells is critically important to limit tumor development and proliferation. Because established tumors have escaped immune recognition and elimination, novel strategies to enhance antitumor immunity have been developed. A unique approach has used the introduction of genes encoding major histocompatibility complex (MHC) antigens into tumor cells. Experiments in mice have shown that the expression of syngeneic class II MHC antigens in tumor cells completely abrogates tumorigenicity and induces tumor-specific immunity. In this study we sought to determine whether a more effective antitumor immune response would be generated by introducing xenogeneic class II MHC genes into tumor cells. To address this question we used recombinant retroviruses to express human class II MHC genes in a highly malignant murine neuroblastoma cell line, Neuro-2a. We found that normal mice inoculated with Neuro-2a expressing the human class II MHC antigen did not develop tumors and were immune to subsequent challenge with unmodified Neuro-2a cells. In addition, mice bearing small established Neuro-2a tumors were cured by vaccination with Neuro-2a expressing human class II MHC. We hypothesize that a similar approach using retroviral-mediated transduction of class II MHC genes into human tumor cells may be an effective alternative to current cancer treatment.

  8. CD4 binding to major histocompatibility complex class II antigens induces LFA-1-dependent and -independent homotypic adhesion of B lymphocytes.

    PubMed

    Kansas, G S; Cambier, J C; Tedder, T F

    1992-01-01

    T helper cells recognize processed antigen (Ag) in the context of major histocompatibility complex (MHC) class II antigens present on the surface of B cells and other Ag-presenting cells. This interaction is mediated through the T cell receptor complex with associate recognition of class II molecules by the CD4 molecule. In this study, the binding of a soluble recombinant CD4/Ig heavy chain fusion protein (CD4-gamma 3) or monoclonal antibody (mAb) to class II antigens on human B cells was shown to induce rapid and specific homotypic adhesion of B cells and most B lymphoblastoid cell lines. mAb reactive with CD4 inhibited CD4-gamma 3-induced adhesion and a mutant B lymphoblastoid cell line deficient in class II antigens failed to respond. Induction of homotypic adhesion was dependent on energy metabolism and a functional cytoskeleton, and class II+ pre-B cells did not exhibit adhesion in response to these stimuli, suggesting that cross-linking of class II molecules generated a transmembrane signal and did not simply aggregate cells. In addition, MHC class II-induced adhesion was Fc receptor independent, as 15 mAb of different Ig isotypes reactive with HLA-D or HLA-DQ gene products induced adhesion. Anti-class II mAb and CD4-gamma 3 were able to induce adhesion at concentrations as low as 10 ng/ml and 100 ng/ml, respectively. Suboptimal stimulation of B cell lines through HLA-D antigens induced homotypic adhesion that was dependent on the activation of LFA-1 (CD11a/CD18), and which could be blocked by specific mAb. However, at greater signal strengths, adhesion was not blocked by mAb against the known adhesion receptors, suggesting the induction of a novel adhesion pathway. Consistent with this, homotypic adhesion induced by engagement of MHC class II antigens was observed with LFA-1-deficient B cell lines, and was independent of CD49d or CD18 expression. Thus, the direct engagement of B cell class II antigens by CD4 is likely to generate transmembrane signals which

  9. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases.

    PubMed

    Fruci, D; Romania, P; D'Alicandro, V; Locatelli, F

    2014-08-01

    Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases.

  10. A synthetic peptide from the third hypervariable region of major histocompatibility complex class II beta chain as a vaccine for treatment of experimental autoimmune encephalomyelitis.

    PubMed Central

    Topham, D J; Nag, B; Arimilli, S; Sriram, S

    1994-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a class II major histocompatibility complex (MHC)-restricted, T-cell-mediated, demyelinating autoimmune disease of the central nervous system and represents a model for human multiple sclerosis. The present study demonstrates that vaccination of SJL/J mice with an 18-amino acid synthetic peptide from the third hypervariable region of the murine class II MHC IAs beta chain (IAs beta 58-75; 18-mer peptide) is capable of eliciting auto-anti-IAs antibodies specific for the IAs beta chain and preventing and treating EAE. A similar approach may be useful in the treatment of human autoimmune diseases in which susceptibility is linked to class II MHC genes. Images PMID:8058747

  11. Antigen processing by epidermal Langerhans cells correlates with the level of biosynthesis of major histocompatibility complex class II molecules and expression of invariant chain

    PubMed Central

    1990-01-01

    Two prior studies with a small number of T cell lines have shown that the presentation of native protein antigens by epidermal Langerhans cells (LC) is regulated. When freshly isolated, LC are efficient antigen-presenting cells (APC), but after a period of culture LC are inefficient or even inactive. The deficit in culture seems to be a selective loss in antigen processing, since cultured LC are otherwise rich in major histocompatibility complex (MHC) class II products and are active APC for alloantigens and mitogens, which do not require processing. We have extended the analysis by studying presentation to bulk populations of primed lymph node and a T-T hybrid. Only freshly isolated LC can be pulsed with the protein antigens myoglobin and conalbumin, but once pulsed, antigen is retained in an immunogenic form for at least 2 d. The acquisition of antigen, presumably as MHC-peptide complexes, is inhibited if the fresh LC are exposed to foreign protein in the presence of chloroquine or cycloheximide. The latter, in contrast, improves the efficacy of antigen pulsing in anti-Ig- stimulated B blasts. In additional studies of mechanism, we noted that both fresh and cultured LC endocytose similar amounts of an antigen, rhodamineovalbumin, into perinuclear granules. However, freshly isolated LC synthesize high levels class II MHC molecules and express higher amounts of the class II-associated invariant chain. Fresh LC are at least 5-10 times more active than many other cells types in the level of biosynthesis of MHC class II products. These findings provide a physiologic model in which newly synthesized MHC class II molecules appear to be the principal vehicle for effective antigen processing by APC of the dendritic cell lineage. Another APC, the B lymphoblast, does not appear to require newly synthesized MHC class II molecules for presentation. PMID:2121888

  12. Major histocompatibility complex class I-specific and -restricted killing of beta 2-microglobulin-deficient cells by CD8+ cytotoxic T lymphocytes.

    PubMed Central

    Glas, R; Franksson, L; Ohlén, C; Höglund, P; Koller, B; Ljunggren, H G; Kärre, K

    1992-01-01

    Cytotoxic T lymphocytes (CTLs) recognize major histocompatibility complex (MHC) class I molecules, normally composed of a heavy chain, a beta 2-microglobulin (beta 2m), and peptide antigens. beta 2m is considered essential for the assembly and intracellular transport of MHC class I molecules as well as their peptide presentation to CTLs. Contrary to this dogma, we now report the generation of allospecific and restricted CD8+ and TCR alpha beta+ CTLs (where TCR is T-cell receptor) capable of killing beta 2m-deficient cells. Such CTLs were obtained by priming mice with live allogeneic beta 2m- spleen cells or mutant lymphoma cells producing MHC class I protein but no detectable beta 2m. Although both beta 2m- and beta 2m-expressing lymphoma cells were rejected in allogeneic mice, only the former were efficient inducers of CTLs recognizing beta 2m- cells. These CTLs were MHC class I (H-2Kb or Db)-specific and CD8-dependent and did not require serum as a source of external beta 2m in the culture. They could be induced across major and minor histocompatibility barriers. The H-2-restricted CTLs generated in the latter case failed to kill the antigen-processing-deficient target RMA-S cells. The results show that MHC class I heavy chains in beta 2m- cells can be transported to the cell surface and act as antigens or antigen-presenting molecules to allospecific and MHC-restricted CTLs. PMID:1454824

  13. Major histocompatibility complex class II dextramers: New tools for the detection of antigen-specific, CD4 T cells in basic and clinical research

    PubMed Central

    Massilamany, Chandirasegaran; Krishnan, Bharathi; Reddy, Jay

    2015-01-01

    The advent of major histocompatibility complex (MHC) tetramer technology has been a major contribution to T cell immunology, because tetramer reagents permit detection of antigen-specific T cells at the single-cell level in heterogeneous populations by flow cytometry. However, unlike MHC class I tetramers, the utility of MHC class II tetramers has been less frequently reported. MHC class II tetramers can be used successfully to enumerate the frequencies of antigen-specific CD4 T cells in cells activated in vitro, but their use for ex vivo analyses continues to be a problem, due in part to their activation dependency for binding with T cells. To circumvent this problem, we recently reported the creation of a new generation of reagents called MHC class II dextramers, which were found to be superior to their counterparts. In this review, we discuss the utility of class II dextramers vis-a-vis tetramers, with respect to their specificity and sensitivity, including potential applications and limitations. PMID:26207337

  14. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule.

    SciTech Connect

    Wang, J.-H.; Meijers, R.; Xiong, Y.; Liu, J.-H.; Sakihama, T.; Zhang, R.-G.; Joachimiak, A.; Reinherz, E. L.; Biosciences Division; Dana-Farber Cancer Inst.; Harvard Medical School

    2001-09-11

    The structural basis of the interaction between the CD4 coreceptor and a class II major histocompatibility complex (MHC) is described. The crystal structure of a complex containing the human CD4 N-terminal two-domain fragment and the murine I-A{sup k }class II MHC molecule with associated peptide (pMHCII) shows that only the 'top corner' of the CD4 molecule directly contacts pMHCII. The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both {alpha}2 and {beta}2 domains. A ternary model of the CD4-pMHCII-T-cell receptor (TCR) reveals that the complex appears V-shaped with the membrane-proximal pMHCII at the apex. This configuration excludes a direct TCR-CD4 interaction and suggests how TCR and CD4 signaling is coordinated around the antigenic pMHCII complex. Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHCII. Additional contacts between gp120 and CD4 give the CD4-gp120 complex a greater affinity. Thus, ligation of the viral envelope glycoprotein to CD4 occludes the pMHCII-binding site on CD4, contributing to immunodeficiency.

  15. A mechanism for repression of class II gene transcription through specific binding of NC2 to TBP-promoter complexes via heterodimeric histone fold domains.

    PubMed Central

    Goppelt, A; Stelzer, G; Lottspeich, F; Meisterernst, M

    1996-01-01

    Negative co-factor 2 (NC2) regulates transcription of the class II genes through binding to TFIID and inhibition of pre-initiation complex formation. We have isolated and cloned NC2, and investigated the molecular mechanism underlying repression of transcription. NC2 consists of two subunits, termed NC2alpha and NC2beta, the latter of which is identical to Dr1. The NC2 subunits dimerize and bind to TATA binding protein (TBP)-promoter complexes via histone fold domains of the H2A-H2B type. Repression of basal transcription requires the histone fold and carboxy-terminal domains of the NC2 subunits. Several mechanisms probably contribute to transcriptional repression. Binding of NC2 inhibits association of TFIIB with TBP-promoter complexes. NC2 binds directly to DNA, and binding of NC2 to TBP-promoter complexes affects the conformation of DNA, which could be one cause for the inhibition of TFIIB. In addition, multimerization of repressor-TBP complexes on DNA might inhibit the assembly of the pre-initiation complex. We suggest that binding of the repressor to TRP-promoter complexes establishes a mechanism that controls the rate of transcription by RNA polymerase II. Images PMID:8670811

  16. Immune complexes (IC) down-regulate the basal and interferon-γ-induced expression of MHC Class II on human monocytes

    PubMed Central

    Barrionuevo, P; Beigier-Bompadre, M; De La Barrera, S; Alves-Rosa, M F; Fernandez, G; Palermo, M S; Isturiz, M A

    2001-01-01

    The interaction of Fc receptors for IgG (FcγRs) on monocytes/macrophages with immune complexes (IC) triggers regulatory and effector functions. Previous studies have shown that FcγR–IC interactions inhibit the IFN-γ-induced expression of MHC class II in murine macrophages. However, the mechanism(s) responsible for these effects have not been elucidated. In addition, whether this IC-dependent effect also occurs in human cells is not known. Taking into account the fact that IC and IFN-γ are frequently found in infections and autoimmune disorders, together with the crucial role MHC class II molecules play in the regulation of immune response, we explored the effect and mechanism of IC-induced MHC class II down-regulation in human peripheral blood mononuclear cells (PBMC). This effect was studied either in the presence or absence of IFN-γ. We demonstrate that IC exert a drastic inhibition of basal and IFN-γ-induced expression of MHC class II on human monocytes. This effect was mediated through the interaction of IC with both FcγRI and FcγRII. Moreover, similar results were obtained using supernatants from IC-treated PBMC. The IC-induced down-regulation of MHC class II is abrogated by pepstatin and phosphoramidon, supporting the role of aspartic protease(s) and metalloprotease(s) in this process. In parallel with MHC class II expression, antigen presentation was markedly inhibited in the presence of IC. PMID:11529917

  17. Metal complexes of ONO donor Schiff base ligand as a new class of bioactive compounds; Synthesis, characterization and biological evolution

    NASA Astrophysics Data System (ADS)

    Kumar Naik, K. H.; Selvaraj, S.; Naik, Nagaraja

    2014-10-01

    Present work reviews that, the synthesis of (E)-N";-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide [L] ligand and their metal complexes. The colored complexes were prepared of type [M2+L]X2, where M2+ = Mn, Co, Ni, Cu, Sr and Cd, L = (7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide, X = Cl-. Ligand derived from the condensation of 8-formyl-7-hydroxy-4-methylcoumarin and benzohydrazide in the molar ratio 1:1 and in the molar ratio 1:2 for metal complexes have been prepared. The chelation of the ligand to metal ions occurs through the both oxygen groups, as well as the nitrogen atoms of the azomethine group of the ligand. Reactions of the Schiff base ligand with Manganese(II), Cobalt(II), Nickel(II), Copper(II), Strontium(II), and Cadmium(II) afforded the corresponding metal complexes. The structures of the obtained ligand and their respective metal complexes were elucidated by infra-red, elemental analysis, Double beam UV-visible spectra, conductometric measurements, magnetic susceptibility measurements and also thermochemical studies. The metal complex exhibits octahedral coordination geometrical arrangement. Schiff base ligand and their metal complexes were tested against antioxidants, antidiabetic and antimicrobial activities have been studied. The Schiff base metal complexes emerges effective α-glucosidase inhibitory activity than free Schiff base ligand.

  18. Metal complexes of ONO donor Schiff base ligand as a new class of bioactive compounds: synthesis, characterization and biological evolution.

    PubMed

    Kumar Naik, K H; Selvaraj, S; Naik, Nagaraja

    2014-10-15

    Present work reviews that, the synthesis of (E)-N'-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide [L] ligand and their metal complexes. The colored complexes were prepared of type [M(2+)L]X2, where M(2+)=Mn, Co, Ni, Cu, Sr and Cd, L=(7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide, X=Cl(-). Ligand derived from the condensation of 8-formyl-7-hydroxy-4-methylcoumarin and benzohydrazide in the molar ratio 1:1 and in the molar ratio 1:2 for metal complexes have been prepared. The chelation of the ligand to metal ions occurs through the both oxygen groups, as well as the nitrogen atoms of the azomethine group of the ligand. Reactions of the Schiff base ligand with Manganese(II), Cobalt(II), Nickel(II), Copper(II), Strontium(II), and Cadmium(II) afforded the corresponding metal complexes. The structures of the obtained ligand and their respective metal complexes were elucidated by infra-red, elemental analysis, Double beam UV-visible spectra, conductometric measurements, magnetic susceptibility measurements and also thermochemical studies. The metal complex exhibits octahedral coordination geometrical arrangement. Schiff base ligand and their metal complexes were tested against antioxidants, antidiabetic and antimicrobial activities have been studied. The Schiff base metal complexes emerges effective α-glucosidase inhibitory activity than free Schiff base ligand.

  19. Development of novel major histocompatibility complex class I and class II-deficient NOD-SCID IL2R gamma chain knockout mice for modeling human xenogeneic graft-versus-host disease.

    PubMed

    Pino, Steve; Brehm, Michael A; Covassin-Barberis, Laurence; King, Marie; Gott, Bruce; Chase, Thomas H; Wagner, Jennifer; Burzenski, Lisa; Foreman, Oded; Greiner, Dale L; Shultz, Leonard D

    2010-01-01

    Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdc ( scid ) (scid) and recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rgamma) have been reported. The addition of the mutated IL2rgamma gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rgamma gene have been studied in several laboratories on NOD-scid, NOD-Rag1 ( null ), BALB/c-Rag1 ( null ), BALB/c-Rag2 ( null ), and Stock-H2(d)-Rag2 ( null ) strain backgrounds. Parameters to induce human xeno-GVHD in H2(d)-Rag2 ( null ) IL2rgamma ( null ) mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rgamma ( null ) stock that engrafts more readily with human PBMC than does the Stock-H2(d)-Rag2 ( null ) IL2rgamma ( null ) stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rgamma ( null ) beta2m ( null ) and NOD-scid IL2rgamma ( null ) Ab ( null ) stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rgamma ( null ) stocks that engraft at high

  20. A Class of Multiresponsive Colorimetric and Fluorescent pH Probes via Three Different Reaction Mechanisms of Salen Complexes: A Selective and Accurate pH Measurement.

    PubMed

    Cheng, Jinghui; Gou, Fei; Zhang, Xiaohong; Shen, Guangyu; Zhou, Xiangge; Xiang, Haifeng

    2016-09-19

    We report a class of multiresponsive colorimetric and fluorescent pH probes based on three different reaction mechanisms including cation exchange, protonation, and hydrolysis reaction of K(I), Ca(II), Zn(II), Cu(II), Al(III), and Pd(II) Salen complexes. Compared with traditional pure organic pH probes, these complex-based pH probes exhibited a much better selectivity due to the shielding function of the filled-in metal ion in the complex. Their pH sensing performances were affected by the ligand structure and the central metal ion. This work is the first report of "off-on-on'-off" colorimetric and fluorescent pH probes that possess three different reaction mechanisms and should inspire the design of multiple-responsive probes for important analytes in biological systems.

  1. Cloning and modeling of CD8 beta in the amphibian ambystoma Mexicanum. Evolutionary conserved structures for interactions with major histocompatibility complex (MHC) class I molecules.

    PubMed

    Fellah, Julien S; Tuffèry, Pierre; Etchebest, Catherine; Guillet, Françoise; Bleux, Christian; Charlemagne, Jacques

    2002-04-17

    Mammalian and avian T-cells exhibit a large number of well characterized surface molecules associated with their maturation degree. Very little is known in comparison with T-cell differentiation in ectothermic vertebrates. This is mainly due to the lack of probes to identify T-cell subsets. We cloned and sequenced the first ectothermic CD8 beta DNA complementary to RNA from an amphibian species, the Mexican axolotl. The CD8 beta chain was 30-36% identical with its avian and mammalian homologues. The extracellular V-like domain contained the two typically conserved cysteines and was followed by a J-like sequence containing the canonical Phe-Gly-X-Gly stretch. The connecting peptide was much longer than in other species and contained potential O-glycosylation sites. The axolotl CD8 beta and major histocompatibility complex class I molecules were modeled using human HLA-A2/CD8 alphaalpha complex as template. The backbone conformation of axolotl CD8 beta matched well with the CD8 alpha-2 subunit of the human complex but significant structural differences were located in the CDR1, CDR2 and DE loops. Both axolotl and human class I showed large negative surface potential. The interacting area of the human CD8 alpha chain and of the corresponding region of axolotl CD8 beta had positive electrostatic potential compatible with complexation with the corresponding class I molecules. The presence of a CD8 beta homologue in an amphibian species implies that it was already present in the Devonian ancestor of amphibians and mammals, i.e. more than 400 million years ago. PMID:12034498

  2. Evolution of the major histocompatibility complex: Isolation of class II beta cDNAs from two monotremes, the platypus and the short-beaked echidna.

    PubMed

    Belov, Katherine; Lam, Mary K P; Hellman, Lars; Colgan, Donald J

    2003-09-01

    Extant mammals are composed of three lineages: the eutherians, the marsupials and the monotremes. The majority of the mammalian major histocompatibility complex (MHC) data is based on the eutherian mammals, which generally have three classical MHC class II beta chain gene clusters - DRB, DQB and DPB, as well as the non-classical DMB and DOB. Marsupial DMB, DAB and DBB have been characterised. Confusion still surrounds the relationship of the marsupial DAB and DBB genes with the classical eutherian class II clusters. Here we present the first monotreme MHC class II beta chain sequences. Four MHC class II beta chain sequences were isolated from a spleen cDNA library from the short-beaked echidna, and one from a spleen cDNA library from platypus using a brushtail possum DAB probe. Given the non-orthologous relationship of the monotreme sequences with marsupial and eutherian beta chain clusters, we recommend that the five new monotreme sequences be assigned the nomenclature 'DZB', signifying the description of a new mammalian beta chain cluster. Our analysis suggests that all mammalian beta chain sequences (except DMB) evolved from a common ancestor. Maximum likelihood analysis places the monotreme beta chain sequences at the base of the mammalian clade, indicating their ancestral status. However, within the mammalian clade, monophyletic clades are not robust, and elucidation of the order of gene duplication that gave rise to the present-day gene clusters is not yet possible.

  3. Gene Conversion in the Evolution of Both the H-2 and Qa Class I Genes of the Murine Major Histocompatibility Complex

    PubMed Central

    Kuhner, M.; Watts, S.; Klitz, W.; Thomson, G.; Goodenow, R. S.

    1990-01-01

    In order to better understand the role of gene conversion in the evolution of the class I gene family of the major histocompatibility complex (MHC), we have used a computer algorithm to detect clustered sequence similarities among 24 class I DNA sequences from the H-2, Qa, and Tla regions of the murine MHC. Thirty-four statistically significant clusters were detected; individual analysis of the clusters suggested at least 25 past gene conversion or recombination events. These clusters are comparable in size to the conversions observed in the spontaneously occurring H-2K(bm) and H-2K(km2) mutations, and are distributed throughout all exons of the class I gene. Thus, gene conversion does not appear to be restricted to the regions of the class I gene encoding their antigen-presentation function. Moreover, both the highly polymorphic H-2 loci and the relatively monomorphic Qa and Tla loci appear to have participated as donors and recipients in conversion events. If gene conversion is not limited to the highly polymorphic loci of the MHC, then another factor, presumably natural selection, must be responsible for maintaining the observed differences in level of variation. PMID:2076814

  4. Major Histocompatibility Complex Class II Expression and Hemagglutinin Subtype Influence the Infectivity of Type A Influenza Virus for Respiratory Dendritic Cells ▿

    PubMed Central

    Hargadon, Kristian M.; Zhou, Haixia; Albrecht, Randy A.; Dodd, Haley A.; García-Sastre, Adolfo; Braciale, Thomas J.

    2011-01-01

    Dendritic cells (DC) play a key role in antiviral immunity, functioning both as innate effector cells in early phases of the immune response and subsequently as antigen-presenting cells that activate the adaptive immune response. In the murine respiratory tract, there are several respiratory dendritic cell (RDC) subsets, including CD103+ DC, CD11bhi DC, monocyte/macrophage DC, and plasmacytoid DC. However, little is known about the interaction between these tissue-resident RDC and viruses that are encountered during natural infection in the respiratory tract. Here, we show both in vitro and in vivo that the susceptibility of murine RDC to infection with type A influenza virus varies with the level of MHC class II expression by RDC and with the virus strain. Both CD103+ and CD11bhi RDC, which express the highest basal level of major histocompatibility complex (MHC) class II, are highly susceptible to infection by type A influenza virus. However, efficient infection is restricted to type A influenza virus strains of the H2N2 subtype. Furthermore, enhanced infectivity by viruses of the H2N2 subtype is linked to expression of the I-E MHC class II locus product. These results suggest a potential novel role for MHC class II molecules in influenza virus infection and pathogenesis in the respiratory tract. PMID:21917972

  5. Characterization of the oligodeoxynucleotide-mediated inhibition of interferon-gamma-induced major histocompatibility complex class I and intercellular adhesion molecule-1.

    PubMed

    Ramanathan, M; Lantz, M; MacGregor, R D; Garovoy, M R; Hunt, C A

    1994-10-01

    The major histocompatibility complex (MHC) Class I and II genes and intercellular adhesion molecule-1 (ICAM-1) are regulated by interferon-gamma in a variety of cell types. We have previously shown that the oligodeoxynucleotide 5'-GGG GTT GGT TGT GTT GGG TGT TGT GT-RNH2 (oligo I) inhibits the interferon-gamma-mediated enhancement of MHC Class I and ICAM-1 proteins in the K562 cell line. We have now investigated the mechanism of action of oligo I and report that it acts by inhibiting the binding of interferon-gamma to cells. We also show that the dose-response curves, the selectivity profile, and the kinetics of oligo I are consistent with this novel mechanism of action. The dose-response curves for oligo I, obtained using antibodies against the MHC Class I heavy chain, beta 2-microglobulin, or ICAM-1, are almost superimposable at each observation time. MHC Class I induction by 6400 units/ml interferon-alpha or interferon-beta or ICAM-1 enhancement by 800 units/ml tumor necrosis factor-alpha is not inhibited by oligo I. However, the synergistic induction of MHC Class I by mixtures of tumor necrosis factor-alpha and interferon-gamma is inhibited. Oligo I belongs to a class of active oligodeoxynucleotides that inhibits interferon-gamma-induced MHC Class I and ICAM-1 in K562 cells. The activity and potency is sequence-dependent, but remarkably different sequences can have comparable effects. The activity of oligo I in the HeLa S3 cell line inhibits the interferon-gamma-mediated enhancement of both ICAM-1 and MHC Class II DR and the interferon-gamma-mediated reduction in transferrin receptor expression. Thus, oligo I appears to specifically inhibit interferon-gamma-induced changes in protein expression, which is consistent with oligo I acting at an early step(s) in the induction process. Taken together, our results show that oligo I exerts its effects by inhibiting the association of interferon-gamma with the cell surface, which is a novel mechanism of action for

  6. A step-by-step overview of the dynamic process of epitope selection by major histocompatibility complex class II for presentation to helper T cells

    PubMed Central

    Sadegh-Nasseri, Scheherazade

    2016-01-01

    T cell antigen receptors (TCRs) expressed on cytotoxic or helper T cells can only see their specific target antigen as short sequences of peptides bound to the groove of proteins of major histocompatibility complex (MHC) class I, and class II respectively. In addition to the many steps, several participating proteins, and multiple cellular compartments involved in the processing of antigens, the MHC structure, with its dynamic and flexible groove, has perfectly evolved as the underlying instrument for epitope selection. In this review, I have taken a step-by-step, and rather historical, view to describe antigen processing and determinant selection, as we understand it today, all based on decades of intense research by hundreds of laboratories. PMID:27347387

  7. Latent class model with familial dependence to address heterogeneity in complex diseases: adapting the approach to family-based association studies.

    PubMed

    Bureau, Alexandre; Croteau, Jordie; Tayeb, Arafat; Mérette, Chantal; Labbe, Aurélie

    2011-04-01

    Clinical diagnoses of complex diseases may often encompass multiple genetically heterogeneous disorders. One way of dissecting this heterogeneity is to apply latent class (LC) analysis to measurements related to the diagnosis, such as detailed symptoms, to define more homogeneous disease sub-types, influenced by a smaller number of genes that will thus be more easily detectable. We have previously developed a LC model allowing dependence between the latent disease class status of relatives within families. We have also proposed a strategy to incorporate the posterior probability of class membership of each subject in parametric linkage analysis, which is not directly transferable to genetic association methods. Under the framework of family-based association tests (FBAT), we now propose to make the contribution of an affected subject to the FBAT statistic proportional to his or her posterior class membership probability. Simulations showed a modest but robust power advantage compared to simply assigning each subject to his or her most probable class, and important power gains over the analysis of the disease diagnosis without LC modeling under certain scenarios. The use of LC analysis with FBAT is illustrated using autism spectrum disorder (ASD) symptoms on families from the Autism Genetics Research Exchange, where we examined eight regions previously associated to autism in this sample. The analysis using the posterior probability of membership to an LC detected an association in the JARID2 gene as significant as that for ASD (P = 3 × 10(-5)) but with a larger effect size (odds ratio = 2.17 vs. 1.55).

  8. Complex Phenotypic and Genotypic Responses of Listeria monocytogenes Strains Exposed to the Class IIa Bacteriocin Sakacin P▿ †

    PubMed Central

    Tessema, Girum Tadesse; Møretrø, Trond; Kohler, Achim; Axelsson, Lars; Naterstad, Kristine

    2009-01-01

    Sakacin P is a class IIa bacteriocin that is active against the food-borne pathogen Listeria monocytogenes, and use of this compound as a biopreservative in foods has been suggested. In the present study, we characterized 30 spontaneous sakacin P-resistant mutants of L. monocytogenes obtained after single exposure to sakacin P. The frequency of development of sakacin P resistance for all strains was in the range from 10−8 to 10−9. Using the 50% inhibitory concentration (IC50) of sakacin P, the strains could be grouped into strains with high levels of resistance (IC50, ≥104 ng ml−1) and strains with low levels of resistance (IC50, <104 ng ml−1). Resistant strains belonging to the same IC50 group also had similar physiological and genetic characteristics. Generally, the resistant strains showed substantial variations in many parameters, such as differences in the stability of the acquired resistance to sakacin P, growth fitness, food-related stress tolerance, and biofilm-forming ability. Fourier transform infrared spectroscopy revealed differences between wild-type and resistant strains in polysaccharide, fatty acid, and, protein regions. A mannose-specific phosphotransferase (PTS) operon has been described for class IIa bacteriocin resistance, and the sakacin P-resistant strains displayed both up- and downregulation of the expression of the mptA gene encoding the PTS system. This is the first comprehensive study of the diversity of a large number of spontaneous resistant mutants obtained after one exposure to a class IIa bacteriocin, particularly to sakacin P. The great diversity among the resistant strains exposed to the same stress conditions suggests that there are different resistance mechanisms. PMID:19767478

  9. Murine aortic smooth muscle cells acquire, though fail to present exogenous protein antigens on major histocompatibility complex class II molecules.

    PubMed

    Maddaluno, Marcella; MacRitchie, Neil; Grassia, Gianluca; Ialenti, Armando; Butcher, John P; Garside, Paul; Brewer, James M; Maffia, Pasquale

    2014-01-01

    In the present study aortic murine smooth muscle cell (SMC) antigen presentation capacity was evaluated using the Eα-GFP/Y-Ae system to visualize antigen uptake through a GFP tag and tracking of Eα peptide/MHCII presentation using the Y-Ae Ab. Stimulation with IFN-γ (100 ng/mL) for 72 h caused a significant (P < 0.01) increase in the percentage of MHC class II positive SMCs, compared with unstimulated cells. Treatment with Eα-GFP (100 μg/mL) for 48 h induced a significant (P < 0.05) increase in the percentage of GFP positive SMCs while it did not affect the percentage of Y-Ae positive cells, being indicative of antigen uptake without its presentation in the context of MHC class II. After IFN-γ-stimulation, ovalbumin- (OVA, 1 mg/mL) or OVA323-339 peptide-(0.5 μg/mL) treated SMCs failed to induce OT-II CD4(+) T cell activation/proliferation; this was also accompanied by a lack of expression of key costimulatory molecules (OX40L, CD40, CD70, and CD86) on SMCs. Finally, OVA-treated SMCs failed to induce DO11.10-GFP hybridoma activation, a process independent of costimulation. Our results demonstrate that while murine primary aortic SMCs express MHC class II and can acquire exogenous antigens, they fail to activate T cells through a failure in antigen presentation and a lack of costimulatory molecule expression.

  10. Monocyclometalated gold(III) monoaryl complexes--a new class of triplet phosphors with highly tunable and efficient emission properties.

    PubMed

    Szentkuti, Alexander; Bachmann, Michael; Garg, Jai Anand; Blacque, Olivier; Venkatesan, Koushik

    2014-02-24

    Highly tunable and rich phosphorescent emission properties based on the stable monocyclometalated gold(III) monoaryl structural motif are reported. Monochloro complexes of the type cis-[(N^C)Au(C6 H2 (CF3)3)(Cl)] N^C=2-phenylpyridine (ppy)] (1), [N^C=benzo[h]quinoline (bzq)] (2), [N^C=2-(5-Methyl-2-thienyl)pyridine (5m-thpy)] (3) were successfully prepared in modest to good yields by reacting an excess of 2, 4, 6-tris(trifluoromethyl)phenyl lithium (LiFmes) with the corresponding dichloride complexes cis-[(N^C)AuCl2]. Subsequent replacement of the chloride ligand in 1 with strong ligand field strength such as cyanide and terminal alkynes resulted in complexes of the type cis-[(ppy)Au(Fmes)(R)] R=CN (4), I (5), C≡C-C6 H5 (6) and C≡C-C6 H4 N(C6 H5)-p (7). Single crystal X-ray diffraction studies of all the complexes except 7 were performed to further corroborate their chemical identity. Thermogravimetric analysis (TGA) studies of the uncommon cis configured aryl alkyne complex 7 confirmed the high stability of this complex. Detailed photophysical investigations carried out in solution at room temperature, at 77 K (2-MeTHF) in rigidified media, solid state and 5 wt % PMMA revealed the phosphorescent nature of emission in these complexes. Additionally, their behavior was found to be governed based on both the nature of the cyclometalated ligand and the electronic properties of the ancillary ligands. Highly efficient interligand charge transfer in complex 7 provides access to a wide range of emission colors (solvent-dependent) from deep blue to red with phosphorescence emission quantum yield of 30 % (441 nm) and 39 % (622 nm) in solution and solid state, respectively, and is the highest reported for any Au(III) complexes. DFT and TDDFT calculations carried out further validated the observations and assignments based on the photophysical experimental findings. PMID:24481957

  11. Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells.

    PubMed

    Weiler, Andrea M; Das, Arpita; Akinyosoye, Oluwasayo; Cui, Sherry; O'Connor, Shelby L; Scheef, Elizabeth A; Reed, Jason S; Panganiban, Antonito T; Sacha, Jonah B; Rakasz, Eva G; Friedrich, Thomas C; Maness, Nicholas J

    2016-02-01

    Nef-specific CD8(+) T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165-173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication. PMID:26637459

  12. Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells.

    PubMed

    Weiler, Andrea M; Das, Arpita; Akinyosoye, Oluwasayo; Cui, Sherry; O'Connor, Shelby L; Scheef, Elizabeth A; Reed, Jason S; Panganiban, Antonito T; Sacha, Jonah B; Rakasz, Eva G; Friedrich, Thomas C; Maness, Nicholas J

    2015-12-04

    Nef-specific CD8(+) T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165-173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication.

  13. Analysis of global O(t(-α)) stability and global asymptotical periodicity for a class of fractional-order complex-valued neural networks with time varying delays.

    PubMed

    Rakkiyappan, R; Sivaranjani, R; Velmurugan, G; Cao, Jinde

    2016-05-01

    In this paper, the problem of the global O(t(-α)) stability and global asymptotic periodicity for a class of fractional-order complex-valued neural networks (FCVNNs) with time varying delays is investigated. By constructing suitable Lyapunov functionals and a Leibniz rule for fractional differentiation, some new sufficient conditions are established to ensure that the addressed FCVNNs are globally O(t(-α)) stable. Moreover, some sufficient conditions for the global asymptotic periodicity of the addressed FCVNNs with time varying delays are derived, showing that all solutions converge to the same periodic function. Finally, numerical examples are given to demonstrate the effectiveness and usefulness of our theoretical results.

  14. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism.

    PubMed Central

    Pickles, A; Bolton, P; Macdonald, H; Bailey, A; Le Couteur, A; Sim, C H; Rutter, M

    1995-01-01

    The use of the family history method to examine the pattern of recurrence risks for complex disorders such as autism is not straightforward. Problems such as uncertain phenotypic definition, unreliable measurement with increased error rates for more distant relatives, and selection due to reduced fertility all complicate the estimation of risk ratios. Using data from a recent family history study of autism, and a similar study of twins, this paper shows how a latent-class approach can be used to tackle these problems. New findings are presented supporting a multiple-locus model of inheritance, with three loci giving the best fit. PMID:7668301

  15. Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells

    PubMed Central

    Weiler, Andrea M.; Das, Arpita; Akinyosoye, Oluwasayo; Cui, Sherry; O'Connor, Shelby L.; Scheef, Elizabeth A.; Reed, Jason S.; Panganiban, Antonito T.; Sacha, Jonah B.; Rakasz, Eva G.; Friedrich, Thomas C.

    2015-01-01

    Nef-specific CD8+ T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165–173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication. PMID:26637459

  16. Predicting the properties of a new class of host-guest complexes: C60 fullerene and CB[9] cucurbituril.

    PubMed

    Fileti, Eudes; Colherinhas, Guilherme; Malaspina, Thaciana

    2014-11-01

    DFT, semi-empirical and classical molecular dynamics methods were used to describe the structure and stability of the inclusion complex formed by the fullerene C60 and the cucurbituril CB[9]. Our results indicate a high structural compatibility between the two monomers, which is evident from the potential energy curve for the inclusion process of the C60 into the CB[9] cavity. The interaction between the two monomers is mainly of the van der Waals type and leads to a highly stable complex. Thermal contributions and environmental interaction are taken into account by the free energy of binding of -224 kJ mol(-1), indicating that even in aqueous medium the complex remains very stable.

  17. Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors.

    PubMed

    Silberman, Daniel; Krovi, Sai Harsha; Tuttle, Kathryn D; Crooks, James; Reisdorph, Richard; White, Janice; Gross, James; Matsuda, Jennifer L; Gapin, Laurent; Marrack, Philippa; Kappler, John W

    2016-09-20

    The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC. PMID:27588903

  18. Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

    PubMed Central

    Silberman, Daniel; Krovi, Sai Harsha; Tuttle, Kathryn D.; Crooks, James; Reisdorph, Richard; White, Janice; Gross, James; Matsuda, Jennifer L.; Gapin, Laurent; Marrack, Philippa; Kappler, John W.

    2016-01-01

    The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line–encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC. PMID:27588903

  19. Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors.

    PubMed

    Silberman, Daniel; Krovi, Sai Harsha; Tuttle, Kathryn D; Crooks, James; Reisdorph, Richard; White, Janice; Gross, James; Matsuda, Jennifer L; Gapin, Laurent; Marrack, Philippa; Kappler, John W

    2016-09-20

    The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC.

  20. Transloading of tumor cells with foreign major histocompatibility complex class I peptide ligand: a novel general strategy for the generation of potent cancer vaccines.

    PubMed Central

    Schmidt, W; Steinlein, P; Buschle, M; Schweighoffer, T; Herbst, E; Mechtler, K; Kirlappos, H; Birnstiel, M L

    1996-01-01

    The major hurdle to be cleared in active immunotherapy of cancer is the poor immunogenicity of cancer cells. In previous attempts to overcome this problem, whole tumor cells have been used as vaccines, either admixed with adjuvant(s) or genetically engineered to express nonself proteins or immunomodulatory factors before application. We have developed a novel approach to generate an immunogeneic, highly effective vaccine: major histocompatibility complex (MHC) class I-positive cancer cells are administered together with MHC class I-matched peptide ligands of foreign, nonself origin, generated by a procedure we term transloading. Murine tumor lines of the H2-Kd or the H2-Db haplotype, melanoma M-3 and B16-F10, respectively, as well as colon carcinoma CT-26 (H2-Kd), were transloaded with MHC-matched influenza virus-derived peptides and applied as irradiated vaccines. Mice bearing a deposit of live M-3 melanoma cells were efficiently cured by this treatment. In the CT-26 colon carcinoma and the B16-F10 melanoma, high efficacies were obtained against tumor challenge, suggesting the universal applicability of this new type of vaccine. With foreign peptide ligands adapted to the requirements of a desired MHC class I haplotype, this concept may be used for the treatment of human cancers. Images Fig. 1 PMID:8790404

  1. Introduction of protein or DNA delivered via recombinant Salmonella typhimurium into the major histocompatibility complex class I presentation pathway of macrophages.

    PubMed

    Catic, A; Dietrich, G; Gentschev, I; Goebel, W; Kaufmann, S H; Hess, J

    1999-02-01

    Recombinant (r) Salmonella typhimurium aroA strains which display the hen egg ovalbumin OVA(257-264) peptide SIINFEKL in secreted form were constructed. In addition, attenuated rS. typhimurium pcDNA-OVA constructs harbouring a eukaryotic expression plasmid encoding complete OVA were used to introduce the immunodominant OVA(257-264) epitope into the major histocompatibility complex (MHC) class I presentation pathway. Both modes of antigen delivery (DNA and protein) by Salmonella vaccine carriers stimulated OVA(257-264)-specific CD8 T-cell hybridomas. An in vitro infection system was established that allowed both rSalmonella carrier devices to facilitate MHC class I delivery of OVA(257-264) by coexpression of listeriolysin (Hly) or by coinfection with rS. typhimurium Hlys (Hess J., Gentschev I., Miko D., Welzel M., Ladel C., Goebel W., Kaufmann S.H.E., Proc. Natl. Acad. Sci. USA 93 (1996) 1458-1463). Coexpression of Hly and coinfection with rS. typhimurium Hlys slightly improved MHC class I processing of OVA. Our data provide further evidence for the feasibility of attenuated, Hly-expressing rS. typhimurium carriers secreting heterologous antigens or harbouring heterologous DNA as effective vaccines for stimulating CD8 T cells in addition to CD4 T cells. PMID:10594975

  2. Introduction of protein or DNA delivered via recombinant Salmonella typhimurium into the major histocompatibility complex class I presentation pathway of macrophages.

    PubMed

    Catic, A; Dietrich, G; Gentschev, I; Goebel, W; Kaufmann, S H; Hess, J

    1999-02-01

    Recombinant (r) Salmonella typhimurium aroA strains which display the hen egg ovalbumin OVA(257-264) peptide SIINFEKL in secreted form were constructed. In addition, attenuated rS. typhimurium pcDNA-OVA constructs harbouring a eukaryotic expression plasmid encoding complete OVA were used to introduce the immunodominant OVA(257-264) epitope into the major histocompatibility complex (MHC) class I presentation pathway. Both modes of antigen delivery (DNA and protein) by Salmonella vaccine carriers stimulated OVA(257-264)-specific CD8 T-cell hybridomas. An in vitro infection system was established that allowed both rSalmonella carrier devices to facilitate MHC class I delivery of OVA(257-264) by coexpression of listeriolysin (Hly) or by coinfection with rS. typhimurium Hlys (Hess J., Gentschev I., Miko D., Welzel M., Ladel C., Goebel W., Kaufmann S.H.E., Proc. Natl. Acad. Sci. USA 93 (1996) 1458-1463). Coexpression of Hly and coinfection with rS. typhimurium Hlys slightly improved MHC class I processing of OVA. Our data provide further evidence for the feasibility of attenuated, Hly-expressing rS. typhimurium carriers secreting heterologous antigens or harbouring heterologous DNA as effective vaccines for stimulating CD8 T cells in addition to CD4 T cells.

  3. On conjugate gradient type methods and polynomial preconditioners for a class of complex non-Hermitian matrices

    NASA Technical Reports Server (NTRS)

    Freund, Roland

    1988-01-01

    Conjugate gradient type methods are considered for the solution of large linear systems Ax = b with complex coefficient matrices of the type A = T + i(sigma)I where T is Hermitian and sigma, a real scalar. Three different conjugate gradient type approaches with iterates defined by a minimal residual property, a Galerkin type condition, and an Euclidian error minimization, respectively, are investigated. In particular, numerically stable implementations based on the ideas behind Paige and Saunder's SYMMLQ and MINRES for real symmetric matrices are proposed. Error bounds for all three methods are derived. It is shown how the special shift structure of A can be preserved by using polynomial preconditioning. Results on the optimal choice of the polynomial preconditioner are given. Also, some numerical experiments for matrices arising from finite difference approximations to the complex Helmholtz equation are reported.

  4. Molecular and biological interaction between major histocompatibility complex class I antigens and luteinizing hormone receptors or beta-adrenergic receptors triggers cellular response in mice.

    PubMed Central

    Solano, A R; Cremaschi, G; Sánchez, M L; Borda, E; Sterin-Borda, L; Podestá, E J

    1988-01-01

    Purified IgG from BALB/c mouse anti-C3H serum exerts positive inotropic and chronotropic effects in C3H mouse atria and induces testosterone synthesis in C3H mouse Leydig cells. The effect depends on IgG concentration and can be abolished by beta-adrenergic-receptor and luteinizing hormone-receptor antagonists. IgG interferes with the binding of dihydroalprenolol and luteinizing hormone. Monoclonal antibodies against major histocompatibility complex class I antigens were active on the Leydig cells of C3H and BALB/c mice. There was a parallelism between the effect of each individual monoclonal antibody with specificity for a particular haplotype and the response of the target cell from the strains carrying such haplotypes. These antibodies could precipitate the soluble luteinizing hormone-receptor complex. The results suggested that bound hormone triggers the association of major histocompatibility class I antigen with the receptor, thereby activating the respective target cells. PMID:2839829

  5. Crystallographic and Computational Studies of a Class II MHC Complex with a Nonconforming Peptide: HLA-DRA/DRB3*0101

    NASA Astrophysics Data System (ADS)

    Parry, Christian S.; Gorski, Jack; Stern, Lawrence J.

    2003-03-01

    The stable binding of processed foreign peptide to a class II major histocompatibility (MHC) molecule and subsequent presentation to a T cell receptor is a central event in immune recognition and regulation. Polymorphic residues on the floor of the peptide binding site form pockets that anchor peptide side chains. These and other residues in the helical wall of the groove determine the specificity of each allele and define a motif. Allele specific motifs allow the prediction of epitopes from the sequence of pathogens. There are, however, known epitopes that do not satisfy these motifs: anchor motifs are not adequate for predicting epitopes as there are apparently major and minor motifs. We present crystallographic studies into the nature of the interactions that govern the binding of these so called nonconforming peptides. We would like to understand the role of the P10 pocket and find out whether the peptides that do not obey the consensus anchor motif bind in the canonical conformation observed in in prior structures of class II MHC-peptide complexes. HLA-DRB3*0101 complexed with peptide crystallized in unit cell 92.10 x 92.10 x 248.30 (90, 90, 90), P41212, and the diffraction data is reliable to 2.2ÅWe are complementing our studies with dynamical long time simulations to answer these questions, particularly the interplay of the anchor motifs in peptide binding, the range of protein and ligand conformations, and water hydration structures.

  6. Copper(I) Complexes of Zwitterionic Imidazolium-2-Amidinates, a Promising Class of Electroneutral, Amidinate-Type Ligands.

    PubMed

    Márquez, Astrid; Ávila, Elena; Urbaneja, Carmen; Álvarez, Eleuterio; Palma, Pilar; Cámpora, Juan

    2015-11-16

    The first complexes containing imidazolium-2-amidinates as ligands (betaine-type adducts of imidazolium-based carbenes and carbodiimides, NHC-CDI) are reported. Interaction of the sterically hindered betaines ICyCDI(DiPP) and IMeCDI(DiPP) [both bearing 2,6-diisopropylphenyl (DiPP) substituents on the terminal N atoms] with Cu(I) acetate affords mononuclear, electroneutral complexes 1a and 1b, which contain NHC-CDI and acetate ligands terminally bound to linear Cu(I) centers. In contrast, the less encumbered ligand ICyCDI(p-Tol), with p-tolyl substituents on the nitrogen donor atoms, affords a dicationic trigonal paddlewheel complex, [Cu2(μ-ICyCDI(p-Tol))3](2+)[OAc(-)]2 (2-OAc). The nuclear magnetic resonance (NMR) resonances of this compound are broad and indicate that in solution the acetate anion and the betaine ligands compete for binding the Cu atom. Replacing the external acetate with the less coordinating tetraphenylborate anion provides the corresponding derivative 2-BPh4 that, in contrast with 2-OAc, gives rise to sharp and well-defined NMR spectra. The short Cu-Cu distance in the binuclear dication [Cu2(μ-ICyCDI(p-Tol))3](2+) observed in the X-ray structures of 2-BPh4 and 2-OAc, ca. 2.42 Å, points to a relatively strong "cuprophilic" interaction. Attempts to force the bridging coordination mode of IMeCDI(DiPP) displacing the acetate anion with BPh4(-) led to the isolation of the cationic mononuclear derivative [Cu(IMeCDI(DiPP))2](+)[BPh4](-) (3b) that contains two terminally bound betaine ligands. Compound 3b readily decomposes upon being heated, cleanly affording the bis-carbene complex [Cu(IMe)2](+)[BPh4(-)] (4) and releasing the corresponding carbodiimide (C(═N-DiPP)2). PMID:26517572

  7. Isolation of a class C transcription factor which forms a stable complex with tRNA genes.

    PubMed Central

    Ruet, A; Camier, S; Smagowicz, W; Sentenac, A; Fromageot, P

    1984-01-01

    A yeast extract was fractionated to resolve the factors involved in the transcription of yeast tRNA genes. An in vitro transcription system was reconstituted with two separate protein fractions and purified RNA polymerase C (III). Optimal conditions for tRNA synthesis have been determined. One essential component, termed tau factor, was partially purified by conventional chromatographic methods on heparin-agarose and DEAE-Sephadex; it sedimented as a large macromolecule in glycerol gradients (mol. wt. approximately 300 000). tau factor was found to form a stable complex with the tRNA gene in the absence of other transcriptional components. Complex formation is very fast, is not temperature dependent between 10 degrees C and 25 degrees C and does not require divalent cations. The factor-DNA complex is stable for at least 30 min at high salt concentration (0.1 M ammonium sulfate). These results indicate that gene recognition by a specific factor is a primary event in tRNA synthesis. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 6. Fig. 7. Fig. 8. Fig. 9. PMID:6370678

  8. Stable isotope tagging of epitopes: a highly selective strategy for the identification of major histocompatibility complex class I-associated peptides induced upon viral infection.

    PubMed

    Meiring, Hugo D; Soethout, Ernst C; Poelen, Martien C M; Mooibroek, Dennis; Hoogerbrugge, Ronald; Timmermans, Hans; Boog, Claire J; Heck, Albert J R; de Jong, Ad P J M; van Els, Cécile A C M

    2006-05-01

    Identification of peptides presented in major histocompatibility complex (MHC) class I molecules after viral infection is of strategic importance for vaccine development. Until recently, mass spectrometric identification of virus-induced peptides was based on comparative analysis of peptide pools isolated from uninfected and virus-infected cells. Here we report on a powerful strategy aiming at the rapid, unambiguous identification of naturally processed MHC class I-associated peptides, which are induced by viral infection. The methodology, stable isotope tagging of epitopes (SITE), is based on metabolic labeling of endogenously synthesized proteins during infection. This is accomplished by culturing virus-infected cells with stable isotope-labeled amino acids that are expected to be anchor residues (i.e. residues of the peptide that have amino acid side chains that bind into pockets lining the peptide-binding groove of the MHC class I molecule) for the human leukocyte antigen allele of interest. Subsequently these cells are mixed with an equal number of non-infected cells, which are cultured in normal medium. Finally peptides are acid-eluted from immunoprecipitated MHC molecules and subjected to two-dimensional nanoscale LC-MS analysis. Virus-induced peptides are identified through computer-assisted detection of characteristic, binomially distributed ratios of labeled and unlabeled molecules. Using this approach we identified novel measles virus and respiratory syncytial virus epitopes as well as infection-induced self-peptides in several cell types, showing that SITE is a unique and versatile method for unequivocal identification of disease-related MHC class I epitopes.

  9. Rapid Evolution of Major Histocompatibility Complex Class I Genes in Primates Generates New Disease Alleles in Humans via Hitchhiking Diversity

    PubMed Central

    Shiina, Takashi; Ota, Masao; Shimizu, Sayoko; Katsuyama, Yoshihiko; Hashimoto, Nami; Takasu, Miwa; Anzai, Tatsuya; Kulski, Jerzy K.; Kikkawa, Eri; Naruse, Taeko; Kimura, Natsuki; Yanagiya, Kazuyo; Watanabe, Atsushi; Hosomichi, Kazuyoshi; Kohara, Sakae; Iwamoto, Chie; Umehara, Yumi; Meyer, Alice; Wanner, Valérie; Sano, Kazumi; Macquin, Cécile; Ikeo, Kazuho; Tokunaga, Katsushi; Gojobori, Takashi; Inoko, Hidetoshi; Bahram, Seiamak

    2006-01-01

    A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC class I region (coding units or full contigs) in several human and nonhuman primate haplotypes allowed an analysis of single nucleotide variations (SNV) across this entire segment. This diversity was not evenly distributed. It was rather concentrated within two gene-rich clusters. These were each centered, but importantly not limited to, the antigen-presenting HLA-A and HLA-B/-C loci. Rapid evolution of MHC-I alleles, as evidenced by an unusually high number of haplotype-specific (hs) and hypervariable (hv) (which could not be traced to a single species or haplotype) SNVs within the classical MHC-I, seems to have not only hitchhiked alleles within nearby genes, but also hitchhiked deleterious mutations in these same unrelated loci. The overrepresentation of a fraction of these hvSNV (hv1SNV) along with hsSNV, as compared to those that appear to have been maintained throughout primate evolution (trans-species diversity; tsSNV; included within hv2SNV) tends to establish that the majority of the MHC polymorphism is de novo (species specific). This is most likely reminiscent of the fact that these hsSNV and hv1SNV have been selected in adaptation to the constantly evolving microbial antigenic repertoire. PMID:16702430

  10. You Can't Get There From Here! Problems and Potential Solutions in Developing New Classes of Complex Systems

    NASA Technical Reports Server (NTRS)

    Hinchey, Michael G.; Rash, James L.; Truszkowski, Walter F.; Rouff, Christopher A.; Sterritt, Roy

    2005-01-01

    The explosion of capabilities and new products within the sphere of Information Technology (IT) has fostered widespread, overly optimistic opinions regarding the industry, based on common but unjustified assumptions of quality and correctness of software. These assumptions are encouraged by software producers and vendors, who at this late date have not succeeded in finding a way to overcome the lack of an automated, mathematically sound way to develop correct systems from requirements. NASA faces this dilemma as it envisages advanced mission concepts that involve large swarms of small spacecraft that will engage cooperatively to acheve science goals. Such missions entail levels of complexity that beg for new methods for system development far beyond today's methods, which are inadequate for ensuring correct behavior of large numbers of interacting intelligent mission elements. New system development techniques recently devised through NASA-led research will offer some innovative approaches to achieving correctness in complex system development, including autonomous swarm missions that exhibit emergent behavior, as well as general software products created by the computing industry.

  11. Dialkyldiselenophosphinato-metal complexes - a new class of single source precursors for deposition of metal selenide thin films and nanoparticles

    NASA Astrophysics Data System (ADS)

    Malik, Sajid N.; Akhtar, Masood; Revaprasadu, Neerish; Qadeer Malik, Abdul; Azad Malik, Mohammad

    2014-08-01

    We report here a new synthetic approach for convenient and high yield synthesis of dialkyldiselenophosphinato-metal complexes. A number of diphenyldiselenophosphinato-metal as well as diisopropyldiselenophosphinato-metal complexes have been synthesized and used as precursors for deposition of semiconductor thin films and nanoparticles. Cubic Cu2-xSe and tetragonal CuInSe2 thin films have been deposited by AACVD at 400, 450 and 500 °C whereas cubic PbSe and tetragonal CZTSe thin films have been deposited through doctor blade method followed by annealing. SEM investigations revealed significant differences in morphology of the films deposited at different temperatures. Preparation of Cu2-xSe and In2Se3 nanoparticles using diisopropyldiselenophosphinato-metal precursors has been carried out by colloidal method in HDA/TOP system. Cu2-xSe nanoparticles (grown at 250 °C) and In2Se3 nanoparticles (grown at 270 °C) have a mean diameter of 5.0 ± 1.2 nm and 13 ± 2.5 nm, respectively.

  12. The Transmembrane Domain of the Adenovirus E3/19K Protein Acts as an Endoplasmic Reticulum Retention Signal and Contributes to Intracellular Sequestration of Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Sester, Martina; Ruszics, Zsolt; Mackley, Emma

    2013-01-01

    The human adenovirus E3/19K protein is a type I transmembrane glycoprotein of the endoplasmic reticulum (ER) that abrogates cell surface transport of major histocompatibility complex class I (MHC-I) and MHC-I-related chain A and B (MICA/B) molecules. Previous data suggested that E3/19K comprises two functional modules: a luminal domain for interaction with MHC-I and MICA/B molecules and a dilysine motif in the cytoplasmic tail that confers retrieval from the Golgi apparatus back to the ER. This study was prompted by the unexpected phenotype of an E3/19K molecule that was largely retained intracellularly despite having a mutated ER retrieval motif. To identify additional structural determinants responsible for ER localization, chimeric molecules were generated containing the luminal E3/19K domain and the cytoplasmic and/or transmembrane domain (TMD) of the cell surface protein MHC-I Kd. These chimeras were analyzed for transport, cell surface expression, and impact on MHC-I and MICA/B downregulation. As with the retrieval mutant, replacement of the cytoplasmic tail of E3/19K allowed only limited transport of the chimera to the cell surface. Efficient cell surface expression was achieved only by additionally replacing the TMD of E3/19K with that of MHC-I, suggesting that the E3/19K TMD may confer static ER retention. This was verified by ER retention of an MHC-I Kd molecule with the TMD replaced by that of E3/19K. Thus, we have identified the E3/19K TMD as a novel functional element that mediates static ER retention, thereby increasing the concentration of E3/19K in the ER. Remarkably, the ER retrieval signal alone, without the E3/19K TMD, did not mediate efficient HLA downregulation, even in the context of infection. This suggests that the TMD is required together with the ER retrieval function to ensure efficient ER localization and transport inhibition of MHC-I and MICA/B molecules. PMID:23514889

  13. Characterization and evolution of major histocompatibility complex class II genes in the aye-aye, Daubentonia madagascariensis.

    PubMed

    Go, Yasuhiro; Rakotoarisoa, Gilbert; Kawamoto, Yoshi; Shima, Taizo; Koyama, Naoki; Randrianjafy, Albert; Mora, Roger; Hirai, Hirohisa

    2005-04-01

    Major histocompatibility complex genes (Mhc-DQB and Mhc-DRB) were sequenced in seven aye-ayes (Daubentonia madagascariecsis), which is an endemic and endangered species in Madagascar. An aye-aye from a north-eastern population showed genetic relatedness to individuals of a north-western population and had a somewhat different repertoire from another north-eastern individual. These observations suggest that the extent of genetic variation in Mhc genes is not excessively small in the aye-aye in spite of recent rapid destruction of their habitat by human activities. In light of Mhc gene evolution, trans-species and allelic polymorphisms can be estimated to have been retained for more than 50 Ma (million years) based on the time scale of lemur evolution. PMID:15322927

  14. HLA-F complex without peptide binds to MHC class I protein in the open conformer form1

    PubMed Central

    Goodridge, Jodie P.; Burian, Aura; Lee, Ni; Geraghty, Daniel E.

    2013-01-01

    HLA-F has very low levels of polymorphism in humans and is highly conserved among primates suggesting a conserved function in the immune response. In this study we probed the structure of HLA-F on the surface of B-LCLs and activated lymphocytes by direct measurement of peptide binding of native HLA-F. Our findings suggested that HLA-F is expressed independently of bound peptide, at least with respect to peptide complexity profiles similar to those of either HLA-E or classical MHC-I. As a further probe of native HLA-F structure, we used a number of complementary approaches to explore the interactions of HLA-F with other molecules, at the cell surface, intracellularly, and in direct physical biochemical measurements. This analysis demonstrated that HLA-F surface expression was coincident with MHC-I heavy chain (HC) expression and was down regulated upon perturbation of MHC-I HC structure. It was further possible to directly demonstrate that MHC-I would only interact with HLA-F when in the form of open conformer free of peptide and not as trimeric complex. This interaction was directly observed by co-immunoprecipitation and by surface plasmon resonance and indirectly on the surface of cells through coincident tetramer and MHC-I HC co-localization. Together these data suggest that HLA-F is expressed independent of peptide and that a physical interaction specific to MHC-I HC plays a role in the function of MHC-I HC expression in activated lymphocytes. PMID:20483783

  15. New class of scorpionate: tris(tetrazolyl)-iron complex and its different coordination modes for alkali metal ions.

    PubMed

    Park, Ka Hyun; Lee, Kang Mun; Go, Min Jeong; Choi, Sung Ho; Park, Hyoung-Ryun; Kim, Youngjo; Lee, Junseong

    2014-08-18

    We report formation of a new metallascorpionate ligand, [FeL3](3-) (IPtz), containing a Fe core and three 5-(2-hydroxyphenyl)-1H-tetrazole (LH2) ligands. It features two different binding sites, oxygen and nitrogen triangles, which consist of three oxygen or nitrogen donors from tetrazole. The binding affinities of the complex for three alkali metal ions were studied using UV spectrophotometry titrations. All three alkali metal ions show high affinities and binding constants (>3 × 10(6) M(-1)), based on the 1:1 binding isotherms to IPtz. The coordination modes of the alkali metals and IPtz in the solid were studied using X-ray crystallography; two different electron-donor sites show different coordination numbers for Li(+), Na(+), and K(+) ions. The oxygen triangles have the κ(2) coordination mode with Li(+) and κ(3) coordination mode with Na(+) and K(+) ions, whereas the nitrogen triangles show κ(3) coordination with K(+) only. The different binding affinities of IPtz in the solid were manipulated using multiple metal precursors. A Fe-K-Zn trimetallic complex was constructed by assembly of an IPtz ligand, K, and Zn precursors and characterized using X-ray crystallography. Oxygen donors are coordinated with the K ion via the κ(3) coordination mode, and nitrogen donors are coordinated with Zn metal by κ(3) coordination. The solid-state structure was confirmed to be a honeycomb coordination polymer with a one-dimensional infinite metallic array, i.e., -(K-K-Fe-Zn-Fe-K)n-.

  16. Guanidinium-Rich, Glycerol-Derived Oligocarbonates: A New Class of Cell-Penetrating Molecular Transporters That Complex, Deliver, and Release siRNA

    PubMed Central

    Wender, Paul A.; Huttner, Melanie A.; Staveness, Daryl; Vargas, Jessica R.; Xu, Adele F.

    2015-01-01

    A highly versatile and step-economical route to a new class of guanidinium-rich molecular transporters and evaluation of their ability to complex, deliver, and release siRNA are described. These new drug/probe delivery systems are prepared in only two steps, irrespective of length or composition, using an organocatalytic ring-opening co-oligomerization of glycerol-derived cyclic carbonate monomers incorporating either protected guanidine or lipid side chains. The resultant amphipathic co-oligomers are highly effective vehicles for siRNA delivery, providing an excellent level of target protein suppression (>85%). These new oligocarbonates are nontoxic at levels required for cell penetration and can be tuned for particle size. Relative to the previously reported methyl(trimethylene)carbonate (MTC) scaffold, the ether linkage at C2 in the new transporters markedly enhances the stability of the siRNA/co-oligomer complexes. Both hybrid co-oligomers, containing a mixture of glycerol- and MTC-derived monomers, and co-oligomers containing only glycerol monomers are found to provide tunable control over siRNA complex stability. On the basis of a glycerol and CO2 backbone, these new co-oligomers represent a rapidly tunable and biocompatible siRNA delivery system that is highly effective in suppressing target protein synthesis. PMID:25588140

  17. Closely Related Mycobacterial Strains Demonstrate Contrasting Levels of Efficacy as Antitumor Vaccines and Are Processed for Major Histocompatibility Complex Class I Presentation by Multiple Routes in Dendritic Cells

    PubMed Central

    Cheadle, Eleanor J.; O'Donnell, Dearbhaile; Selby, Peter J.; Jackson, Andrew M.

    2005-01-01

    Mycobacteria expressing recombinant antigens are already being developed as vaccines against both infections and tumors. Little is known about how dendritic cells might process such antigens. Two different mycobacterial species, the fast-growing Mycobacterium smegmatis and the slow-growing M. bovis M. bovis BCG, were engineered to express a model tumor antigen, the Kb-restricted dominant cytotoxic T-lymphocyte epitope OVA257-264. Recombinant M. bovis BCG but not recombinant M. smegmatis conferred protection to mice challenged with the B16-OVA tumor cell line. We went on to investigate whether the contrast in antitumor efficacy could be due to differences in how dendritic cells process antigen from the two mycobacterial strains for class I presentation. Both strains of mycobacteria caused phenotypic maturation of dendritic cells, but recombinant M. smegmatis infection led to a greater degree of dendritic cell maturation than recombinant M. bovis BCG infection. Antigen from recombinant M. smegmatis was processed and presented as OVA257-264 on Kb molecules by the dendritic cell line DC2.4 but not by bone marrow-derived dendritic cells (BMDC) or splenic dendritic cells. In contrast, antigen from recombinant M. bovis BCG was presented by all three dendritic cell types as long as the mycobacteria were viable. Such presentation was dependent on proteasome function and nascent major histocompatibility complex (MHC) class I molecules in DC2.4 cells but independent of the proteasome and transporter associated with antigen processings (TAP) in BMDC and splenic dendritic cells. These data demonstrate for the first time that antigen vectored by the slow-growing M. bovis BCG but not that vectored by fast-growing, readily destroyed M. smegmatis is processed and presented on MHC class I by in vitro-generated dendritic cells, which has implications for recombinant microbial vaccine development. PMID:15664917

  18. Association between Single Nucleotide Polymorphisms of the Major Histocompatibility Complex Class II Gene and Newcastle Disease Virus Titre and Body Weight in Leung Hang Khao Chickens

    PubMed Central

    Molee, A.; Kongroi, K.; Kuadsantia, P.; Poompramun, C.; Likitdecharote, B.

    2016-01-01

    The aim of the present study was to investigate the effect of single nucleotide polymorphisms in the major histocompatibility complex (MHC) class II gene on resistance to Newcastle disease virus and body weight of the Thai indigenous chicken, Leung Hang Khao (Gallus gallus domesticus). Blood samples were collected for single nucleotide polymorphism analysis from 485 chickens. Polymerase chain reaction sequencing was used to classify single nucleotide polymorphisms of class II MHC. Body weights were measured at the ages of 3, 4, 5, and 7 months. Titres of Newcastle disease virus at 2 weeks to 7 months were determined and the correlation between body weight and titre was analysed. The association between single nucleotide polymorphisms and body weight and titre were analysed by a generalized linear model. Seven single nucleotide polymorphisms were identified: C125T, A126T, C209G, C242T, A243T, C244T, and A254T. Significant correlations between log titre and body weight were found at 2 and 4 weeks. Associations between single nucleotide polymorphisms and titre were found for C209G and A254T, and between all single nucleotide polymorphisms (except A243T) and body weight. The results showed that class II MHC is associated with both titre of Newcastle disease virus and body weight in Leung Hang Khao chickens. This is of concern because improved growth traits are the main goal of breeding selection. Moreover, the results suggested that MHC has a pleiotropic effect on the titre and growth performance. This mechanism should be investigated in a future study. PMID:26732325

  19. SU-8/Pyrex microchip electrophoresis with integrated electrochemical detection for class-selective electrochemical index determination of phenolic compounds in complex samples.

    PubMed

    Castañeda, Raquel; Vilela, Diana; González, María Cristina; Mendoza, Sandra; Escarpa, Alberto

    2013-07-01

    A SU-8/Pyrex single-channel microchip integrating three 100 μm Pt electrodes (MCE-ED) for class-selective electrochemical index determination (CSEID) of phenolic acids and flavonoids in complex extracts of Tagetes lucida (Tl), Mentha piperita (Mp), Cymbopogon citratus (Cc), Calendula officinalis (Co), and Cynara scolymus (Cs) is proposed. Under strategic conditions controlled by a MES buffer (pH 5.0; 25 mM) and accordingly to the antioxidant acid-base properties, the simultaneous measurement of total acids and flavonoids indexes was achieved in less than 100 s with excellent analytical performance. The reliability of MCE-ED approach was demonstrated toward the high agreement between the total phenolic content obtained using microchip approach with those obtained by the well-established HPLC-DAD; revealing both identical order regarding the total phenolic content in the target samples. In addition, further comparison of MCE-ED with the traditional Folin-Ciocalteu antioxidant capacity assay, showed that MCE-ED approach could become a class-selective antioxidant capacity assay revealing that the sample antioxidant capacity was decreasing as Tl > Mp > Cs > Cc > Co according to their endogenous polyphenol content. These results suggested that the microchip approach is not only a reliable method for fast assessment of class-selective antioxidants constituting a very good alternative to the long analysis times and the using of toxic solvents required in HPLC but a novel truly antioxidant capacity assay. This excellent analytical performance is connected with the key-features of the "ready-to-use" system employed in this work such as portability, full integration of electrochemical detection, easy-operation, and potential MCE-ED disposability.

  20. SU-8/Pyrex microchip electrophoresis with integrated electrochemical detection for class-selective electrochemical index determination of phenolic compounds in complex samples.

    PubMed

    Castañeda, Raquel; Vilela, Diana; González, María Cristina; Mendoza, Sandra; Escarpa, Alberto

    2013-07-01

    A SU-8/Pyrex single-channel microchip integrating three 100 μm Pt electrodes (MCE-ED) for class-selective electrochemical index determination (CSEID) of phenolic acids and flavonoids in complex extracts of Tagetes lucida (Tl), Mentha piperita (Mp), Cymbopogon citratus (Cc), Calendula officinalis (Co), and Cynara scolymus (Cs) is proposed. Under strategic conditions controlled by a MES buffer (pH 5.0; 25 mM) and accordingly to the antioxidant acid-base properties, the simultaneous measurement of total acids and flavonoids indexes was achieved in less than 100 s with excellent analytical performance. The reliability of MCE-ED approach was demonstrated toward the high agreement between the total phenolic content obtained using microchip approach with those obtained by the well-established HPLC-DAD; revealing both identical order regarding the total phenolic content in the target samples. In addition, further comparison of MCE-ED with the traditional Folin-Ciocalteu antioxidant capacity assay, showed that MCE-ED approach could become a class-selective antioxidant capacity assay revealing that the sample antioxidant capacity was decreasing as Tl > Mp > Cs > Cc > Co according to their endogenous polyphenol content. These results suggested that the microchip approach is not only a reliable method for fast assessment of class-selective antioxidants constituting a very good alternative to the long analysis times and the using of toxic solvents required in HPLC but a novel truly antioxidant capacity assay. This excellent analytical performance is connected with the key-features of the "ready-to-use" system employed in this work such as portability, full integration of electrochemical detection, easy-operation, and potential MCE-ED disposability. PMID:23595251

  1. Association of Major Histocompatibility Complex Class 1 Chain-Related Gene A Dimorphism with Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Algerian Population

    PubMed Central

    Belanteur, Khadidja; Amroun, Habiba; Benyahia, Amel; Heniche, Amel; Azzouz, Malha; Mimouni, Safia; Gervais, Thibaud; Latinne, Dominique; Boudiba, Aissa; Attal, Nabila; Abbadi, Mohamed Cherif

    2012-01-01

    Major histocompatibility complex class I chain-related gene A (MICA-129) dimorphism was investigated in 73 autoimmune diabetes patients (type 1 diabetes and latent autoimmune diabetes in adults) and 75 controls from Algeria. Only MICA-129 Val allele and MICA-129 Val/Val genotype frequencies were higher among patients than in the control group. Statistical analysis of the estimated extended HLA-DR-DQ-MICA haplotypes shown that individual effects of MICA alleles on HLA-DQ2-DR3-MICA-129 Val/Val and HLA-DQ8-DR4-MICA-129 Val/Val haplotypes were significantly higher in patients than in the control groups. These preliminary data might suggest a relevant role of MICA-129 Val/Val single nucleotide polymorphism (weak/weak binders of NKG2D receptor) in the pathogenesis of T1D and LADA. PMID:22323559

  2. Detection of blaCTX-M-type genes in complex class 1 integrons carried by Enterobacteriaceae isolated from retail chicken meat in Brazil.

    PubMed

    Casella, Tiago; Rodríguez, María Margarita; Takahashi, Juliana Tiemi; Ghiglione, Barbara; Dropa, Milena; Assunção, Ednei; Nogueira, Maurício Lacerda; Lincopan, Nilton; Gutkind, Gabriel; Nogueira, Mara Corrêa Lelles

    2015-03-16

    CTX-M-type extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae have been increasingly identified in humans and animals, and their potential transmission by contaminated food has been highlighted. In this study, we report for the first time the isolation of multidrug-resistant (MDR) Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis strains harboring blaCTXM-2 or blaCTXM-8 gene variants in chicken meat sold in markets in southeast Brazil. In this regard, the genetic environment of the blaCTX-M-2 gene is composed of a complex class 1 integron and an ISCR1-associated sequence with dfr and/or aadA gene cassettes located within the variable region. In summary, chicken meat may be a reservoir of MDR Enterobacteriaceae harboring blaCTX-M-type genes, which is a public health concern.

  3. Class II major histocompatibility complex molecules regulate the development of the T4+T8- inducer phenotype of cultured human thymocytes.

    PubMed Central

    Blue, M L; Daley, J F; Levine, H; Schlossman, S F

    1985-01-01

    We demonstrate that a variety of Ia+ cells has the ability to promote the development of human T4+T8- thymocytes in vitro. Prolonged thymocyte culture in the absence of Ia+ accessory cells results in a predominantly T8+T4- cell population. The generation of T4+ cells in the presence of irradiated Ia+ cells could be suppressed up to 70% by a monoclonal antibody directed against a nonpolymorphic epitope on HLA-DR. Using two-color fluorescence sorting techniques, we were able to identify the activated T4+T8+ thymocyte as the cell that interacts with Ia and gives rise to the T4+T8- cell subset. These results directly and specifically implicate class II major histocompatibility complex molecules in the differentiative pathway of the human thymocyte. Images PMID:2933749

  4. Detection of blaCTX-M-type genes in complex class 1 integrons carried by Enterobacteriaceae isolated from retail chicken meat in Brazil.

    PubMed

    Casella, Tiago; Rodríguez, María Margarita; Takahashi, Juliana Tiemi; Ghiglione, Barbara; Dropa, Milena; Assunção, Ednei; Nogueira, Maurício Lacerda; Lincopan, Nilton; Gutkind, Gabriel; Nogueira, Mara Corrêa Lelles

    2015-03-16

    CTX-M-type extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae have been increasingly identified in humans and animals, and their potential transmission by contaminated food has been highlighted. In this study, we report for the first time the isolation of multidrug-resistant (MDR) Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis strains harboring blaCTXM-2 or blaCTXM-8 gene variants in chicken meat sold in markets in southeast Brazil. In this regard, the genetic environment of the blaCTX-M-2 gene is composed of a complex class 1 integron and an ISCR1-associated sequence with dfr and/or aadA gene cassettes located within the variable region. In summary, chicken meat may be a reservoir of MDR Enterobacteriaceae harboring blaCTX-M-type genes, which is a public health concern. PMID:25576985

  5. Evidence for a conformational change in a class II major histocompatibility complex molecule occurring in the same pH range where antigen binding is enhanced

    PubMed Central

    1996-01-01

    Many class II histocompatibility complex molecules bind antigenic peptides optimally at low pH, consistent with their exposure to antigen in acidic endosomal compartments. While it has been suggested that a partially unfolded state serves as an intermediate involved in peptide binding, very little evidence for such a state has been obtained. In this report, we show that the murine class II molecule IE becomes increasingly less stable to sodium dodecyl sulfate-induced dissociation since the pH is decreased in the same range that enhances antigenic peptide binding. Furthermore, at mildly acidic pH levels, IEk binds the fluorescent dye 1-anilino-naphthalene-8-sulfonic acid (ANS), a probe for exposed nonpolar sites in proteins, suggesting that protonation produces a molten globule-like state. The association of IEk with a single high-affinity peptide had only a small effect in these two assays, indicating that the changes that occur are distal to the peptide-binding groove. Circular dichroism analysis shows that a pH shift from neutral to mildly acidic pH causes subtle changes in the environment of aromatic residues but does not grossly disrupt the secondary structure of IEk. We propose a model in which perturbations in interdomain contacts outside the peptide-binding domain of IEk occur at acidic pH, producing a partially unfolded state that facilitates optimal antigen binding. PMID:8551214

  6. Increased susceptibility to Strongyloides venezuelensis infection is related to the parasite load and absence of major histocompatibility complex (MHC) class II molecules.

    PubMed

    Rodrigues, Rosângela Maria; Cardoso, Cristina Ribeiro; Gonçalves, Ana Lúcia Ribeiro; Silva, Neide Maria; Massa, Virgínia; Alves, Ronaldo; Ueta, Marlene Tiduko; Silva, João Santana; Costa-Cruz, Julia Maria

    2013-11-01

    In human and murine models strongyloidiasis induce a Th2 type response. In the current study we investigated the role of different loads of Strongyloides venezuelensis in the immune response raised against the parasite and the participation of the major histocompatibility complex (MHC) class II molecule in the disease outcome in face of the different parasite burden. The C57BL/6 wild type (WT) and MHC II(-/-) mice were individually inoculated by subcutaneous injection with 500 or 3000 S. venezuelensis L3. The MHC II(-/-) mice infected with 3000L3 were more susceptible to S. venezuelensis infection when compared with WT groups, in which the parasite was completely eliminated. The production of Th2 cytokines and specific IgG1 or IgE antibodies against parasite were significantly lowered in MHC II(-/-) infected mice with different larvae inoculums. The infection of MHC II(-/-) mice with S. venezuelensis induced slight inflammatory alterations in the small intestine, and these lesions were lower when compared with WT mice, irrespective of the parasite load utilized to infect animals. Finally, we concluded that MHC class II molecules are essential in the immune response against S. venezuelensis mainly when infection occurs with high parasite inoculum.

  7. Complex Structure in Class 0 Protostellar Envelopes. III. Velocity Gradients in Non-axisymmetric Envelopes, Infall, or Rotation?

    NASA Astrophysics Data System (ADS)

    Tobin, John J.; Hartmann, Lee; Bergin, Edwin; Chiang, Hsin-Fang; Looney, Leslie W.; Chandler, Claire J.; Maret, Sébastien; Heitsch, Fabian

    2012-03-01

    We present an interferometric kinematic study of morphologically complex protostellar envelopes based on observations of the dense gas tracers N2H+ and NH3. The strong asymmetric nature of most envelopes in our sample leads us to question the common interpretation of velocity gradients as rotation, given the possibility of projection effects in the observed velocities. Several "idealized" sources with well-ordered velocity fields and envelope structures are now analyzed in more detail. We compare the interferometric data to position-velocity (PV) diagrams of kinematic models for spherical rotating collapse and filamentary rotating collapse. For this purpose, we developed a filamentary parameterization of the rotating collapse model to explore the effects of geometric projection on the observed velocity structures. We find that most envelopes in our sample have PV structures that can be reproduced by an infalling filamentary envelope projected at different angles within the plane of the sky. The infalling filament produces velocity shifts across the envelope that can mimic rotation, especially when viewed at single-dish resolutions and the axisymmetric rotating collapse model does not uniquely describe any data set. Furthermore, if the velocities are assumed to reflect rotation, then the inferred centrifugal radii are quite large in most cases, indicating significant fragmentation potential or more likely another component to the line-center velocity. We conclude that ordered velocity gradients cannot be interpreted as rotation alone when envelopes are non-axisymmetric and that projected infall velocities likely dominate the velocity field on scales larger than 1000 AU. Based on observations carried out with the IRAM Plateau de Bure Interferometer, Combined Array for Research in Millimeter-wave Astronomy (CARMA), and the NRAO Very Large Array.

  8. Major histocompatibility complex class II DAB alleles associated with intestinal parasite load in the vulnerable Chinese egret (Egretta eulophotes).

    PubMed

    Lei, Wei; Zhou, Xiaoping; Fang, Wenzhen; Lin, Qingxian; Chen, Xiaolin

    2016-07-01

    The maintenance of major histocompatibility complex (MHC) polymorphism has been hypothesized to result from many mechanisms such as rare-allele advantage, heterozygote advantage, and allele counting. In the study reported herein, 224 vulnerable Chinese egrets (Egretta eulophotes) were used to examine these hypotheses as empirical results derived from bird studies are rare. Parasite survey showed that 147 (65.63%) individuals were infected with 1-3 helminths, and 82.31% of these infected individuals carried Ascaridia sp. Using asymmetric polymerase chain reaction technique, 10 DAB1, twelve DAB2, and three DAB3 exon 2 alleles were identified at each single locus. A significant association of the rare allele Egeu-DAB2*05 (allele frequency: 0.022) with helminth resistance was found for all helminths, as well as for the most abundant morphotype Ascaridia sp. in the separate analyses. Egeu-DAB2*05 occurred frequently in uninfected individuals, and individuals carrying Egeu-DAB2*05 had significantly lower helminth morphotypes per individual (HMI) (the number of HMI) and the fecal egg count values. Further, the parasite infection measurements were consistently lower in individuals with an intermediate number of different alleles in the duplicated DAB loci. Significantly, heterozygosity within each DAB locus was not correlated with any parasite infection measurements. These results indicate that the diversity in MHC Egeu-DAB gene is associated with intestinal parasite load and maintained by pathogen-driven selection that probably operate through both the rare-allele advantage and the allele counting strategy, and suggest that Egeu-DAB2*05 might be a valuable indicator of better resistance to helminth diseases in the vulnerable Chinese egret. PMID:27386085

  9. Heterogenous graft rejection pathways in class I major histocompatibility complex-disparate combinations and their differential susceptibility to immunomodulation induced by intravenous presensitization with relevant alloantigens

    PubMed Central

    1991-01-01

    The present study investigates the heterogeneity of graft rejection pathways in class I major histocompatibility complex (MHC)-disparate combinations and the susceptibility of each pathway to immunomodulation induced by intravenous presensitization with alloantigens. Depletion of CD8+ T cells was induced by repeated administration of anti-CD8 monoclonal antibody. CD8+ T cell-depleted mice failed to generate anti- allo class I MHC cytotoxic T cell (CTL) responses but exhibited anti- allo class I MHC T cell responses, such as mixed lymphocyte reaction (MLR)/IL-2 production, that were induced by CD4+ T cells. In contrast, donor-specific intravenous presensitization (DSP), as a model of donor- specific transfusion, induced almost complete elimination of CD4+ and CD8+ T cell-mediated MLR/IL-2 production, whereas this regimen did not affect the generation of CTL responses induced by DSP-resistant elements (CD8+ CTL precursors and CD4+ CTL helpers). Prolongation of skin graft survival was not induced by either of the above two regimens alone, but by the combination of these. Prolonged graft survival was obtained irrespective of whether the administration of anti-CD8 antibody capable of eliminating CTL was started before or after DSP. The combination of DSP with injection of anti-CD4 antibody also effectively prolonged graft survival. However, this was the case only when the injection of antibody was started before DSP, because such antibody administration was capable of inhibiting the generation of CTL responses by eliminating DSP-resistant CD4+ CTL helpers. These results indicate that (a) the graft rejection in class I-disparate combinations is induced by CD8+ CTL-involved and -independent pathways that are resistant and susceptible to DSP, respectively; (b) DSP contributes to, but is not sufficient for, the prolongation of graft survival; and (c) the suppression of graft rejection requires an additional treatment for reducing DSP-resistant CTL responses. The results are

  10. Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

    PubMed Central

    Guo, Xuancheng; Liu, Taixiang; Shi, Hengfei; Wang, Jingjing; Ji, Ping; Wang, Hongwei; Hou, Yayi; Tan, Ren Xiang

    2015-01-01

    ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease. IMPORTANCE Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial

  11. Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors.

    PubMed

    Nakakido, Makoto; Tamura, Kenji; Chung, Suyoun; Ueda, Koji; Fujii, Risa; Kiyotani, Kazuma; Nakamura, Yusuke

    2016-09-01

    We identified phosphatidylinositol glycan anchor biosynthesis, class X (PIGX), which plays a critical role in the biosynthetic pathway of glycosylphosphatidylinositol (GPI)-anchor motif, to be upregulated highly and frequently in breast cancer cells. Knockdown of PIGX as well as reticulocalbin 1 (RCN1) and reticulocalbin 2 (RCN2), which we found to interact with PIGX and was indicated to regulate calcium-dependent activities, significantly suppressed the growth of breast cancer cells. We also identified PIGX to be a core protein in an RCN1/PIGX/RCN2 complex. Microarray analysis revealed that the expression of two putative tumor suppressor genes, Zic family member 1 (ZIC1) and EH-domain containing 2 (EHD2), were upregulated commonly in cells in which PIGX, RCN1, or RCN2 was knocked down, suggesting that this RCN1/PIGX/RCN2 complex could negatively regulate the expression of these two genes and thereby contribute to human breast carcinogenesis. Our results imply that PIGX may be a good candidate molecule for development of novel anticancer drugs for breast cancer. PMID:27572108

  12. Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors

    PubMed Central

    Nakakido, Makoto; Tamura, Kenji; Chung, Suyoun; Ueda, Koji; Fujii, Risa; Kiyotani, Kazuma; Nakamura, Yusuke

    2016-01-01

    We identified phosphatidylinositol glycan anchor biosynthesis, class X (PIGX), which plays a critical role in the biosynthetic pathway of glycosylphosphatidylinositol (GPI)-anchor motif, to be upregulated highly and frequently in breast cancer cells. Knockdown of PIGX as well as reticulocalbin 1 (RCN1) and reticulocalbin 2 (RCN2), which we found to interact with PIGX and was indicated to regulate calcium-dependent activities, significantly suppressed the growth of breast cancer cells. We also identified PIGX to be a core protein in an RCN1/PIGX/RCN2 complex. Microarray analysis revealed that the expression of two putative tumor suppressor genes, Zic family member 1 (ZIC1) and EH-domain containing 2 (EHD2), were upregulated commonly in cells in which PIGX, RCN1, or RCN2 was knocked down, suggesting that this RCN1/PIGX/RCN2 complex could negatively regulate the expression of these two genes and thereby contribute to human breast carcinogenesis. Our results imply that PIGX may be a good candidate molecule for development of novel anticancer drugs for breast cancer. PMID:27572108

  13. "Racializing" Class

    ERIC Educational Resources Information Center

    Hatt-Echeverria, Beth; Urrieta, Luis, Jr.

    2003-01-01

    In an effort to explore how racial and class oppressions intersect, the authors use their autobiographical narratives to depict cultural and experiential continuity and discontinuity in growing up white working class versus Chicano working class. They specifically focus on "racializing class" due to the ways class is often used as a copout by…

  14. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  15. The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides.

    PubMed Central

    van Bleek, G M; Nathenson, S G

    1991-01-01

    We have examined the effect of diversity in the antigen-binding groove of the Kb, Db, Kbm1, and Kbm8 major histocompatibility complex (MHC) class I molecules on the set of self-peptides they present on the cell surface, by using a procedure we recently developed in our laboratory to isolate endogenously processed peptides bound to MHC class I molecules. We found that such naturally processed peptides are 7-10 amino acids long. A major motif of tyrosine and phenylalanine residues at positions three and five was found for peptides binding to Kb. The availability of Kb mutant molecules Kbm1 and Kbm8, each with localized clustered changes in the antigen-binding cleft, allowed us to probe the effect of such small alterations on peptide selection. We found that such changes in different regions in the antigen-binding groove exert an absolute effect by changing subsets of self-peptides bound to these MHC molecules. In the Kbm1 mutant, the binding of the characteristic major set of Kb-associated peptides with tyrosine at position three or both positions three and five is abrogated, although this MHC molecule still binds peptides with tyrosine at position seven; the latter peptides also bind to Kb. Kbm8 shares the major Tyr-3, Tyr-5 peptide set that binds to Kb but does not bind the peptides with tyrosine at position seven. Thus differences in binding selectivity in Kbm1 and Kbm8 appear to be the major determinant for the observed alterations in in vivo immune responses. PMID:1763019

  16. Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation.

    PubMed

    Zika, Eleni; Greer, Susanna F; Zhu, Xin-Sheng; Ting, Jenny P-Y

    2003-05-01

    The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-gamma) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-gamma-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-gamma- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs.

  17. The QTL within the H2 Complex Involved in the Control of Tuberculosis Infection in Mice Is the Classical Class II H2-Ab1 Gene

    PubMed Central

    Logunova, Nadezhda; Korotetskaya, Maria; Polshakov, Vladimir; Apt, Alexander

    2015-01-01

    The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole-genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17. For the present study, we have established a panel of new congenic, MHC-recombinant mouse strains bearing differential small segments of chromosome 17 transferred from the TB-susceptible I/St (H2 j) strain onto the genetic background of TB-resistant C57BL/6 (B6) mice (H2 b). This allowed narrowing the QTL interval to 17Ch: 33, 77–34, 34 Mb, containing 36 protein-encoding genes. Cloning and sequencing of the H2 j allelic variants of these genes demonstrated profound polymorphic variations compare to the H2 b haplotype. In two recombinant strains, B6.I-249.1.15.100 and B6.I-249.1.15.139, recombination breakpoints occurred in different sites of the H2-Aβ 1 gene (beta-chain of the Class II heterodimer H2-A), providing polymorphic variations in the domain β1 of the Aβ-chain. These variations were sufficient to produce different TB-relevant phenotypes: the more susceptible B6.I-249.1.15.100 strain demonstrated shorter survival time, more rapid body weight loss, higher mycobacterial loads in the lungs and more severe lung histopathology compared to the more resistant B6.I-249.1.15.139 strain. CD4+ T cells recognized mycobacterial antigens exclusively in the context of the H2-A Class II molecule, and the level of IFN-γ-producing CD4+ T cells in the lungs was significantly higher in the resistant strain. Thus, we directly demonstrated for the first time that the classical H2- Ab1 Class II gene is involved in TB control. Molecular modeling of the H2-Aj product predicts that amino acid (AA) substitutions in the Aβ-chain modify the motif of the peptide–MHC binding groove. Moreover, unique AA substitutions in both α- and β-chains of the H2-Aj molecule

  18. Crystal structure of Fushi tarazu factor 1 ligand binding domain/Fushi tarazu peptide complex identifies new class of nuclear receptors.

    PubMed

    Yoo, Jiho; Ko, Sunggeon; Kim, Hyeyon; Sampson, Heidi; Yun, Ji-Hye; Choe, Kwang-Min; Chang, Iksoo; Arrowsmith, Cheryl H; Krause, Henry M; Cho, Hyun-Soo; Lee, Weontae

    2011-09-01

    The interaction between the orphan nuclear receptor FTZ-F1 (Fushi tarazu factor 1) and the segmentation gene protein FTZ is critical for specifying alternate parasegments in the Drosophila embryo. Here, we have determined the structure of the FTZ-F1 ligand-binding domain (LBD)·FTZ peptide complex using x-ray crystallography. Strikingly, the ligand-binding pocket of the FTZ-F1 LBD is completely occupied by helix 6 (H6) of the receptor, whereas the cofactor FTZ binds the co-activator cleft site of the FTZ-F1 LBD. Our findings suggest that H6 is essential for transcriptional activity of FTZ-F1; this is further supported by data from mutagenesis and activity assays. These data suggest that FTZ-F1 might belong to a novel class of ligand-independent nuclear receptors. Our findings are intriguing given that the highly homologous human steroidogenic factor-1 and liver receptor homolog-1 LBDs exhibit sizable ligand-binding pockets occupied by putative ligand molecules.

  19. Low Major Histocompatibility Complex Class II Variation in the Endangered Indo-Pacific Humpback Dolphin (Sousa chinensis): Inferences About the Role of Balancing Selection.

    PubMed

    Zhang, Xiyang; Lin, Wenzhi; Zhou, Ruilian; Gui, Duan; Yu, Xinjian; Wu, Yuping

    2016-03-01

    It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis. PMID:26787544

  20. Transcription of non-classic major histocompatibility complex (MHC) class I in the bovine placenta throughout gestation and after Brucella abortus infection.

    PubMed

    Dos Santos, Larissa Sarmento; da Silva Mol, Juliana Pinto; de Macedo, Auricélio Alves; Silva, Ana Patrícia Carvalho; Dos Santos Ribeiro, Diego Luiz; Santos, Renato Lima; da Paixão, Tatiane Alves; de Carvalho Neta, Alcina Vieira

    2015-10-15

    Transcription of non-classical major histocompatibility complex class I (MHC-I) was assessed in the bovine placenta throughout gestation. Additionally, the effect of Brucella abortus infection on expression of non-classical MHC-I was also evaluated using a chorioallantoic membrane explant model of infection. The non-classical MHC-I genes MICB and NC3 had higher levels of transcription in the intercotyledonary region when compared to the placentome, which had higher levels of transcription at the second trimester of gestation. NC1 and classical MHC-I had very low levels of transcription throughout gestation. Trophoblastic cells of B. abortus-infected chorioallantoic membrane explants had an increase in transcription of non-classical MHC-I at 4h post infection. Therefore, this study provides an analysis of non-classical MHC-I transcription at different stages of gestation and different placental tissues, and during B. abortus infection. These findings provide additional knowledge on immune regulation in placental tissues, a known immune-privileged site.

  1. Extensive polymorphism and evidence of selection pressure on major histocompatibility complex DLA-DRB1, DQA1 and DQB1 class II genes in Croatian grey wolves.

    PubMed

    Arbanasić, H; Huber, Đ; Kusak, J; Gomerčić, T; Hrenović, J; Galov, A

    2013-01-01

    The genes of the major histocompatibility complex (MHC) are a key component of the mammalian immune system and have become important molecular markers for measuring fitness-related genetic variation in wildlife populations. Because of human persecution and habitat fragmentation, the grey wolf has become extinct from a large part of Western and Central Europe, and remaining populations have become isolated. In Croatia, the grey wolf population, part of the Dinaric-Balkan population, shrank nearly to extinction during the 20th century, and is now legally protected. Using the cloning-sequencing method, we investigated the genetic diversity and evolutionary history of exon 2 of MHC class II DLA-DRB1, DQA1 and DQB1 genes in 77 individuals. We identified 13 DRB1, 7 DQA1 and 11 DQB1 highly divergent alleles, and 13 DLA-DRB1/DQA1/DQB1 haplotypes. Selection analysis comparing the relative rates of non-synonymous to synonymous mutations (d(N)/d(S)) showed evidence of positive selection pressure acting on all three loci. Trans-species polymorphism was found, suggesting the existence of balancing selection. Evolutionary codon models detected considerable difference between alpha and beta chain gene selection patterns: DRB1 and DQB1 appeared to be under stronger selection pressure, while DQA1 showed signs of moderate selection. Our results suggest that, despite the recent contraction of the Croatian wolf population, genetic variability in selectively maintained immune genes has been preserved. PMID:23134500

  2. Low Major Histocompatibility Complex Class II Variation in the Endangered Indo-Pacific Humpback Dolphin (Sousa chinensis): Inferences About the Role of Balancing Selection.

    PubMed

    Zhang, Xiyang; Lin, Wenzhi; Zhou, Ruilian; Gui, Duan; Yu, Xinjian; Wu, Yuping

    2016-03-01

    It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis.

  3. Major histocompatibility complex class I chain related (MIC) A gene, TNFa microsatellite alleles and TNFB alleles in juvenile idiopathic arthritis patients from Latvia.

    PubMed

    Nikitina Zake, Liene; Cimdina, Ija; Rumba, Ingrida; Dabadghao, Preethi; Sanjeevi, Carani B

    2002-05-01

    In order to analyze involvement of major histocompatibility complex class I chain-related gene A (MICA) and tumor necrosis factor a (TNFa) microsatellite polymorphisms as well as TNFB gene in juvenile idiopathic arthritis (JIA), we studied 128 patients divided into groups according to clinical features [monoarthritis (n = 14), oligoarthritis (n = 58), polyarthritis (n = 50), and systemic (n = 6)], and 114 age- and sex-matched healthy controls from Latvia. DNA samples were amplified with specific primers and used for genotyping of MICA and TNFa microsatellite. Typing for a biallelic NcoI polymerase chain reaction RFLP polymorphism located at the first intron of TNFB gene was done as follows: restriction digests generated fragments of 555bp and 185bp for TNFB*1 allele, and 740bp for TNFB*2 allele. The results were compared between cases and controls. We found significant increase of MICA allele A4 (p = 0.009; odds ratio [OR] = 2.3) and allele TNFa2 (p = 0.0001; OR = 4.4) in patients compared with controls. The frequency of allele TNFa9 was significantly decreased (p = 0.0001; OR = 0.1) in patients with JIA. No significant differences of TNFB allele frequency were found. Our data suggest that MICA and TNFa microsatellite polymorphisms may be used as markers for determination of susceptibility and protection from JIA.

  4. Molecular components of the B cell antigen receptor complex of class IgD differ partly from those of IgM.

    PubMed Central

    Wienands, J; Hombach, J; Radbruch, A; Riesterer, C; Reth, M

    1990-01-01

    Two classes of immunoglobulin, IgM and IgD, are present as antigen receptors on the surface of mature B lymphocytes. We show here that IgD molecules are noncovalently associated in the B cell membrane with a heterodimer consisting of two proteins of 35 kd (IgD-alpha) and 39 kd (Ig-beta), respectively. The two novel proteins are not found in the IgD-expressing myeloma J558L delta m, which fails to bring IgD antigen receptor onto the cell surface. In a surface IgD positive variant line of this myeloma, however, membrane-bound IgD molecules are associated with the heterodimer, suggesting that the formation of an antigen receptor complex is required for surface IgD expression. We further demonstrate that the IgD-associated heterodimer differs partly from that of the IgM antigen receptor and that its binding to the heavy chain only requires the presence of the last constant domain and the transmembrane part of the delta m chain. Images Fig. 3. Fig. 5. Fig. 6. Fig. 7. PMID:2303036

  5. Allelic and haplotype variation of major histocompatibility complex class II DRB1 and DQB loci in the St Lawrence beluga (Delphinapterus leucas).

    PubMed

    1999-07-01

    In order to assess levels of major histocompatibility complex (Mhc) variation within the St Lawrence beluga (Delphinapterus leucas) the variation at the beluga Mhc DRB1 class II locus was assessed by single-strand conformation polymorphism (SSCP) analysis of the peptide-binding region for 313 whales collected from 13 sampling locations across North America. In addition, samples from west Greenland and the St Lawrence were also typed at the DQB locus, allowing comparison to a previous study and assessment of linkage disequilibrium of alleles at the two loci. Comparisons of DRB1 and DQB allele frequencies among all sampling locations indicated genetic structure (alpha < 0.005). Most of this structure resulted from differences between the different wintering groups. Significant genetic structure (alpha = 0.05) exists among each pair of the following groups at both the DRB1 and DQB loci; St Lawrence, Hudson Strait, Bering Sea, Cunningham Inlet, and Davis Strait (minus Cunningham Inlet), except the St Lawrence and Hudson Strait for the DQB locus. In the St Lawrence population, six of the eight DRB1 alleles are present representing all five known allelic lineages. Evidence of linkage disequilibrium between the DRB1 and DQB is present in two sampling locations, the St Lawrence and Nuussuaq (alpha = 0.05). Analysis of probable DRB1-DQB haplotypes among groups of beluga suggests a haplotype reduction in the St Lawrence. PMID:10447854

  6. Equine Herpesvirus 1 Multiply Inserted Transmembrane Protein pUL43 Cooperates with pUL56 in Downregulation of Cell Surface Major Histocompatibility Complex Class I

    PubMed Central

    Huang, Teng; Ma, Guanggang

    2015-01-01

    ABSTRACT Herpesviruses have evolved an array of strategies to counteract antigen presentation by major histocompatibility complex class I (MHC-I). Previously, we identified pUL56 of equine herpesvirus 1 (EHV-1) as one major determinant of the downregulation of cell surface MHC-I (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van de Walle, J. Virol. 86:3554–3563, 2012, http://dx.doi.org/10.1128/JVI.06994-11; T. Huang, M. J. Lehmann, A. Said, G. Ma, and N. Osterrieder, J. Virol. 88:12802–12815, 2014, http://dx.doi.org/10.1128/JVI.02079-14). Since pUL56 was able to exert its function only in the context of virus infection, we hypothesized that pUL56 cooperates with another viral protein. Here, we generated and screened a series of EHV-1 single-gene deletion mutants and found that the pUL43 orthologue was required for downregulation of cell surface MHC-I expression at the same time of infection as when pUL56 exerts its function. We demonstrate that the absence of pUL43 was not deleterious to virus growth and that expression of pUL43 was detectable from 2 h postinfection (p.i.) but decreased after 8 h p.i. due to lysosomal degradation. pUL43 localized within Golgi vesicles and required a unique hydrophilic N-terminal domain to function properly. Finally, coexpression of pUL43 and pUL56 in transfected cells reduced the cell surface expression of MHC-I. This process was dependent on PPxY motifs present in pUL56, suggesting that late domains are required for pUL43- and pUL56-dependent sorting of MHC class I for lysosomal degradation. IMPORTANCE We describe here that the poorly characterized herpesviral protein pUL43 is involved in downregulation of cell surface MHC-I. pUL43 is an early protein and degraded in lysosomes. pUL43 resides in the Golgi vesicles and needs an intact N terminus to induce MHC-I downregulation in infected cells. Importantly, pUL43 and pUL56 cooperate to reduce MHC-I expression on the surface of transfected cells. Our results suggest a model for

  7. Disentangling the effects of recombination, selection, and demography on the genetic variation at a major histocompatibility complex class II gene in the alpine chamois.

    PubMed

    Mona, S; Crestanello, B; Bankhead-Dronnet, S; Pecchioli, E; Ingrosso, S; D'Amelio, S; Rossi, L; Meneguz, P G; Bertorelle, G

    2008-09-01

    The major histocompatibility complex (MHC) harbours some of the most polymorphic loci in vertebrate genomes. MHC genes are thought to be subject to some form of balancing selection, most likely pathogen-mediated selection. Hence, MHC genes are excellent candidates for exploring adaptive processes. In this study, we investigated the genetic variation at exon 2 of the DRB class II MHC locus in 191 alpine chamois (Rupicapra rupicapra) from 10 populations in the eastern Alps of Italy. In particular, we were interested in distinguishing and estimating the relative impact of selective and demographic factors, while taking into account the confounding effect of recombination. The extremely high d(n)/d(s) ratio and the presence of trans-species polymorphisms suggest that a strong long-term balancing selection effect has been operating at this locus throughout the evolutionary history of this species. We analysed patterns of genetic variation within and between populations, and the mitochondrial D-loop polymorphism patterns were analysed to provide a baseline indicator of the effects of demographic processes. These analyses showed that (i) the chamois experienced a demographic decline in the last 5000-30 000 years, most likely related to the postglacial elevation in temperature; (ii) this demographic process can explain the results of neutrality tests applied to MHC variation within populations, but cannot justify the much weaker divergence between populations implied by MHC as opposed to mitochondrial DNA; (iii) similar sets of divergent alleles are probably maintained with similar frequencies by balancing selection in different populations, and this mechanism is also operating in small isolated populations, which are strongly affected by drift.

  8. The major histocompatibility complex in monotremes: an analysis of the evolution of Mhc class I genes across all three mammalian subclasses.

    PubMed

    Miska, Katarzyna B; Harrison, Gavan A; Hellman, Lars; Miller, Robert D

    2002-09-01

    We report the isolation and characterization of cDNA clones of expressed, functional major histocompatibility complex class-I ( Mhc-I) genes from two species of monotremes: the duck-billed platypus and the short-beaked echidna. The cDNA clones were isolated from libraries constructed from spleen RNA, clearly establishing their expression in at least this one peripheral lymphoid organ. From the presence of conserved amino acid residues, it appears the expressed sequences encode molecules that likely function as classical Mhc-I. These clones were isolated using monotreme Mhc-I processed pseudogenes as probes. These processed pseudogenes were isolated from genomic DNA and, based on their structure, are likely independently derived in the platypus and echidna. When all the monotreme sequences were included in phylogenetic analyses, we found no apparent orthologous relationships between the platypus and echidna Mhc-I. Analyses that included a large number of Mhc-I sequences from other taxa support a separate monotreme Mhc-I clade, basal to a therian Mhc-I clade that is comprised of sequences from marsupial and placental mammals. The phylogenies also support the hypothesis that Mhc-I genes of placental mammals, marsupials, and monotremes are derived from three separate lineages of Mhc-I genes, best explained by two rounds of duplications and deletions. The first round would have occurred prior to the divergence of monotremes and therians, and the second prior to the divergence of marsupials and placental mammals. The sequences described here represent the first reported functional monotreme Mhc-I, as well as the first processed pseudogenes of any type from monotremes.

  9. Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

    PubMed Central

    Ferrero, Mariana C.; Hielpos, M. Soledad; Carvalho, Natalia B.; Barrionuevo, Paula; Corsetti, Patricia P.; Giambartolomei, Guillermo H.; Oliveira, Sergio C.

    2014-01-01

    Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-α), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1β (IL-1β), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID:24478078

  10. Key role of Toll-like receptor 2 in the inflammatory response and major histocompatibility complex class ii downregulation in Brucella abortus-infected alveolar macrophages.

    PubMed

    Ferrero, Mariana C; Hielpos, M Soledad; Carvalho, Natalia B; Barrionuevo, Paula; Corsetti, Patricia P; Giambartolomei, Guillermo H; Oliveira, Sergio C; Baldi, Pablo C

    2014-02-01

    Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-α), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1β (IL-1β), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID:24478078

  11. In silico prediction of peptide binding affinity to class I mouse major histocompatibility complexes: a comparative molecular similarity index analysis (CoMSIA) study.

    PubMed

    Hattotuwagama, Channa K; Doytchinova, Irini A; Flower, Darren R

    2005-01-01

    Current methods for the in silico identification of T cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate prediction of peptide-major histocompatibility complex (MHC) affinity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) for the prediction of peptide binding to class I MHC molecules was established using the comparative molecular similarity index analysis (CoMSIA) method. Three MHC alleles were studied: H2-D(b), H2-K(b), and H2-K(k). Models were produced for each allele. Each model consisted of five physicochemical descriptors-steric bulk, electrostatic potentials, hydrophobic interactions, and hydrogen-bond donor and hydrogen-bond acceptor abilities. The models have an acceptable level of predictivity: cross-validation leave-one-out statistical terms q2 and SEP (standard error of prediction) ranged between 0.490 and 0.679 and between 0.525 and 0.889, respectively. The non-cross-validated statistical terms r2 and SEE (standard error of estimate) ranged between 0.913 and 0.979 and between 0.167 and 0.248, respectively. The use of coefficient contour maps, which indicate favored and disfavored areas for each position of the MHC-bound peptides, allowed the binding specificity of each allele to be identified, visualized, and understood. The present study demonstrates the effectiveness of CoMSIA as a method for studying peptide-MHC interactions. The peptides used in this study are available on the Internet (http://www.jenner.ac.uk/AntiJen). The partial least-squares method is available commercially in the SYBYL molecular modeling software package. PMID:16180918

  12. Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells.

    PubMed

    Imai, Takahiko; Koyanagi, Naoto; Ogawa, Ryo; Shindo, Keiko; Suenaga, Tadahiro; Sato, Ayuko; Arii, Jun; Kato, Akihisa; Kiyono, Hiroshi; Arase, Hisashi; Kawaguchi, Yasushi

    2013-01-01

    Detection and elimination of virus-infected cells by CD8(+) cytotoxic T lymphocytes (CTLs) depends on recognition of virus-derived peptides presented by major histocompatibility complex class I (MHC-I) molecules on the surface of infected cells. In the present study, we showed that inactivation of the activity of viral kinase Us3 encoded by herpes simplex virus 1 (HSV-1), the etiologic agent of several human diseases and a member of the alphaherpesvirinae, significantly increased cell surface expression of MHC-I, thereby augmenting CTL recognition of infected cells in vitro. Overexpression of Us3 by itself had no effect on cell surface expression of MHC-I and Us3 was not able to phosphorylate MHC-I in vitro, suggesting that Us3 indirectly downregulated cell surface expression of MHC-I in infected cells. We also showed that inactivation of Us3 kinase activity induced significantly more HSV-1-specific CD8(+) T cells in mice. Interestingly, depletion of CD8(+) T cells in mice significantly increased replication of a recombinant virus encoding a kinase-dead mutant of Us3, but had no effect on replication of a recombinant virus in which the kinase-dead mutation was repaired. These results indicated that Us3 kinase activity is required for efficient downregulation of cell surface expression of MHC-I and mediates evasion of HSV-1-specific CD8(+) T cells. Our results also raised the possibility that evasion of HSV-1-specific CD8(+) T cells by HSV-1 Us3-mediated inhibition of MHC-I antigen presentation might in part contribute to viral replication in vivo.

  13. Brucella abortus Inhibits Major Histocompatibility Complex Class II Expression and Antigen Processing through Interleukin-6 Secretion via Toll-Like Receptor 2▿

    PubMed Central

    Barrionuevo, Paula; Cassataro, Juliana; Delpino, M. Victoria; Zwerdling, Astrid; Pasquevich, Karina A.; Samartino, Clara García; Wallach, Jorge C.; Fossati, Carlos A.; Giambartolomei, Guillermo H.

    2008-01-01

    The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC-II)-restricted gamma interferon (IFN-γ)-producing CD4+ T lymphocytes are poorly understood. We report here that infection of THP-1 cells with B. abortus inhibited expression of MHC-II molecules and antigen (Ag) processing. Heat-killed B. abortus (HKBA) also induced both these phenomena, indicating the independence of bacterial viability and involvement of a structural component of the bacterium. Accordingly, outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, inhibited both MHC-II expression and Ag processing to the same extent as HKBA. Moreover, a synthetic lipohexapeptide that mimics the structure of the protein lipid moiety also inhibited MHC-II expression, indicating that any Brucella lipoprotein could down-modulate MHC-II expression and Ag processing. Inhibition of MHC-II expression and Ag processing by either HKBA or lipidated Omp19 (L-Omp19) depended on Toll-like receptor 2 and was mediated by interleukin-6. HKBA or L-Omp19 also inhibited MHC-II expression and Ag processing of human monocytes. In addition, exposure to the synthetic lipohexapeptide inhibited Ag-specific T-cell proliferation and IFN-γ production of peripheral blood mononuclear cells from Brucella-infected patients. Together, these results indicate that there is a mechanism by which B. abortus may prevent recognition by T cells to evade host immunity and establish a chronic infection. PMID:17984211

  14. Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection.

    PubMed

    Leroux, Louis-Philippe; Nishi, Manami; El-Hage, Sandy; Fox, Barbara A; Bzik, David J; Dzierszinski, Florence S

    2015-10-01

    Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely, the MHC-II-associated invariant chain (Ii or CD74) and the peptide editor H2-DM, in professional antigen-presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were, surprisingly, elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impacts of genetic deletion of CD74 and H2-DM genes on parasite dissemination toward lymphoid organs in mice, as well as activation of CD4(+) T cells and interferon gamma (IFN-γ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight the fact that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway. PMID:26195549

  15. The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model.

    PubMed Central

    Giblin, P A; Leahy, D J; Mennone, J; Kavathas, P B

    1994-01-01

    The CD8 dimer interacts with the alpha 3 domain of major histocompatibility complex class I molecules through two immunoglobulin variable-like domains. In this study a crystal structure-informed mutational analysis has been performed to identify amino acids in the CD8 alpha/alpha homodimer that are likely to be involved in binding to class I. Several key residues are situated on the top face of the dimer within loops analogous to the complementarity-determining regions (CDRs) of immunoglobulin. In addition, other important amino acids are located in the A and B beta-strands on the sides of the dimer. The potential involvement of amino acids on both the top and the side faces of the molecule is consistent with a bivalent model for the interaction between a single CD8 alpha/alpha homodimer and two class I molecules and may have important implications for signal transduction in class I-expressing cells. This study also demonstrates a role for the positive surface potential of CD8 in class I binding and complements previous work demonstrating the importance of a negatively charged loop on the alpha 3 domain of class I for CD8 alpha/alpha-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the alpha 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B beta-strands contact the alpha 2 domain of class I. Images PMID:8127870

  16. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    SciTech Connect

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor; Anderson, Robert P.; McCluskey, James; Rossjohn, Jamie

    2007-12-01

    The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported.

  17. Class Size.

    ERIC Educational Resources Information Center

    Ellis, Thomas I.

    1985-01-01

    After a brief introduction identifying current issues and trends in research on class size, this brochure reviews five recent studies bearing on the relationship of class size to educational effectiveness. Part 1 is a review of two interrelated and highly controversial "meta-analyses" or statistical integrations of research findings on class size,…

  18. Class Matters

    ERIC Educational Resources Information Center

    Valdata, Patricia

    2005-01-01

    Ever since George Washington opted for the title of president rather than king, Americans have been uncomfortable with the idea of class distinctions. This article presents an interview with Dr. Janet Galligani Casey regarding the idea of class distinctions. Galligani Casey, who grew up in a working-class neighborhood in Somerville, Massachusetts,…

  19. Early detection of dominant Env-specific and subdominant Gag-specific CD8+ lymphocytes in equine infectious anemia virus-infected horses using major histocompatibility complex class I/peptide tetrameric complexes.

    PubMed

    Mealey, Robert H; Sharif, Amin; Ellis, Shirley A; Littke, Matt H; Leib, Steven R; McGuire, Travis C

    2005-08-15

    Cytotoxic T lymphocytes (CTL) are critical for control of lentiviruses, including equine infectious anemia virus (EIAV). Measurement of equine CTL responses has relied on chromium-release assays, which do not allow accurate quantitation. Recently, the equine MHC class I molecule 7-6, associated with the ELA-A1 haplotype, was shown to present both the Gag-GW12 and Env-RW12 EIAV CTL epitopes. In this study, 7-6/Gag-GW12 and 7-6/Env-RW12 MHC class I/peptide tetrameric complexes were constructed and used to analyze Gag-GW12- and Env-RW12-specific CTL responses in two EIAV-infected horses (A2164 and A2171). Gag-GW12 and Env-RW12 tetramer-positive CD8+ cells were identified in nonstimulated peripheral blood mononuclear cells as early as 14 days post-EIAV inoculation, and frequencies of tetramer-positive cells ranged from 0.4% to 6.7% of nonstimulated peripheral blood CD8+ cells during the 127-day study period. Although both horses terminated the initial viremic peak, only horse A2171 effectively controlled viral load. Neutralizing antibody was present during the initial control of viral load in both horses, but the ability to maintain control correlated with Gag-GW12-specific CD8+ cells in A2171. Despite Env-RW12 dominance, Env-RW12 escape viral variants were identified in both horses and there was no correlation between Env-RW12-specific CD8+ cells and control of viral load. Although Gag-GW12 CTL escape did not occur, a Gag-GW12 epitope variant arose in A2164 that was recognized less efficiently than the original epitope. These data indicate that tetramers are useful for identification and quantitation of CTL responses in horses, and suggest that the observed control of EIAV replication and clinical disease was associated with sustained CTL recognition of Gag-specific epitopes. PMID:15979679

  20. Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C.

    PubMed

    Sullivan, Lucy C; Berry, Richard; Sosnin, Natasha; Widjaja, Jacqueline M L; Deuss, Felix A; Balaji, Gautham R; LaGruta, Nicole L; Mirams, Michiko; Trapani, Joseph A; Rossjohn, Jamie; Brooks, Andrew G; Andrews, Daniel M

    2016-09-01

    Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules. PMID:27385590

  1. Expression of bovine non-classical major histocompatibility complex class I proteins in mouse P815 and human K562 cells.

    PubMed

    Parasar, Parveen; Wilhelm, Amanda; Rutigliano, Heloisa M; Thomas, Aaron J; Teng, Lihong; Shi, Bi; Davis, William C; Suarez, Carlos E; New, Daniel D; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-classical MHC-I isoforms, we expressed the MHC proteins in murine P815 and human K562 (MHC-I deficient) cells. Following antibiotic selection, stably transfected cell lines were stained with H1A or W6/32 antibodies to detect expression of the MHC-I proteins by flow cytometry. Two non-classical proteins (BoLA-NC1*00501 and BoLA-NC3*00101) were expressed on the cell surface in both cell lines. Surprisingly, the BoLA-NC4*00201 protein was expressed on the cell membrane of human K562 but not mouse P815 cells. Two non-classical proteins (BoLA-NC1*00401, which lacks a transmembrane domain, and BoLA-NC2*00102) did not exhibit cell surface expression. Nevertheless, Western blot analyses demonstrated expression of the MHC-I heavy chain in all transfected cell lines. Ammonium-sulfate precipitation of proteins from culture supernatants showed that BoLA-NC1*00401 was secreted and that all surface expressed proteins where shed from the cell membrane by the transfected cells. Interestingly, the surface expressed MHC-I proteins were present in culture supernatants at a much higher concentration than BoLA-NC1*00401. This comprehensive study shows that bovine non-classical MHC-I proteins BoLA-NC1*00501, BoLA-NC3*00101, and BoLA-NC4*00201 are expressed as surface isoforms with the latter reaching the cell membrane only in K562 cells. Furthermore, it demonstrated that BoLA-NC1*00401 is a secreted isoform and that significant quantities of membrane associated MHC-I proteins can be shed from the cell membrane. PMID:27473990

  2. Gamma interferon and 5-azacytidine cause transcriptional elevation of class I major histocompatibility complex gene expression in K562 leukemia cells in the absence of differentiation.

    PubMed

    Chen, E; Karr, R W; Frost, J P; Gonwa, T A; Ginder, G D

    1986-05-01

    We studied the effects of gamma interferon (IFN-gamma) on HLA class I gene expression, differentiation, and proliferative capacity of K562 human leukemia cells. In the uninduced state, K562 cells show little or no class I gene expression but actively express the erythroid-specific gamma-globin gene as well as genes associated with cell proliferation, including the transferrin receptor, c-myc, and alpha-actin genes At both the surface protein and mRNA levels, IFN-gamma induces class I and beta 2-microglobulin gene expression, but does not alter the expression of the gamma-globin, transferrin receptor, c-myc, or alpha-actin genes. A 10-fold maximal induction of both class I surface protein and mRNA occurs at 48 h and is reversible upon withdrawal of IFN-gamma from the culture medium. In vitro nuclear run-on transcription assays were performed to directly establish that IFN-gamma exerts an early effect at the level of transcription, with maximal transcription rates occurring within 4 h. The difference between the time course of transcription induction and that of mRNA accumulation suggests that the regulation of class I gene expression in this human leukemic cell line also involves posttranscriptional mechanisms. Measurements of cell proliferation rates and cell cycle distribution, as well as the reversibility of the effects of IFN-gamma, demonstrate that the selective induction of class I genes in these cells occurs in the absence of differentiation.

  3. Dynamics of the Major Histocompatibility Complex Class I Processing and Presentation Pathway in the Course of Malaria Parasite Development in Human Hepatocytes: Implications for Vaccine Development

    PubMed Central

    Ma, Jinxia; Trop, Stefanie; Baer, Samantha; Rakhmanaliev, Elian; Arany, Zita; Dumoulin, Peter; Zhang, Hao; Romano, Julia; Coppens, Isabelle; Levitsky, Victor; Levitskaya, Jelena

    2013-01-01

    Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver. PMID:24086507

  4. Structural analysis of the human interferon gamma receptor: a small segment of the intracellular domain is specifically required for class I major histocompatibility complex antigen induction and antiviral activity.

    PubMed Central

    Cook, J R; Jung, V; Schwartz, B; Wang, P; Pestka, S

    1992-01-01

    Mutations of the human interferon gamma (IFN-gamma) receptor intracellular domain have permitted us to define a restricted region of that domain as necessary for both induction of class I major histocompatibility complex antigen by IFN-gamma and protection against encephalomyocarditis virus. This region consists of five amino acids (YDKPH), all of which are conserved in the human and murine receptors. Tyr-457 and His-461 are essential for activity. Approximately 80% of the amino acids of the intracellular domain of the receptor is not required for major histocompatibility complex class I antigen induction or for antiviral protection against encephalomyocarditis virus. The observation that there was no protection by IFN-gamma against vesiculostomatitis virus indicates that other factors, in addition to chromosome 21 accessory factor(s), are required to generate the full complement of transduction signals from the human IFN-gamma receptor. Images PMID:1454813

  5. SHOC1 and PTD form an XPF-ERCC1-like complex that is required for formation of class I crossovers.

    PubMed

    Macaisne, Nicolas; Vignard, Julien; Mercier, Raphaël

    2011-08-15

    Two distinct pathways for meiotic crossover formation coexist in most eukaryotes. The Arabidopsis SHOC1 protein is required for class I crossovers and shows sequence similarity with the XPF endonuclease family. Active XPF endonucleases form a heterodimer with ERCC1 proteins. Here, we show that PTD, an ERCC1-like protein, is required for class-I-interfering crossovers along with SHOC1, MSH4, MSH5, MER3 and MLH3. SHOC1 interacts with PTD in a two-hybrid assay, through its XPF-like nuclease-(HhH)(2) domain. We propose that a XPF-ERCC1-like heterodimer, represented by SHOC1 and PTD in Arabidopsis, involving Zip2 in Saccharomyces cerevisiae and C9orf84 in human, is required for formation of class I crossovers. PMID:21771883

  6. Lysis of pig endothelium by IL-2 activated human natural killer cells is inhibited by swine and human major histocompatibility complex (MHC) class I gene products.

    PubMed

    Itescu, S; Artrip, J H; Kwiatkowski, P A; Wang, S F; Minanov, O P; Morgenthau, A S; Michler, R E

    1997-01-01

    We have previously described a form of xenograft rejection, mediated by natural killer (NK) cells, occurring in pig-to-primate organ transplants beyond the period of antibody-mediated hyperacute rejection. In this study, two distinct NK activation pathways were identified as mechanisms of pig aortic endotheliual cell (PAEC) lysis by human NK cells. Using an antibody-dependent cellular cytotoxicity (ADCC) assay, a progressive increase in human NK lysis of PAEC was observed following incubation with human IgG at increasing serum titer. In the absence of IgG, a second mechanism of PAEC lysis by human NK cells was observed following activation with IL-2. IL-2 activation of human NK cells increased lysis of PAEC by over 3-fold compared with ADCC. These results indicate that IL-2 activation of human NK cells induces significantly higher levels of lytic activity than does conventional ADCC involving IgG and FcRIII. We next investigated the role of MHC class I molecules in the regulation of NK lysis following IL-2 activation. PAEC expression of SLA class I molecules was increased by up to 75% by treatment with human TNFa. Following treatment with TNFa at 1 u/ml, IL-2 activated human NK lysis of PAEC was inhibited at every effector:target (E:T) ratio tested. Maximal effect occurred at an E:T ratio of 10:1, with TNFa inhibiting specific lysis by 59% (p < 0.01). Incubation with an anti-SLA class I Mab, but not IgG isotype control, abrogated the protective effects of TNFa on NK lysis of PAEC, suggesting direct inhibitory effects of SLA class I molecules on human NK function. To investigate whether human MHC class I molecules might have similar effects on human NK lysis of PAEC, further experiments were performed using a soluble peptide derived from the alpha-helical region of HLA-B7. Incubation with the HLA-B7 derived peptide significantly reduced the IL-2 activated NK lytic activity against PAEC in a dose-dependent fashion. Maximal effect occurred at a concentration of 10 mg

  7. Evidence of a second polymorphic ELA class I (ELA-B) locus and gene order for three loci of the equine major histocompatibility complex.

    PubMed

    Bernoco, D; Byrns, G; Bailey, E; Lew, A M

    1987-01-01

    Two antisera, B-442 and R-2046, were produced by immunizing offspring with purified peripheral blood lymphocytes from a parent matched for the ELA-A specificity carried on the unshared haplotype. Absorption analysis demonstrated that these antisera contained at least two families of cytotoxic antibodies, one directed against antigens present on T and B cells, and a second directed preferentially against antigens present on surface Ig positive cells. Immunoprecipitation studies using these antisera demonstrated that both antisera contain antibodies specific for glycoproteins with molecular weights characteristic of class I and class II MHC antigens. In lymphocyte typing tests of unfractionated lymphocytes, only the class I activity was readily detectable since the class II activity killed less than 25% of the cells. Family studies demonstrated that these antisera recognize products of genes linked to the ELA system. Based on two recombinants in an extended family it became apparent that the specificities detected by B-442 and R-2046 are not products of the ELA-A locus, but rather they are products of at least one other locus, defined in this paper as ELA-B. In this family a third recombinant was found between the A blood group system and the ELA-A locus. Based on these three recombinants, the most probable linear relationship of the following genes is: A blood group system/ELA-A/ELA-B.

  8. An Important Role for Major Histocompatibility Complex Class I-Restricted T Cells, and a Limited Role for Gamma Interferon, in Protection of Mice against Lethal Herpes Simplex Virus Infection

    PubMed Central

    Holterman, Ai-Xuan; Rogers, Kathleen; Edelmann, Kurt; Koelle, David M.; Corey, Lawrence; Wilson, Christopher B.

    1999-01-01

    Herpes simplex virus (HSV) inhibits major histocompatibility complex (MHC) class I expression in infected cells and does so much more efficiently in human cells than in murine cells. Given this difference, if MHC class I-restricted T cells do not play an important role in protection of mice from HSV, an important role for these cells in humans would be unlikely. However, the contribution of MHC class I-restricted T cells to the control of HSV infection in mice remains unclear. Further, the mechanisms by which these cells may act to control infection, particularly in the nervous system, are not well understood, though a role for gamma interferon (IFN-γ) has been proposed. To address the roles of MHC class I and of IFN-γ, C57BL/6 mice deficient in MHC class I expression (β2 microglobulin knockout [β2KO] mice), in IFN-γ expression (IFN-γKO mice), or in both (IFN-γKO/β2KO mice) were infected with HSV by footpad inoculation. β2KO mice were markedly compromised in their ability to control infection, as indicated by increased lethality and higher concentrations of virus in the feet and spinal ganglia. In contrast, IFN-γ appeared to play at most a limited role in viral clearance. The results suggest that MHC class I-restricted T cells play an important role in protection of mice against neuroinvasive HSV infection and do so largely by mechanisms other than the production of IFN-γ. PMID:9971787

  9. The seirena B Class Floral Homeotic Mutant of California Poppy (Eschscholzia californica) Reveals a Function of the Enigmatic PI Motif in the Formation of Specific Multimeric MADS Domain Protein Complexes[C][W][OA

    PubMed Central

    Lange, Matthias; Orashakova, Svetlana; Lange, Sabrina; Melzer, Rainer; Theißen, Günter; Smyth, David R.; Becker, Annette

    2013-01-01

    The products of B class floral homeotic genes specify petal and stamen identity, and loss of B function results in homeotic conversions of petals into sepals and stamens into carpels. Here, we describe the molecular characterization of seirena-1 (sei-1), a mutant from the basal eudicot California poppy (Eschscholzia californica) that shows homeotic changes characteristic of floral homeotic B class mutants. SEI has been previously described as EScaGLO, one of four B class–related MADS box genes in California poppy. The C terminus of SEI, including the highly conserved PI motif, is truncated in sei-1 proteins. Nevertheless, like the wild-type SEI protein, the sei-1 mutant protein is able to bind CArG-boxes and can form homodimers, heterodimers, and several higher order complexes with other MADS domain proteins. However, unlike the wild type, the mutant protein is not able to mediate higher order complexes consisting of specific B, C, and putative E class related proteins likely involved in specifying stamen identity. Within the PI motif, five highly conserved N-terminal amino acids are specifically required for this interaction. Several families lack this short conserved sequence, including the Brassicaceae, and we propose an evolutionary scenario to explain these functional differences. PMID:23444328

  10. Salmonella typhimurium delta aroA delta aroD mutants expressing a foreign recombinant protein induce specific major histocompatibility complex class I-restricted cytotoxic T lymphocytes in mice.

    PubMed Central

    Turner, S J; Carbone, F R; Strugnell, R A

    1993-01-01

    Recombinant Salmonella typhimurium aroA aroD mutants which expressed ovalbumin were constructed. The two expression constructs used were based on either pUC18 or pBR322. The pBR322-based construct was more stable in vitro and in vivo than the pUC-based construct. Salmonellae containing the stable pBR322-based plasmid induced major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL), in contrast to salmonellae containing the pUC18-based expression construct. The priming of MHC class I-restricted CTL was increased by multiple immunizations. The study described in this report suggest that S. typhimurium delta aro mutants have the capacity to induce MHC class I-restricted CTL against carried antigens and that MHC class I-restricted CTL responses require stable in vivo expression of the target antigen. Further, the results indicate that the Salmonella typhi delta aro mutants currently undergoing evaluation in studies with humans may be good carriers of viral antigens with CTL determinants. Images PMID:8225611

  11. Human CD4-major histocompatibility complex class II (DQw6) transgenic mice in an endogenous CD4/CD8-deficient background: reconstitution of phenotype and human-restricted function

    PubMed Central

    1994-01-01

    To reconstitute the human immune system in mice, transgenic mice expressing human CD4 and human major histocompatibility complex (MHC) class II (DQw6) molecules in an endogenous CD4- and CD8-deficient background (mCD4/8-/-), after homologous recombination, have been generated. We report that expression of human CD4 molecule in mCD4/8-/- mice rescues thymocyte development and completely restores the T cell compartment in peripheral lymphoid organs. Upon vesicular stomatitis virus (VSV) challenge, the reconstituted mature T cell population effectively provide T help to B cells in immunoglobulin class switching from IgM to specific IgG-neutralizing antibodies. Human CD4+DQw6+ double transgenic mice are tolerant to DQw6 and the DQw6 molecule functions in antigen presentation, effectively generating a human MHC class II-restricted T cell response to streptococcal M6C2 peptide. These data show that both the hCD4 and DQw6 molecules are functional in mCD4/8-/- mice, fully and stably reconstituting this limb of the human immune system in mice. This animal model provides a powerful in vivo tool to dissect the human CD4-human class II MHC interaction, especially its role in human autoimmune diseases, superantigen-mediated diseases, and acquired immunodeficiency syndrome (AIDS). PMID:7964466

  12. A trans-acting major histocompatibility complex-linked gene whose alleles determine gain and loss changes in the antigenic structure of a classical class I molecule

    PubMed Central

    1989-01-01

    The RT1.A locus of the rat MHC encodes the H chain of the single classical class I molecule of this species. One of the alleles of this polymorphic locus, RT1.Aa, is present in several laboratory inbred, congenic, and MHC recombinant rat strains. Studies of the RT1.Aa class I molecule from a number of these strains as a target for CTL show that its antigenicity, both as an alloantigen and a restricting element, is subject to gain and loss alterations by the action of a gene mapping in the MHC to the right of RT1.A. This locus is apparently present in two allelic forms (one possibly a null allele) corresponding to the presence or absence of a dominant transacting modifier, and has been named class I modification, or cim. The antigenic change brought about by cim is scarcely detectable serologically but highly immunogenic for CTL. Biochemical investigations show that cim affects the post- translational modification of RT1.Aa. PMID:2475574

  13. Matrine compromises mouse sperm functions by a [Ca(2+)]i-related mechanism.

    PubMed

    Luo, Tao; Zou, Qian-Xing; He, Yuan-Qiao; Wang, Hua-Feng; Wang, Tao; Liu, Min; Chen, Ying; Wang, Bing

    2016-04-01

    Matrine, a bioactive alkaloid widely used in Chinese medicine, inhibits mouse sperm functions in vitro. In this study, we investigated the reproductive toxicity of matrine to male mice in vivo. C57BL/6J mice were administered with daily doses of 0, 1, 10 and 50mg/kg matrine by intraperitoneal injection for 30 days. The results showed that matrine did not affect testis size, testis weight, sperm count and sperm viability, but it significantly inhibited total motility, progressive motility, linear velocity, capacitation and the progesterone-induced acrosome reaction of mouse sperm. Furthermore, the intracellular Ca(2+) concentration ([Ca(2+)]i), a key regulator of sperm function, was reduced in sperm of matrine-exposed mice. The current and gene expression of the sperm specific Ca(2+) channel, CatSper, which modulates Ca(2+) influx in sperm, were decreased in testes of matrine-exposed mice. These results indicate that matrine inhibits mouse sperm functions by a [Ca(2+)]i-related mechanism via CatSper channel.

  14. T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire

    PubMed Central

    1991-01-01

    We report here the first extensive study of a T cell repertoire for a class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) response. We have found that the T cell receptors (TCRs) carried by 28 H-2Kd-restricted CTL clones specific for a single Plasmodium berghei circumsporozoite nonapeptide are highly diverse in terms of V alpha, J alpha, and J beta segments and aminoacid composition of the junctional regions. However, despite this extensive diversity, a high proportion of the TCRs contain the same V beta segment. These results are in contrast to most previously reported T cell responses towards class II MHC-peptide complexes, where the TCR repertoires appeared to be much more limited. In our study, the finding of a dominant V beta in the midst of otherwise highly diverse TCRs suggests the importance of the V beta segment in shaping the T cell repertoire specific for a given MHC-peptide complex. As an additional finding, we observed that nearly all clones have rearranged both TCR alpha loci. Moreover, as many as one-third of the CTL clones that we analyzed apparently display two productive alpha rearrangements. This argues against a regulated model of sequential recombination at the alpha locus and consequently raises the question of whether allelic exclusion of the TCR alpha chain is achieved at all. PMID:1836010

  15. Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells

    PubMed Central

    Okada, Kouji; Hakata, Shuko; Terashima, Jun; Gamou, Toshie; Habano, Wataru; Ozawa, Shogo

    2016-01-01

    Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene

  16. Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells.

    PubMed

    Okada, Kouji; Hakata, Shuko; Terashima, Jun; Gamou, Toshie; Habano, Wataru; Ozawa, Shogo

    2016-10-01

    Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC

  17. T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells

    PubMed Central

    1988-01-01

    Staphylococcal enterotoxins (SE) are the most potent mitogens for T lymphocytes known; concentrations of less than 10(-9) M are sufficient for T cell activation. The mechanism of T cell activation by SE is unknown. We have used cloned human cytotoxic and proliferative T lymphocytes to dissect the molecular mechanism of T cell activation by SE. With rare exceptions, all TCR alpha/beta chain-expressing T cell clones of CD4+ or CD8+ phenotype, as well as CD4-8- TCR alpha/beta chain negative chain-expressing T lymphocyte clones, respond with proliferation and/or cytotoxicity to SE. For triggering of all these clones, the presence of autologous or allogeneic MHC class II molecules on accessory or target cells is necessary. This requirement for class II antigens is not due to an immunological recognition of processed SE, since inhibition of antigen processing has no influence on the T cell response to SE. SE acts on the T cells directly since (a) they stimulate a rise in intracellular calcium concentration in T cell lines or purified T cells, and (b) accessory cells can be replaced by phorbolesters in the proliferative activation of resting T cells by SE. Furthermore, the T cell response to SE shows extensive clonal heterogeneity. These results suggest that SE are functionally bivalent mitogens binding highly selectively to HLA class II molecules and the TCR. Thus, compared with other polyclonal T cell activating agents, activation with SE most closely mimicks the physiological way of MHC- restricted antigen recognition by T lymphocytes. PMID:3259256

  18. A low polymorphic mouse H-2 class I gene from the Tla complex is expressed in a broad variety of cell types

    PubMed Central

    1987-01-01

    We have previously described the isolation of pH-2d-37, a cDNA clone that encodes a so far unknown, poorly polymorphic, class I surface molecule. We report here the isolation of the corresponding gene, its nucleotide sequence, and its localization in the Tla region of the murine MHC. Using a RNase mapping assay, we have confirmed that the second domain coding region of the 37 gene displays very limited polymorphism, and that the gene is transcribed in a broad variety of cell types, in contrast to the genes encoding the known Qa and TL antigens. Possible functions are discussed. PMID:3036997

  19. Characterization of a divergent non-classical MHC class I gene in sharks.

    PubMed

    Wang, Carren; Perera, Thushara V; Ford, Heide L; Dascher, Christopher C

    2003-04-01

    Sharks are the most ancient group of vertebrates known to possess members of the major histocompatibility complex (MHC) gene family. For this reason, sharks provide a unique opportunity to gain insight into the evolution of the vertebrate immune system through comparative analysis. Two genes encoding proteins related to the MHC class I gene family were isolated from splenic cDNA derived from spiny dogfish shark ( Squalus acanthias). The genes have been designated MhcSqac-UAA*01 and MhcSqac-UAA*NC1. Comparative analysis demonstrates that the Sqac-UAA*01 protein sequence clusters with classical MHC class I of several shark species and has structural elements common to most classical MHC class I molecules. In contrast, Sqac-UAA*NC1 is highly divergent from all vertebrate classical MHC class I proteins, including the Sqac-UAA *01 sequence and those of other shark species. Although Sqac-UAA*NC1 is clearly related to the MHC class I gene family, no orthologous genes from other species were identified due to the high degree of sequence divergence. In fact, the Sqac NC1 protein sequence is the most divergent MHC class-I-like protein identified thus far in any shark species. This high degree of divergence is similar in magnitude to some of the MHC class-I-related genes found in mammals, such as MICA or CD1. These data support the existence of a class of highly divergent non-classical MHC class I genes in the most primitive vertebrates known to possess homologues of the MHC and other components of the adaptive immune system.

  20. Class, Identity, and Teacher Education

    ERIC Educational Resources Information Center

    Van Galen, Jane A.

    2010-01-01

    This paper explores the possibilities of working with White, working-class teacher education students to explore the "complex social trajectory" (Reay in Women's Stud Int Forum 20(2):225-233, 1997a, p. 19) of class border crossing as they progress through college. Through analysis of a course that I have developed, "Education and the American…

  1. Pseudomonas aeruginosa Cif protein enhances the ubiquitination and proteasomal degradation of the transporter associated with antigen processing (TAP) and reduces major histocompatibility complex (MHC) class I antigen presentation.

    PubMed

    Bomberger, Jennifer M; Ely, Kenneth H; Bangia, Naveen; Ye, Siying; Green, Kathy A; Green, William R; Enelow, Richard I; Stanton, Bruce A

    2014-01-01

    Cif (PA2934), a bacterial virulence factor secreted in outer membrane vesicles by Pseudomonas aeruginosa, increases the ubiquitination and lysosomal degradation of some, but not all, plasma membrane ATP-binding cassette transporters (ABC), including the cystic fibrosis transmembrane conductance regulator and P-glycoprotein. The goal of this study was to determine whether Cif enhances the ubiquitination and degradation of the transporter associated with antigen processing (TAP1 and TAP2), members of the ABC transporter family that play an essential role in antigen presentation and intracellular pathogen clearance. Cif selectively increased the amount of ubiquitinated TAP1 and increased its degradation in the proteasome of human airway epithelial cells. This effect of Cif was mediated by reducing USP10 deubiquitinating activity, resulting in increased polyubiquitination and proteasomal degradation of TAP1. The reduction in TAP1 abundance decreased peptide antigen translocation into the endoplasmic reticulum, an effect that resulted in reduced antigen available to MHC class I molecules for presentation at the plasma membrane of airway epithelial cells and recognition by CD8(+) T cells. Cif is the first bacterial factor identified that inhibits TAP function and MHC class I antigen presentation.

  2. Association of the bovine leukocyte antigen major histocompatibility complex class II DRB3*4401 allele with host resistance to the Lone Star Tick, Amblyomma americanum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The MHC of cattle, known as the bovine leukocyte antigen (BoLA) complex, plays an integral role in disease and parasite susceptibility, and immune responsiveness of the host. While susceptibility to tick infestation in cattle is believed to be heritable, genes that may be responsible for the manife...

  3. [(B3O3H3)(n)M]+ (n = 1, 2;M = Cu, Ag, Au): a new class of metal-cation complexes.

    PubMed

    Li, Da-Zhi; Dong, Chen-Chu; Zhang, Shi-Guo

    2013-08-01

    A density functional theory (DFT) investigation into the structures and bonding characteristics of [(B3O3H3)nM](+)(n = 1, 2;M = Cu, Ag, Au) complexes was performed. DFT calculations and natural bond orbital (NBO) analyses indicate that the ΙB metal complexes of boroxine exhibit intriguing bonding characteristics, different from the typical cation-π interactions between ΙB metal-cations and benzene. The complexes of [B3O3H3M](+) and [(B3O3H3)2 M](+) (M = Cu, Ag, and Au) favor the conformation of perfectly planar structures with the C2v and D2h symmetry along one of the threefold molecular axes of boroxine, respectively. Detailed natural resonance theory (NRT) and canonical molecular orbitals (CMOs) analyses show that interaction between the metal cation and the boroxine in [B3O3H3M](+) (M = Cu, Ag, and Au) is mainly ionic, while the ΙB metal-cations←π donation effect is responsible for the binding site. In these complexes, boroxine serves as terminals η(1)-B3O3H3 with one O atom of the B3O3 ring. The infra-red (IR) spectra of [B3O3H3M](+) were simulated to facilitate their future experimental characterization. The complexes all give two IR active modes at about 1,300 and 2,700 cm(-1), which are inactive in pure boroxine. Simultaneously, the B-H stretching modes of the complexes are red-shifted due to the interaction between the metal-cation and boroxine. To explore the possibility of the structural pattern developed in this work forming mesoporous materials, complexes [(B3O3H3M)6](6+) (M = Cu, Ag, and Au) were also studied, which appear to be unique and particular interesting: they are all true minima with D6h symmetries and pore sizes ranging from 12.04 Å to 13.65 Å. PMID:23636641

  4. Crystal structure of Glycine max glutathione transferase in complex with glutathione: investigation of the mechanism operating by the Tau class glutathione transferases.

    PubMed

    Axarli, Irene; Dhavala, Prathusha; Papageorgiou, Anastassios C; Labrou, Nikolaos E

    2009-08-13

    Cytosolic GSTs (glutathione transferases) are a multifunctional group of enzymes widely distributed in Nature and involved in cellular detoxification processes. The three-dimensional structure of GmGSTU4-4 (Glycine max GST Tau 4-4) complexed with GSH was determined by the molecular replacement method at 2.7 A (1 A=0.1 nm) resolution. The bound GSH is located in a region formed by the beginning of alpha-helices H1, H2 and H3 in the N-terminal domain of the enzyme. Significant differences in the G-site (GSH-binding site) as compared with the structure determined in complex with Nb-GSH [S-(p-nitrobenzyl)-glutathione] were found. These differences were identified in the hydrogen-bonding and electrostatic interaction pattern and, consequently, GSH was found bound in two different conformations. In one subunit, the enzyme forms a complex with the ionized form of GSH, whereas in the other subunit it can form a complex with the non-ionized form. However, only the ionized form of GSH may form a productive and catalytically competent complex. Furthermore, a comparison of the GSH-bound structure with the Nb-GSH-bound structure shows a significant movement of the upper part of alpha-helix H4 and the C-terminal. This indicates an intrasubunit modulation between the G-site and the H-site (electrophile-binding site), suggesting that the enzyme recognizes the xenobiotic substrates by an induced-fit mechanism. The reorganization of Arg111 and Tyr107 upon xenobiotic substrate binding appears to govern the intrasubunit structural communication between the G- and H-site and the binding of GSH. The structural observations were further verified by steady-state kinetic analysis and site-directed mutagenesis studies.

  5. In vitro evaluation of the cyto-genotoxic potential of Ruthenium(II) SCAR complexes: a promising class of antituberculosis agents.

    PubMed

    De Grandis, Rone Aparecido; Resende, Flávia Aparecida; da Silva, Monize Martins; Pavan, Fernando Rogério; Batista, Alzir Azevedo; Varanda, Eliana Aparecida

    2016-03-01

    Tuberculosis is a top infectious disease killer worldwide, caused by the bacteria Mycobacterium tuberculosis. Increasing incidences of multiple drug-resistance (MDR) strains are emerging as one of the major public health threats. However, the drugs in use are still incapable of controlling the appalling upsurge of MDR. In recent years a marked number of research groups have devoted their attention toward the development of specific and cost-effective antimicrobial agents against targeted MDR-Tuberculosis. In previous studies, ruthenium(II) complexes (SCAR) have shown a promising activity against MDR-Tuberculosis although few studies have indeed considered ruthenium toxicity. Therefore, within the preclinical requirements, we have sought to determine the cyto-genotoxicity of three SCAR complexes in this present study. The treatment with the SCARs induced a concentration-dependent decrease in cell viability in CHO-K1 and HepG2 cells. Based on the clonogenic survival, SCAR 5 was found to be more cytotoxic while SCAR 6 exhibited selectivity action on tumor cells. Although SCAR 4 and 5 did not indicate any mutagenic activity as evidenced by the Ames and Cytokinesis block micronucleus cytome assays, the complex SCAR 6 was found to engender a frameshift mutation detected by Salmonella typhimurium in the presence of S9. Similarly, we observed a chromosomal damage in HepG2 cells with significant increases of micronuclei and nucleoplasmic bridges. These data indicate that SCAR 4 and 5 complexes did not show genotoxicity in our models while SCAR 6 was considered mutagenic. This study presented a comprehensive genotoxic evaluation of SCAR complexes were shown to be genotoxic in vitro. All in all, further studies are required to fully elucidate how the properties can affect human health.

  6. Class Trash.

    ERIC Educational Resources Information Center

    Chemecology, 1992

    1992-01-01

    Presents a classroom activity in which students calculate the amount and types of trash thrown out by their class at school to investigate how much trash is generated, where it goes, and speculate about alternatives. Students need to be familiar with the concepts of weight, volume, and numbers. (MCO)

  7. H2-M3 Major Histocompatibility Complex Class Ib-Restricted CD8 T Cells Induced by Salmonella enterica Serovar Typhimurium Infection Recognize Proteins Released by Salmonella Serovar Typhimurium

    PubMed Central

    Ugrinovic, S.; Brooks, C. G.; Robson, J.; Blacklaws, B. A.; Hormaeche, C. E.; Robinson, J. H.

    2005-01-01

    Salmonella enterica serovar Typhimurium causes a typhoid-like disease in mice which has been studied extensively as a model for typhoid fever in humans. CD8 T cells contribute to protection against S. enterica serovar Typhimurium in mice, but little is known about the specificity and major histocompatibility complex (MHC) restriction of the response. We report here that CD8 T-cell lines derived from S. enterica serovar Typhimurium-infected BALB/c mice lysed bone marrow macrophages infected with S. enterica serovar Typhimurium or pulsed with proteins from S. enterica serovar Typhimurium culture supernatants. Cytoxicity was beta-2-microglobulin dependent and largely TAP dependent, although not MHC class Ia restricted, as target cells of several different MHC haplotypes were lysed. The data suggested the participation of class Ib MHC molecules although no evidence for the presence of Qa1-restricted T cells could be found, unlike in previous reports. Instead, the T-cell lines lysed H2-M3-transfected fibroblasts infected with S. enterica serovar Typhimurium SL3261 or treated with Salmonella culture supernatants. Thus, this report increases the number of MHC class Ib antigen-presenting molecules known for Salmonella antigens to three: Qa-1, HLA-E, and now H2-M3. It also expands the range of pathogens that induce H2-M3-restricted CD8 T cells to include an example of gram-negative bacteria. PMID:16299293

  8. Trypanosoma cruzi Infection Modulates In Vivo Expression of Major Histocompatibility Complex Class II Molecules on Antigen-Presenting Cells and T-Cell Stimulatory Activity of Dendritic Cells in a Strain-Dependent Manner

    PubMed Central

    Alba Soto, Catalina D.; Mirkin, Gerardo A.; Solana, Maria E.; González Cappa, Stella M.

    2003-01-01

    A striking feature of Chagas' disease is the diversity of clinical presentations. Such variability may be due to the heterogeneity among Trypanosoma cruzi isolates or to the host immune response. Employing two strains which differ in their virulence, we investigated the effect of in vivo infection on professional antigen-presenting cells (APC). Acute infection with the virulent RA strain downregulated the expression of major histocompatibility complex (MHC) class II on splenic dendritic cells (DC) and inhibited its induction on peritoneal macrophages and splenic B cells. It also impaired the ability of DC to prime allogeneic T cells and to form homotypic clusters, suggesting a low maturation state of these cells. In contrast, the low-virulence K98 strain maintained the expression of MHC class II on DC or stimulated it on peritoneal macrophages and B cells and preserved DC's T-cell priming capacity and homotypic clustering. DC from RA-infected mice elicited a lower activation of T. cruzi-specific T-cell proliferation than those from K98-infected mice. APC from RA-infected mice that reached the chronic phase of infection restored MHC class II levels to those found in K98-infected mice and upregulated costimulatory molecules expression, suggesting that the immunosuppression caused by this strain is only transient. Taken together, the results indicate that in vivo infection with T. cruzi modulates APC functionality and that this is accomplished in a strain-dependent manner. PMID:12595432

  9. Effect of herpes simplex virus types 1 and 2 on surface expression of class I major histocompatibility complex antigens on infected cells.

    PubMed Central

    Jennings, S R; Rice, P L; Kloszewski, E D; Anderson, R W; Thompson, D L; Tevethia, S S

    1985-01-01

    Cytotoxic T lymphocytes (CTL) generated in C57BL/6 (H-2b) mice in response to infection with the serologically distinct herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) were cross-reactive against target cells infected with either serotype. However, HSV-2-infected cells were shown to be much less susceptible to CTL-mediated lysis, and analysis through the use of HSV-1 X HSV-2 intertypic recombinants mapped the reduced susceptibility to a region contained within 0.82 to 1.00 map units of the HSV-2 genome. The study reported here was undertaken to determine the possible reasons for the reduced susceptibility of HSV-2-infected cells to lysis by CTL. Competition for the specific lysis of labeled HSV-1-infected cells by either HSV-1- or HSV-2-infected, unlabeled inhibitor cells and frequency analysis of the CTL precursor able to recognize HSV-1- and HSV-2-infected cells suggested that the reduced susceptibility of HSV-2-infected cells to lysis could be explained, at least in part, by reduced levels of target cell recognition. A determination of the surface expression of the critical elements involved in target cell recognition by CTL following infection with HSV-1 or HSV-2 revealed that all the major HSV-specific glycoprotein species were expressed. Infection with both HSV-1 and HSV-2 caused a reduction in the expression of the class I H-2 antigens. However, this reduction was much greater following infection with HSV-2. This suggested that one important factor contributing to reduced lysis of HSV-2-infected cells may be the altered or reduced expression of the class I H-2 self-antigens. PMID:2999432

  10. Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw.

    PubMed

    Stockmann, Philipp; Nkenke, Emeka; Englbrecht, Matthias; Schlittenbauer, Tilo; Wehrhan, Falk; Rauh, Claudia; Beckmann, Matthias W; Fasching, Peter A; Kreusch, Thomas; Mackensen, Andreas; Wullich, Bernd; Schett, Georg; Spriewald, Bernd M

    2013-01-01

    The aetiology of anti-resorptive agent-induced osteonecrosis of the jaw (ARONJ) is still under debate. Clinical and genetic risk factors are currently being investigated to help understand its pathogenesis. This case-control study analysed a large number of cancer patients (n = 230) under therapy with intravenous bisphosphonates, half of which were diagnosed with ARONJ. Multiple myeloma, greater patient age and the use of more than one bisphosphonate were identified as clinical risk factors on logistic regression analysis. In addition, 204 patients were genotyped for HLA-DRB1 and DQB1 and the allele frequencies were compared between ARONJ (n = 94) and unaffected cancer patients (n = 110). For the HLA class II alleles, a strong increase in the frequency of DRB1*15, DQB1*06:02, DRB1*01 and DQB1*05:01 was observed in the ARONJ group. These results were reinforced on analysis of the respective haplotypes, with DRB1*15-DQB1*06:02 being significantly associated with the development of ARONJ (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0). The presence of at least one of the haplotypes DRB1*15-DQB1*06:02 and DRB1*01-DQB1*05:01 was highly associated with the development of ARONJ (OR 3.0; 95% CI 1.7-5.5). The data in this study of a large number of cancer patients receiving intravenous bisphosphonates suggest that MHC class II polymorphisms represent genetic risk factors for the development of ARONJ. This result supports recent findings that inflammation and infection might play an important role in the pathogenesis of ARONJ.

  11. Brief Note Low diversity of the major histocompatibility complex class II DRA gene in domestic goats (Capra hircus) in Southern China.

    PubMed

    Chen, L P; E, G X; Zhao, Y J; Na, R S; Zhao, Z Q; Zhang, J H; Ma, Y H; Sun, Y W; Zhong, T; Zhang, H P; Huang, Y F

    2015-01-01

    DRA encodes the alpha chain of the DR heterodimer, is closely linked to DRB and is considered almost monomorphic in major histocompatibility complex region. In this study, we identified the exon 2 of DRA to evaluate the immunogenetic diversity of Chinese south indigenous goat. Two single nucleotide polymorphisms in an untranslated region and one synonymous substitution in coding region were identified. These data suggest that high immunodiversity in native Chinese population. PMID:26125900

  12. The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II

    PubMed Central

    Quinn, Laura L.; Williams, Luke R.; White, Claire; Forrest, Calum; Rowe, Martin

    2015-01-01

    ABSTRACT The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8+ cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8+ cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8+ cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4+ cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8+ and CD4+ T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8+ T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8+ T cells specific for

  13. Planck Cold Clumps in the λ Orionis Complex. I. Discovery of an Extremely Young Class 0 Protostellar Object and a Proto-brown Dwarf Candidate in the Bright-rimmed Clump PGCC G192.32-11.88

    NASA Astrophysics Data System (ADS)

    Liu, Tie; Zhang, Qizhou; Kim, Kee-Tae; Wu, Yuefang; Lee, Chang Won; Lee, Jeong-Eun; Tatematsu, Ken'ichi; Choi, Minho; Juvela, Mika; Thompson, Mark; Goldsmith, Paul F.; Liu, Sheng-yuan; Naomi, Hirano; Koch, Patrick; Henkel, Christian; Sanhueza, Patricio; He, JinHua; Rivera-Ingraham, Alana; Wang, Ke; Cunningham, Maria R.; Tang, Ya-Wen; Lai, Shih-Ping; Yuan, Jinghua; Li, Di; Fuller, Gary; Kang, Miju; Nguyen Luong, Quang; Liu, Hauyu Baobab; Ristorcelli, Isabelle; Yang, Ji; Xu, Ye; Hirota, Tomoya; Mardones, Diego; Qin, Sheng-Li; Chen, Huei-Ru; Kwon, Woojin; Meng, FanYi; Zhang, Huawei; Kim, Mi-Ryang; Yi, Hee-Weon

    2016-01-01

    We are performing a series of observations with ground-based telescopes toward Planck Galactic cold clumps (PGCCs) in the λ Orionis complex in order to systematically investigate the effects of stellar feedback. In the particular case of PGCC G192.32-11.88, we discovered an extremely young Class 0 protostellar object (G192N) and a proto-brown dwarf candidate (G192S). G192N and G192S are located in a gravitationally bound bright-rimmed clump. The velocity and temperature gradients seen in line emission of CO isotopologues indicate that PGCC G192.32-11.88 is externally heated and compressed. G192N probably has the lowest bolometric luminosity (˜0.8 {L}⊙ ) and accretion rate (6.3 × 10-7 {M}⊙ yr-1) when compared with other young Class 0 sources (e.g., PACS Bright Red Sources) in the Orion complex. It has slightly larger internal luminosity (0.21 ± 0.01 {L}⊙ ) and outflow velocity (˜14 km s-1) than the predictions of first hydrostatic cores (FHSCs). G192N might be among the youngest Class 0 sources, which are slightly more evolved than an FHSC. Considering its low internal luminosity (0.08 ± 0.01 {L}⊙ ) and accretion rate (2.8 × 10-8 {M}⊙ yr-1), G192S is an ideal proto-brown dwarf candidate. The star formation efficiency (˜0.3%-0.4%) and core formation efficiency (˜1%) in PGCC G192.32-11.88 are significantly smaller than in other giant molecular clouds or filaments, indicating that the star formation therein is greatly suppressed owing to stellar feedback.

  14. Are Small Classes Better? Understanding Relationships between Class Size, Classroom Processes and Pupils' Learning

    ERIC Educational Resources Information Center

    Pedder, David

    2006-01-01

    Twelve years ago Blatchford and Mortimore's authoritative review of class size research appeared in this journal. They concluded that a major problem with class size research was the lack of detailed studies of complex classroom processes that might mediate class size effects on pupils' learning. This article reviews two UK class size reviews and…

  15. Dectin-1-triggered Recruitment of Light Chain 3 Protein to Phagosomes Facilitates Major Histocompatibility Complex Class II Presentation of Fungal-derived Antigens*

    PubMed Central

    Ma, Jun; Becker, Courtney; Lowell, Clifford A.; Underhill, David M.

    2012-01-01

    Dectin-1 is a pattern recognition receptor that is important for innate immune responses against fungi in humans and mice. Dectin-1 binds to β-glucans in fungal cell walls and triggers phagocytosis, production of reactive oxygen by the NADPH oxidase, and inflammatory cytokine production which all contribute to host immune responses against fungi. Although the autophagy pathway was originally characterized for its role in the formation of double-membrane compartments engulfing cytosolic organelles and debris, recent studies have suggested that components of the autophagy pathway may also participate in traditional phagocytosis. In this study, we show that Dectin-1 signaling in macrophages and bone marrow-derived dendritic cells triggers formation of LC3II, a major component of the autophagy machinery. Further, Dectin-1 directs the recruitment of LC3II to phagosomes, and this requires Syk, activation of reactive oxygen production by the NADPH oxidase, and ATG5. Using LC3-deficient dendritic cells we show that whereas LC3 recruitment to phagosomes is not important for triggering phagocytosis, killing or Dectin-1-mediated inflammatory cytokine production, it facilitates recruitment of MHC class II molecules to phagosomes and promotes presentation of fungal-derived antigens to CD4 T cells. PMID:22902620

  16. A mouse aminopeptidase N is a marker for antigen-presenting cells and appears to be co-expressed with major histocompatibility complex class II molecules.

    PubMed

    Hansen, A S; Norén, O; Sjöström, H; Werdelin, O

    1993-09-01

    To analyze the expression of mouse aminopeptidase N (APN) on the cells of the immune system a panel of rat monoclonal antibodies against mouse intestinal APN was generated. These antibodies were used to affinity purify functional mouse APN from both intestine and kidney, and by flow cytometry to examine the APN expression of the cells of the mouse immune system. An APN closely related, perhaps identical, to the intestinal APN was expressed on a subpopulation of spleen cells and stimulated peritoneal exudate cells, primarily representing antigen-presenting cells, such as B cells, macrophages, dendritic cells, and veiled cells. In contrast this APN expression could not be detected on thymocytes or spleen T cells. As a corollary, APN was expressed on monocyte, macrophage, and B lymphoma cell lines, but not on T hybridoma or thymoma cell lines. The expression of APN showed a striking correlation with the MHC class II expression in all the cell populations studied. This apparent co-expression suggests a role for APN in antigen processing.

  17. The three-dimensional structure of class pi glutathione S-transferase in complex with glutathione sulfonate at 2.3 A resolution.

    PubMed Central

    Reinemer, P; Dirr, H W; Ladenstein, R; Schäffer, J; Gallay, O; Huber, R

    1991-01-01

    The three-dimensional structure of class pi glutathione S-transferase from pig lung, a homodimeric enzyme, has been solved by multiple isomorphous replacement at 3 A resolution and preliminarily refined at 2.3 A resolution (R = 0.24). Each subunit (207 residues) is folded into two domains of different structure. Domain I (residues 1-74) consists of a central four-stranded beta-sheet flanked on one side by two alpha-helices and on the other side, facing the solvent, by a bent, irregular helix structure. The topological pattern resembles the bacteriophage T4 thioredoxin fold, in spite of their dissimilar sequences. Domain II (residues 81-207) contains five alpha-helices. The dimeric molecule is globular with dimensions of about 55 A x 52 A x 45 A. Between the subunits and along the local diad, is a large cavity which could possibly be involved in the transport of nonsubstrate ligands. The binding site of the competitive inhibitor, glutathione sulfonate, is located on domain I, and is part of a cleft formed between intrasubunit domains. Glutathione sulfonate is bound in an extended conformation through multiple interactions. Only three contact residues, namely Tyr7, Gln62 and Asp96 are conserved within the family of cytosolic glutathione S-transferases. The exact location of the binding site(s) of the electrophilic substrate is not clear. Catalytic models are discussed on the basis of the molecular structure. Images PMID:2065650

  18. Crystal structure of swine major histocompatibility complex class I SLA-1 0401 and identification of 2009 pandemic swine-origin influenza A H1N1 virus cytotoxic T lymphocyte epitope peptides.

    PubMed

    Zhang, Nianzhi; Qi, Jianxun; Feng, Sijia; Gao, Feng; Liu, Jun; Pan, Xiaocheng; Chen, Rong; Li, Qirun; Chen, Zhaosan; Li, Xiaoying; Xia, Chun; Gao, George F

    2011-11-01

    The presentation of viral epitopes to cytotoxic T lymphocytes (CTLs) by swine leukocyte antigen class I (SLA I) is crucial for swine immunity. To illustrate the structural basis of swine CTL epitope presentation, the first SLA crystal structures, SLA-1 0401, complexed with peptides derived from either 2009 pandemic H1N1 (pH1N1) swine-origin influenza A virus (S-OIV(NW9); NSDTVGWSW) or Ebola virus (Ebola(AY9); ATAAATEAY) were determined in this study. The overall peptide-SLA-1 0401 structures resemble, as expected, the general conformations of other structure-solved peptide major histocompatibility complexes (pMHC). The major distinction of SLA-1 0401 is that Arg(156) has a "one-ballot veto" function in peptide binding, due to its flexible side chain. S-OIV(NW9) and Ebola(AY9) bind SLA-1 0401 with similar conformations but employ different water molecules to stabilize their binding. The side chain of P7 residues in both peptides is exposed, indicating that the epitopes are "featured" peptides presented by this SLA. Further analyses showed that SLA-1 0401 and human leukocyte antigen (HLA) class I HLA-A 0101 can present the same peptides, but in different conformations, demonstrating cross-species epitope presentation. CTL epitope peptides derived from 2009 pandemic S-OIV were screened and evaluated by the in vitro refolding method. Three peptides were identified as potential cross-species influenza virus (IV) CTL epitopes. The binding motif of SLA-1 0401 was proposed, and thermostabilities of key peptide-SLA-1 0401 complexes were analyzed by circular dichroism spectra. Our results not only provide the structural basis of peptide presentation by SLA I but also identify some IV CTL epitope peptides. These results will benefit both vaccine development and swine organ-based xenotransplantation.

  19. Cellular expression or binding of desLys58-beta2 microglobulin is not dependent on the presence of the tri-molecular MHC class I complex.

    PubMed

    Wang, M; Corlin, D B; Heegaard, N H H; Claesson, M H; Nissen, M H

    2008-02-01

    The monoclonal antibody 332-01 is a newly developed antibody which specifically recognizes human desLys58-beta2 microglobulin (dbeta2m). In the present study, we characterized the binding of 332-01 to peripheral blood mononuclear cells (PBMC), a number of human leukaemic and monocytic cell lines, and beta2m gene-deleted murine lymphocytes. dbeta2m was found to be expressed on non-activated and activated monocytes. When cells were pre-exposed to dbeta2m, 332-01 also bound to non-activated T lymphocytes. dbeta2m was expressed on the monocytic cell lines U937 and TIB-202, and binding was significantly increased when cells were pre-incubated with dbeta2m and when TIB-202 cells were exposed to lipopolysaccharide. dbeta2m was also expressed on T leukaemic Jurkat cells as well as on low HLA-expressing erythroleukaemic K562 cells. beta2m gene-deleted murine splenocytes only bound 332-01 after pre-exposure to dbeta2m. Binding of 332-01 antibody could not be displaced by addition of high concentrations of native beta2m. In conclusion, our data indicate that dbeta2m - in contrast to native beta2m - binds to a hitherto unknown cell surface receptor independent of classical MHC class I molecules. As beta2m has previously been shown to display biological activities such as the induction of both growth promotion and apoptosis, C1 complement activity, shown to mediate cleavage of beta2m, could be involved in these processes.

  20. Quantum chemical study of a new class of sensitisers: influence of the substitution of aromatic rings on the properties of copper complexes

    NASA Astrophysics Data System (ADS)

    Baldenebro-López, Jesús; Castorena-González, José; Flores-Holguín, Norma; Glossman-Mitnik, Daniel

    2014-04-01

    We present a computational study of new copper complexes with potential applications as sensitisers for solar cells. The applied methodology for this study is based on the density functional theory (DFT) and time-dependent DFT, using the B3LYP, PBE0 and M06 functionals with the LANL2DZ (D95V on first row), 6-31G(d,p), 6-311G(d,p) and DZVP basis sets. Optimised molecular structure, the absorption spectra, the molecular orbitals energies and the chemical reactivity parameters that arise from conceptual DFT were calculated. Solvent effects have been taken into account by an implicit approach, namely, the polarisable continuum model (PCM), using the non-equilibrium version of the integral equation formalism of the PCM model. Interesting work for experimentalists in the dye sensitised solar cells' field.

  1. Exploring the Complexities of Group Work in Science Class: a Cautionary tale of Voice and Equitable Access to Resources for Learning

    NASA Astrophysics Data System (ADS)

    Richmond, Gail

    The interactions of 2 focus students with others in their cooperative base groups were examined as the students designed, carried out, and interpreted scientific investigations. These 2 students differed with respect to race, gender, socioeconomic status, and academic achievement. They were alike in that both maintained high levels of motivation and interaction with the scientific problems they faced. Their group interactions were not entirely positive, and the difficulties and inequities they faced are described. The data make manifest that group work is a complex process; educators must be sensitive and responsive to the subtle ways understanding can be enhanced or undermined as a result of group dynamics, which are in turn determined by individual expectations - often unfounded - of others' capacities and behaviors, and perceptions of desired group and individual outcomes. These observations also have implications for how educators help prepare prospective teachers to develop effective pedagogical strategies for teaching diverse students.

  2. Class distinction

    NASA Astrophysics Data System (ADS)

    White, M. Catherine

    Typical 101 courses discourage many students from pursuing higher level science and math courses. Introductory classes in science and math serve largely as a filter, screening out all but the most promising students, and leaving the majority of college graduates—including most prospective teachers—with little understanding of how science works, according to a study conducted for the National Science Foundation. Because few teachers, particularly at the elementary level, experience any collegiate science teaching that stresses skills of inquiry and investigation, they simply never learn to use those methods in their teaching, the report states.

  3. Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA.

    PubMed

    Pan, Hongjie; O'Brien, Thomas F; Wright, Gabriela; Yang, Jialong; Shin, Jinwook; Wright, Kenneth L; Zhong, Xiao-Ping

    2013-07-15

    Dendritic cell (DC) maturation is characterized by upregulation of cell-surface MHC class II (MHC-II) and costimulatory molecules, and production of a variety of cytokines that can shape both innate and adaptive immunity. Paradoxically, transcription of the MHC-II genes, as well as its activator, CIITA, is rapidly silenced during DC maturation. The mechanisms that control CIITA/MHC-II expression and silencing have not been fully understood. We report in this article that the tumor suppressor tuberous sclerosis complex 1 (TSC1) is a critical regulator of DC function for both innate and adaptive immunity. Its deficiency in DCs results in increased mammalian target of rapamycin (mTOR) complex 1 but decreased mTORC2 signaling, altered cytokine production, impaired CIITA/MHC-II expression, and defective Ag presentation to CD4 T cells after TLR4 stimulation. We demonstrate further that IFN regulatory factor 4 can directly bind to CIITA promoters, and decreased IFN regulatory factor 4 expression is partially responsible for decreased CIITA/MHC-II expression in TSC1-deficient DCs. Moreover, we identify that CIITA/MHC-II silencing during DC maturation requires mTOR complex 1 activity. Together, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.

  4. Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance

    PubMed Central

    Bonifaz, Laura; Bonnyay, David; Mahnke, Karsten; Rivera, Miguel; Nussenzweig, Michel C.; Steinman, Ralph M.

    2002-01-01

    To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation. PMID:12486105

  5. Tissue-specific and cell surface expression of human major histocompatibility complex class I heavy (HLA-B7) and light (beta 2-microglobulin) chain genes in transgenic mice.

    PubMed Central

    Chamberlain, J W; Nolan, J A; Conrad, P J; Vasavada, H A; Vasavada, H H; Ploegh, H L; Ganguly, S; Janeway, C A; Weissman, S M

    1988-01-01

    We introduced the human genes HLA-B7 and B2M encoding the heavy (HLA-B7) and light [beta 2-microglobulin (beta 2m)] chains of a human major histocompatibility complex class I antigen into separate lines of transgenic mice. The tissue-specific pattern of HLA-B7 RNA expression was similar to that of endogenous class I H-2 genes, although the HLA-B7 gene was about 10-fold underexpressed in liver. Identical patterns of RNA expression were detected whether the HLA-B7 gene contained 12 or 0.66 kilobase(s) (kb) of 5' flanking sequence. The level of expression was copy number dependent and as efficient as that of H-2 genes; gamma interferon enhanced HLA-B7 RNA expression in parallel to that of H-2. In addition to the mechanism(s) responsible for gamma interferon-enhanced expression, there must be at least one other tissue-specific mechanism controlling the constitutive levels of class I RNA. Tissue-specific human beta 2m RNA expression was similar to that of mouse beta 2m, including high-level expression in liver. Cell surface HLA-B7 increased 10- to 17-fold on T cells and on a subset of thymocytes from HLA-B7/B2M doubly transgenic mice compared to HLA-B7 singly transgenic mice. The pattern of expression of HLA-B7 on thymocytes resembled that of H-2K as opposed to H-2D. These results confirm that coexpression of both human chains is required for efficient surface expression and that HLA-B7 may share a regulatory mechanism with H-2K, which distinguishes it from H-2D. Images PMID:2459712

  6. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance.

    PubMed

    Bonifaz, Laura; Bonnyay, David; Mahnke, Karsten; Rivera, Miguel; Nussenzweig, Michel C; Steinman, Ralph M

    2002-12-16

    To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal alphaDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c- cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When alphaDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4-48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of alphaDEC-205:OVA to DCs in the steady state initially induced 4-7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with alphaDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic alphaCD40 antibody produced large amounts of interleukin 2 and interferon gamma, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.

  7. Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    IgG is a major immunoglobulin subclass in mucosal secretions of human female genital tract, where it predominates over the IgA isotype. Despite the abundance of IgG, surprisingly little is known about whether and how IgG enters the lumen of the genital tract and the exact role of local IgG may play ...

  8. Diverse in- and output polarities and high complexity of local synaptic and non-synaptic signaling within a chemically defined class of peptidergic Drosophila neurons

    PubMed Central

    Karsai, Gergely; Pollák, Edit; Wacker, Matthias; Vömel, Matthias; Selcho, Mareike; Berta, Gergely; Nachman, Ronald J.; Isaac, R. Elwyn; Molnár, László; Wegener, Christian

    2013-01-01

    Peptidergic neurons are not easily integrated into current connectomics concepts, since their peptide messages can be distributed via non-synaptic paracrine signaling or volume transmission. Moreover, the polarity of peptidergic interneurons in terms of in- and out-put sites can be hard to predict and is very little explored. We describe in detail the morphology and the subcellular distribution of fluorescent vesicle/dendrite markers in CCAP neurons (NCCAP), a well defined set of peptidergic neurons in the Drosophila larva. NCCAP can be divided into five morphologically distinct subsets. In contrast to other subsets, serial homologous interneurons in the ventral ganglion show a mixed localization of in- and output markers along ventral neurites that defy a classification as dendritic or axonal compartments. Ultrastructurally, these neurites contain both pre- and postsynaptic sites preferably at varicosities. A significant portion of the synaptic events are due to reciprocal synapses. Peptides are mostly non-synaptically or parasynaptically released, and dense-core vesicles and synaptic vesicle pools are typically well separated. The responsiveness of the NCCAP to ecdysis-triggering hormone may be at least partly dependent on a tonic synaptic inhibition, and is independent of ecdysteroids. Our results reveal a remarkable variety and complexity of local synaptic circuitry within a chemically defined set of peptidergic neurons. Synaptic transmitter signaling as well as peptidergic paracrine signaling and volume transmission from varicosities can be main signaling modes of peptidergic interneurons depending on the subcellular region. The possibility of region-specific variable signaling modes should be taken into account in connectomic studies that aim to dissect the circuitry underlying insect behavior and physiology, in which peptidergic neurons act as important regulators. PMID:23914156

  9. Assessment of biodiversity in Chilean cattle using the distribution of major histocompatibility complex class II BoLA-DRB3 allele.

    PubMed

    Takeshima, S-N; Miyasaka, T; Matsumoto, Y; Xue, G; Diaz, V de la Barra; Rogberg-Muñoz, A; Giovambattista, G; Ortiz, M; Oltra, J; Kanemaki, M; Onuma, M; Aida, Y

    2015-01-01

    Bovine leukocyte antigens (BoLAs) are used extensively as markers for bovine disease and immunological traits. In this study, we estimated BoLA-DRB3 allele frequencies using 888 cattle from 10 groups, including seven cattle breeds and three crossbreeds: 99 Red Angus, 100 Black Angus, 81 Chilean Wagyu, 49 Hereford, 95 Hereford × Angus, 71 Hereford × Jersey, 20 Hereford × Overo Colorado, 113 Holstein, 136 Overo Colorado, and 124 Overo Negro cattle. Forty-six BoLA-DRB3 alleles were identified, and each group had between 12 and 29 different BoLA-DRB3 alleles. Overo Negro had the highest number of alleles (29); this breed is considered in Chile to be an 'Old type' European Holstein Friesian descendant. By contrast, we detected 21 alleles in Holstein cattle, which are considered to be a 'Present type' Holstein Friesian cattle. Chilean cattle groups and four Japanese breeds were compared by neighbor-joining trees and a principal component analysis (PCA). The phylogenetic tree showed that Red Angus and Black Angus cattle were in the same clade, crossbreeds were closely related to their parent breeds, and Holstein cattle from Chile were closely related to Holstein cattle in Japan. Overall, the tree provided a thorough description of breed history. It also showed that the Overo Negro breed was closely related to the Holstein breed, consistent with historical data indicating that Overo Negro is an 'Old type' Holstein Friesian cattle. This allelic information will be important for investigating the relationship between major histocompatibility complex (MHC) and disease.

  10. Balancing selection and genetic drift at major histocompatibility complex class II genes in isolated populations of golden snub-nosed monkey (Rhinopithecus roxellana)

    PubMed Central

    2012-01-01

    Background Small, isolated populations often experience loss of genetic variation due to random genetic drift. Unlike neutral or nearly neutral markers (such as mitochondrial genes or microsatellites), major histocompatibility complex (MHC) genes in these populations may retain high levels of polymorphism due to balancing selection. The relative roles of balancing selection and genetic drift in either small isolated or bottlenecked populations remain controversial. In this study, we examined the mechanisms maintaining polymorphisms of MHC genes in small isolated populations of the endangered golden snub-nosed monkey (Rhinopithecus roxellana) by comparing genetic variation found in MHC and microsatellite loci. There are few studies of this kind conducted on highly endangered primate species. Results Two MHC genes were sequenced and sixteen microsatellite loci were genotyped from samples representing three isolated populations. We isolated nine DQA1 alleles and sixteen DQB1 alleles and validated expression of the alleles. Lowest genetic variation for both MHC and microsatellites was found in the Shennongjia (SNJ) population. Historical balancing selection was revealed at both the DQA1 and DQB1 loci, as revealed by excess non-synonymous substitutions at antigen binding sites (ABS) and maximum-likelihood-based random-site models. Patterns of microsatellite variation revealed population structure. FST outlier analysis showed that population differentiation at the two MHC loci was similar to the microsatellite loci. Conclusions MHC genes and microsatellite loci showed the same allelic richness pattern with the lowest genetic variation occurring in SNJ, suggesting that genetic drift played a prominent role in these isolated populations. As MHC genes are subject to selective pressures, the maintenance of genetic variation is of particular interest in small, long-isolated populations. The results of this study may contribute to captive breeding and translocation programs

  11. Towards a class library for mission planning

    NASA Technical Reports Server (NTRS)

    Pujo, Oliver; Smith, Simon T.; Starkey, Paul; Wolff, Thilo

    1994-01-01

    The PASTEL Mission Planning System (MPS) has been developed in C++ using an object-oriented (OO) methodology. While the scope and complexity of this system cannot compare to that of an MPS for a complex mission one of the main considerations of the development was to ensure that we could reuse some of the classes in future MPS. We present here PASTEL MPS classes which could be used in the foundations of a class library for MPS.

  12. Irinotecan Lipid Complex Injection

    MedlinePlus

    Irinotecan lipid complex is used in combination with other medications to treat pancreatic cancer that has spread to other parts of ... after treatment with other chemotherapy medications. Irinotecan lipid complex is in a class of antineoplastic medications called ...

  13. Vincristine Lipid Complex Injection

    MedlinePlus

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer of the ... two different treatments with other medications. Vincristine lipid complex is in a class of medications called vinca ...

  14. Daunorubicin Lipid Complex Injection

    MedlinePlus

    Daunorubicin lipid complex is used to treat advanced Kaposi's sarcoma (a type of cancer that causes abnormal tissue to grow on ... related to acquired immunodeficiency syndrome (AIDS). Daunorubicin lipid complex is in a class of medications called anthracyclines. ...

  15. Cytarabine Lipid Complex Injection

    MedlinePlus

    Cytarabine lipid complex is used to treat lymphomatous meningitis (a type of cancer in the covering of the spinal cord and brain). Cytarabine lipid complex is in a class of medications called antimetabolites. ...

  16. The formation of linked perceptual classes.

    PubMed Central

    Fields, Lanny; Matneja, Priya; Varelas, Antonios; Belanich, James; Fitzer, Adrienne; Shamoun, Kim

    2002-01-01

    Multiple-exemplar training with stimuli in four domains induced two new fill-based (A1' and A2') and satellite-image-based (B1' and B2') perceptual classes. Conditional discriminations were established between the endpoints of the A1' and B1' classes as well as the A2' and B2' classes. The emergence of linked perceptual classes was evaluated by the performances occasioned by nine cross-class probes that contained fill variants as samples and satellite variants as comparisons, along with nine other cross-class probes that consisted of satellite variants as samples and fill variants as comparisons. The 18 probes were first presented serially and then concurrently. Class-consistent responding indicated the emergence of linked perceptual classes. Of the linked perceptual classes, 70% emerged during the initial serial test. An additional 20% of the linked perceptual classes emerged during the subsequently presented concurrent test block. Thus, linked perceptual classes emerged on an immediate or delayed basis. Linked perceptual classes, then, share structural and fuctional similarities with equivalence classes, generalized equivalence classes, cross-modal classes, and complex maturally occurring categories, and may clarify processes such as intersensory perception. PMID:12507004

  17. The formation of linked perceptual classes.

    PubMed

    Fields, Lanny; Matneja, Priya; Varelas, Antonios; Belanich, James; Fitzer, Adrienne; Shamoun, Kim

    2002-11-01

    Multiple-exemplar training with stimuli in four domains induced two new fill-based (A1' and A2') and satellite-image-based (B1' and B2') perceptual classes. Conditional discriminations were established between the endpoints of the A1' and B1' classes as well as the A2' and B2' classes. The emergence of linked perceptual classes was evaluated by the performances occasioned by nine cross-class probes that contained fill variants as samples and satellite variants as comparisons, along with nine other cross-class probes that consisted of satellite variants as samples and fill variants as comparisons. The 18 probes were first presented serially and then concurrently. Class-consistent responding indicated the emergence of linked perceptual classes. Of the linked perceptual classes, 70% emerged during the initial serial test. An additional 20% of the linked perceptual classes emerged during the subsequently presented concurrent test block. Thus, linked perceptual classes emerged on an immediate or delayed basis. Linked perceptual classes, then, share structural and fuctional similarities with equivalence classes, generalized equivalence classes, cross-modal classes, and complex maturally occurring categories, and may clarify processes such as intersensory perception.

  18. HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice.

    PubMed

    Atkins, Katelyn M; Thomas, Laurel; Youker, Robert T; Harriff, Melanie J; Pissani, Franco; You, Huihong; Thomas, Gary

    2008-04-25

    Human immunodeficiency virus, type 1, negative factor (Nef) initiates down-regulation of cell-surface major histocompatibility complex-I (MHC-I) by assembling an Src family kinase (SFK)-ZAP70/Syk-phosphoinositide 3-kinase (PI3K) cascade through the sequential actions of two sites, Nef EEEE(65) and PXXP(75). The internalized MHC-I molecules are then sequestered in endosomal compartments by a process requiring Nef Met(20). How Nef assembles the multikinase cascade to trigger the MHC-I down-regulation pathway is unknown. Here we report that EEEE(65)-dependent binding to the sorting protein PACS-2 targets Nef to the paranuclear region, enabling PXXP(75) to bind and activate a trans-Golgi network (TGN)-localized SFK. This SFK then phosphorylates ZAP-70 to recruit class I PI3K by interaction with the p85 C-terminal Src homology 2 domain. Using splenocytes and embryonic fibroblasts from PACS-2(-/-) mice, we confirm genetically that Nef requires PACS-2 to localize to the paranuclear region and assemble the multikinase cascade. Moreover, genetic loss of PACS-2 or inhibition of class I PI3K prevents Nef-mediated MHC-I down-regulation, demonstrating that short interfering RNA knockdown of PACS-2 phenocopies the gene knock-out. This PACS-2-dependent targeting pathway is not restricted to Nef, because PACS-2 is also required for trafficking of an endocytosed cation-independent mannose 6-phosphate receptor reporter from early endosomes to the TGN. Together, these results demonstrate PACS-2 is required for Nef action and sorting of itinerant membrane cargo in the TGN/endosomal system.

  19. Complex/Symplectic Mirrors

    SciTech Connect

    Chuang, Wu-yen; Kachru, Shamit; Tomasiello, Alessandro; /Stanford U., ITP

    2005-10-28

    We construct a class of symplectic non-Kaehler and complex non-Kaehler string theory vacua, extending and providing evidence for an earlier suggestion by Polchinski and Strominger. The class admits a mirror pairing by construction. Comparing hints from a variety of sources, including ten-dimensional supergravity and KK reduction on SU(3)-structure manifolds, suggests a picture in which string theory extends Reid's fantasy to connect classes of both complex non-Kaehler and symplectic non-Kaehler manifolds.

  20. Identification of the transcription factors NF-YA and NF-YB as factors A and B that bound to the promoter of the major histocompatibility complex class II gene I-A beta.

    PubMed Central

    Celada, A; McKercher, S R; Maki, R A

    1996-01-01

    The Y box is a conserved sequence in the promoter of major histocompatibility complex (MHC) class II genes, which contains a CCAAT sequence (CCAAT box). Previously, we partially purified the DNA-binding protein that recognizes the Y box of the I-A beta gene and showed that it consisted of two components (factors A and B) both of which were necessary for optimal DNA binding. The genes for the heteromeric protein NF-Y (NF-YA and NF-YB), which binds to the I-E alpha Y box have been cloned. We subsequently isolated the genes for NF-YA and NF-YB using oligonucleotides designed from the published sequences. NF-YA and NF-YB were tested for binding to the I-A beta and I-E alpha Y boxes. While neither NF-YA or NF-YB alone bound to the Y box, when the components were mixed the complex bound to the I-A beta Y box with high affinity. Moreover, NF-YA and NF-YB could be complemented for binding to DNA by factor B or factor A, respectively. These results suggest that the active binding protein is NF-YA in factor A extracts and NF-YB in factor B extracts. Finally, antibodies against NF-YA and NF-YB were shown to induce a supershift when nuclear extracts were added to the double-stranded oligodeoxynucleotide covering the Y box of the I-A beta gene. Antisense expression constructs of both NF-YA and NF-YB were made and their effect on expression from the I-A beta promoter was tested. Either antisense construction, when transfected into cells, lowered the expression of a reporter gene linked to the I-A beta promoter. This study provides direct evidence of the identification of NF-YA and NF-YB as the previously described factors A and B. Moreover, these results strongly implicate NF-Y in the expression of the MHC class II gene I-A beta. PMID:8760361

  1. Class Matters: Examining the Impacts of Class on the College Choice Process

    ERIC Educational Resources Information Center

    Spinosa, Hanna Song

    2011-01-01

    Class is a multi-dimensional, complex, and vital construct that is often difficult to define in empirical research. Class can affect our life's chances, potentiality, and our views of the world. Therefore, despite the intricacies and controversial nature of class-based research, it is important to discuss, articulate, and explore the role…

  2. A mutational analysis of the Abetaz/Aalphad major histocompatibility complex class II molecule that restricts autoreactive T cells in (NZBxNZW)F1 mice. The critical influence of alanine at position 69 in the Aalphad chain.

    PubMed

    Sai, T; Mine, M; Fukuoka, M; Koarada, S; Kimoto, M

    1999-03-01

    Autoimmune symptoms of (NZBxNZW)F1 (H-2d/z) mice are reported to be critically related to the heterozygosity at the H-2 complex of the murine major histocompatibility complex (MHC). We previously showed that several Abetaz/Aalphad MHC class II molecule-restricted autoreactive T-cell clones from B/WF1 mice were pathogenic upon transfer to preautoimmune B/WF1 mice. In this study, to identify the crucial amino acid residues in Abetaz/Aalphad molecules for T-cell activation, we generated a panel of transfectant cell lines. These transfectant cell lines express the Abetaz/Aalphad MHC molecules with a mutation at each residue alpha11, alpha28, alpha57, alpha69, alpha70, alpha76 of Aalphad chain and beta86 of Abetaz chain. Replacing alpha69 alanine with threonine, valine or serine completely eliminated the ability to stimulate autoreactive T-cell clones without affecting the ability to present foreign antigen keyhole limpet haemocyanin (KLH) or L-plastin peptide to specific T-cell clones. Replacing beta86 valine with aspartic acid resulted in a decrease in the stimulation for antigen-reactive as well as autoreactive T-cell clones. Substitutions at other residues had minimal or no effect on the stimulation of either auto- or antigen-reactive T-cell clones. These results suggest that alanine at residue 69 of the Aalphad chain is critical for the activation of autoreactive Abetaz/Aalphad-restricted T-cell clones. Possible explanations for this are discussed. PMID:10233712

  3. Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking.

    PubMed

    Mangasarian, A; Piguet, V; Wang, J K; Chen, Y L; Trono, D

    1999-03-01

    The Nef protein of primate lentiviruses triggers the accelerated endocytosis of CD4 and of class I major histocompatibility complex (MHC-I), thereby down-modulating the cell surface expression of these receptors. Nef acts as a connector between the CD4 cytoplasmic tail and intracellular sorting pathways both in the Golgi and at the plasma membrane, triggering the de novo formation of CD4-specific clathrin-coated pits (CCP). The downstream partners of Nef in this event are the adapter protein complex (AP) of CCP and possibly a subunit of the vacuolar ATPase. Whether Nef-induced MHC-I down-regulation stems from a similar mechanism is unknown. By comparing human immunodeficiency virus type 1 (HIV-1) Nef mutants for their ability to affect either CD4 or MHC-I expression, both in transient-transfection assays and in the context of HIV-1 infection, it was determined that Nef-induced CD4 and MHC-I down-regulation constitute genetically and functionally separate properties. Mutations affecting only CD4 regulation mapped to residues previously shown to mediate the binding of Nef to this receptor, such as W57 and L58, as well as to an AP-recruiting dileucine motif and to an acidic dipeptide in the C-terminal region of the protein. In contrast, mutation of residues in an alpha-helical region in the proximal portion of Nef and amino acid substitutions in a proline-based SH3 domain-binding motif selectively affected MHC-I down-modulation. Although both the N-terminal alpha-helix and the proline-rich region of Nef have been implicated in recruiting Src family protein kinases, the inhibitor herbimycin A did not block MHC-I down-regulation, suggesting that the latter process is not mediated through an activation of this family of tyrosine kinases. PMID:9971776

  4. RICE SALT SENSITIVE3 Forms a Ternary Complex with JAZ and Class-C bHLH Factors and Regulates Jasmonate-Induced Gene Expression and Root Cell Elongation[C][W

    PubMed Central

    Toda, Yosuke; Tanaka, Maiko; Ogawa, Daisuke; Kurata, Kyo; Kurotani, Ken-ichi; Habu, Yoshiki; Ando, Tsuyu; Sugimoto, Kazuhiko; Mitsuda, Nobutaka; Katoh, Etsuko; Abe, Kiyomi; Miyao, Akio; Hirochika, Hirohiko; Hattori, Tsukaho; Takeda, Shin

    2013-01-01

    Plasticity of root growth in response to environmental cues and stresses is a fundamental characteristic of land plants. However, the molecular basis underlying the regulation of root growth under stressful conditions is poorly understood. Here, we report that a rice nuclear factor, RICE SALT SENSITIVE3 (RSS3), regulates root cell elongation during adaptation to salinity. Loss of function of RSS3 only moderately inhibits cell elongation under normal conditions, but it provokes spontaneous root cell swelling, accompanied by severe root growth inhibition, under saline conditions. RSS3 is preferentially expressed in the root tip and forms a ternary complex with class-C basic helix-loop-helix (bHLH) transcription factors and JASMONATE ZIM-DOMAIN proteins, the latter of which are the key regulators of jasmonate (JA) signaling. The mutated protein arising from the rss3 allele fails to interact with bHLH factors, and the expression of a significant portion of JA-responsive genes is upregulated in rss3. These results, together with the known roles of JAs in root growth regulation, suggest that RSS3 modulates the expression of JA-responsive genes and plays a crucial role in a mechanism that sustains root cell elongation at appropriate rates under stressful conditions. PMID:23715469

  5. Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region

    PubMed Central

    Drabek, Dubravka; Raguz, Selina; De Wit, Ton P. M.; Dingjan, Gemma M.; Savelkoul, Huub F. J.; Grosveld, Frank; Hendriks, Rudolf W.

    1997-01-01

    Bruton tyrosine kinase (Btk) is essential for the development of pre-B cells to mature B cell stages. Btk-deficient mice manifest an X-linked immunodeficiency (xid) defect characterized by a reduction of peripheral IgMlow IgDhigh B cells, a lack of peritoneal CD5+ B cells, low serum levels of IgM and IgG3, and impaired responses to T cell independent type II (TI-II) antigens. We have generated transgenic mice in which expression of the human Btk gene is driven by the murine class II major histocompatibility complex Ea gene locus control region, which provides gene expression from the pre-B cell stage onwards. When these transgenic mice were mated onto a Btk− background, correction of the xid B cell defects was observed: B cells differentiated to mature IgMlowIgDhigh stages, peritoneal CD5+ B cells were present, and serum Ig levels and in vivo responses to TI-II antigens were in the normal ranges. A comparable rescue by transgenic Btk expression was also observed in heterozygous Btk+/− female mice in those B-lineage cells that were Btk-deficient as a result of X chromosome inactivation. These findings indicate that the Btk− phenotype in the mouse can be corrected by expression of human Btk from the pre-B cell stage onwards. PMID:9012832

  6. Distribution of the multidrug efflux pump genes, adeABC, adeDE and adeIJK, and class 1 integron genes in multiple-antimicrobial-resistant clinical isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus complex.

    PubMed

    Lin, Li; Ling, Bao-Dong; Li, Xian-Zhi

    2009-01-01

    Of 112 non-repetitive clinical isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus complex, 80% were resistant to a variety of structurally unrelated antimicrobials although all isolates were susceptible to minocycline and polymyxin. Resistance to carbapenems occurred in 8% of the isolates. The presence of adeSR-adeABC, adeDE and adeIJK drug efflux system genes and class 1 integron genes (integrase gene int1) was assessed by polymerase chain reaction (PCR) in relation to the susceptibility of the isolates to 20 antimicrobials. The majority of isolates (75%) with high levels of multidrug resistance were positive for adeSR-adeABC and adeIJK as well as int1 and thus belong to A. baumannii (i.e. genomospecies 2). Positive adeE was only observed in adeSR-adeABC/adeIJK/int1-negative isolates (8%; likely belonging to Acinetobacter genomospecies 3) that were relatively susceptible to several agents, and adeE expression was undetectable. The results reveal a possible association between adeABC/adeIJK and int1 in multidrug-resistant isolates of A. baumannii. In addition, differential distribution of the resistance-nodulation-cell division (RND) genes can likely be used as indicators for differentiating Acinetobacter species.

  7. A Rebuttal to Jack Niemonen's "Whither the White Working Class?"

    ERIC Educational Resources Information Center

    Khanna, Nikki; Harris, Cherise A.

    2015-01-01

    Prof. Niemonen claims that the concept of white privilege is "anti-sociological" and "mask[s] complex race-class interactions." He highlights the importance of including social class in discussions of white privilege but focuses exclusively on the white working class, neglecting how race and social class also intersect for…

  8. Does Class Size Matter?

    ERIC Educational Resources Information Center

    Ehrenberg, Ronald G.; Brewer, Dominic J.; Gamoran, Adam; Willms, J. Douglas

    2001-01-01

    Reports on the significance of class size to student learning. Includes an overview of class size in various countries, the importance of teacher adaptability, and the Asian paradox of large classes allied to high test scores. (MM)

  9. Simplified Design Equations for Class-E Neural Prosthesis Transmitters

    PubMed Central

    Troyk, Philip; Hu, Zhe

    2013-01-01

    Extreme miniaturization of implantable electronic devices is recognized as essential for the next generation of neural prostheses, owing to the need for minimizing the damage and disruption of the surrounding neural tissue. Transcutaneous power and data transmission via a magnetic link remains the most effective means of powering and controlling implanted neural prostheses. Reduction in the size of the coil, within the neural prosthesis, demands the generation of a high-intensity radio frequency magnetic field from the extracoporeal transmitter. The Class-E power amplifier circuit topology has been recognized as a highly effective means of producing large radio frequency currents within the transmitter coil. Unfortunately, design of a Class-E circuit is most often fraught by the need to solve a complex set of equations so as to implement both the zero-voltage-switching and zero-voltage-derivative-switching conditions that are required for efficient operation. This paper presents simple explicit design equations for designing the Class-E circuit topology. Numerical design examples are presented to illustrate the design procedure. PMID:23292784

  10. Associations between the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis.

    PubMed

    Song, Gwan Gyu; Kim, Jae-Hoon; Lee, Young Ho

    2014-01-01

    The aim of this study was to assess whether the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism is associated with the susceptibility to psoriasis and psoriatic arthritis (PsA). A meta-analysis was conducted to establish the association between the MICA-TM A9 allele and psoriasis and PsA in the general population and each ethnic group. Ten studies (6 psoriasis, 4 PsA) involving 2,002 cases and 1,933 controls were included in this meta-analysis. The Asian controls showed the lowest A9 allele prevalence (16.6%), whereas the European controls had the highest allele prevalence (33.3%). Meta-analysis revealed a significant association between the MICA-TM A9 allele and the entire study population, which included the psoriasis and PsA cases (OR 1.703; 95% CI 1.301-2.229; p = 1.0 × 10(-5)). We further divided the entire study population into the psoriasis and PsA groups. Meta-analysis revealed a significant association between the MICA-TM A9 allele and the entire study population (OR 1.427, 95% CI 1.021-1.994; p = 0.037) and Asians (OR 1.264; 95% CI 1.014-1.576; p = 0.037). A significant association was found between the MICA-TM A9 allele and PsA (OR 2.227; 95% CI 1.462-3.393; p = 1.9 × 10(-5)) and Europeans (OR 2.039; 95% CI 1.285-3.235; p = 0.002). This meta-analysis showed that the MICA-TM A9 allele is associated with psoriasis susceptibility in Asian populations and that the MICA-TM A9 allele is associated with a PsA risk in Europeans.

  11. HLA class I expression in bladder carcinomas.

    PubMed

    Cabrera, T; Pedrajas, G; Cozar, J M; Garrido, A; Vicente, J; Tallada, M; Garrido, F

    2003-10-01

    HLA class I molecules are frequently lost in a large variety of human carcinomas, possibly because of T-cell immune selection of major histocompatibility complex class I deficient tumor variants. We report that this phenomenon is also a frequent event in bladder carcinomas. Of a total of 72 bladder carcinomas, 72% of the tumors had at least one alteration in HLA class I expression. These altered HLA class I phenotypes were classified as total HLA class I loss (25%; phenotype I); HLA-A or/and HLA-B locus-specific loss (12%; phenotype III); and HLA class I allelic loss (35%; phenotype II or IV). Comparison of histopathological parameters with HLA class I expression showed a statistically significant relationship with the degree of differentiation and tumor recurrence.

  12. Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1

    PubMed Central

    1991-01-01

    Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply

  13. Quality control of MHC class I maturation.

    PubMed

    Paulsson, Kajsa M; Wang, Ping

    2004-01-01

    Assembly of MHC class I molecules in the ER is regulated by the so-called loading complex (LC). This multiprotein complex is of definite importance for class I maturation, but its exact organization and order of assembly are not known. Evidence implies that the quality of peptides loaded onto class I molecules is controlled at multiple stages during MHC class I assembly. We recently found that tapasin, an important component of the LC, interacts with COPI-coated vesicles. Biochemical studies suggested that the tapa-sin-COPI interaction regulates the retrograde transport of immature MHC class I molecules from the Golgi network back to the ER. Also other findings now propose that in addition to the peptide-loading control, the quality control of MHC class I antigen presentation includes the restriction of export of suboptimally loaded MHC class I molecules to the cell surface. In this review, we use recent studies of tapasin to examine the efficiency of TAP, the LC constitution, ER quality control of class I assembly, and peptide optimization. The concepts of MHC class I recycling and ER retention are also discussed. PMID:14718384

  14. In-Class Experiments as an Accompaniment to In-Class Discussion

    ERIC Educational Resources Information Center

    Rauh, Jonathan

    2014-01-01

    Active learning, including in-class debates, is used in social science classrooms as a means of improving meaning and increasing understanding of complex materials. However, in-class debates do not fully satisfy all aspects of experiential learning because students do not get to experience the results of multifaceted concepts, such as strategic…

  15. Pilot Class Testing: Statistics.

    ERIC Educational Resources Information Center

    Washington Univ., Seattle. Washington Foreign Language Program.

    Statistics derived from test score data from the pilot classes participating in the Washington Foreign Language Program are presented in tables in this report. An index accompanies the tables, itemizing the classes by level (FLES, middle, and high school), grade test, language skill, and school. MLA-Coop test performances for each class were…

  16. First-Class Inquiry

    ERIC Educational Resources Information Center

    Hesser, Kathi; Buck, Gayle; Dopp, Sandra

    2005-01-01

    In the activity described in this article, students will explore how variables in a first-class lever, specifically arm length, position of the fulcrum, and placement of the load, affect the effort needed to lift the load. To begin the lesson, demonstrate to the class how a first-class lever works and review what is meant by the terms fulcrum,…

  17. Girls' Class, Infinite Possibilities.

    ERIC Educational Resources Information Center

    Ost, Nancy

    1999-01-01

    The co-director of a small independent school describes Girls' Class, which she created in order to have a special time together with the girls in grades 6 through 8. The class provides guidance and celebrates spirituality and the beginning of menses for the young women. To end the class, each person says a positive self-affirmation and gives…

  18. Contrasting evolutionary histories of MHC class I and class II loci in grouse—Effects of selection and gene conversion

    USGS Publications Warehouse

    Minias, Piotr; Bateson, Zachary W; Whittingham, Linda A; Johnson, Jeff A.; Oyler-McCance, Sara J.; Dunn, Peter O

    2016-01-01

    Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens.

  19. Class network routing

    DOEpatents

    Bhanot, Gyan; Blumrich, Matthias A.; Chen, Dong; Coteus, Paul W.; Gara, Alan G.; Giampapa, Mark E.; Heidelberger, Philip; Steinmacher-Burow, Burkhard D.; Takken, Todd E.; Vranas, Pavlos M.

    2009-09-08

    Class network routing is implemented in a network such as a computer network comprising a plurality of parallel compute processors at nodes thereof. Class network routing allows a compute processor to broadcast a message to a range (one or more) of other compute processors in the computer network, such as processors in a column or a row. Normally this type of operation requires a separate message to be sent to each processor. With class network routing pursuant to the invention, a single message is sufficient, which generally reduces the total number of messages in the network as well as the latency to do a broadcast. Class network routing is also applied to dense matrix inversion algorithms on distributed memory parallel supercomputers with hardware class function (multicast) capability. This is achieved by exploiting the fact that the communication patterns of dense matrix inversion can be served by hardware class functions, which results in faster execution times.

  20. Class and Gender

    ERIC Educational Resources Information Center

    Hart, Mechthild

    2005-01-01

    Everyone is dependent on caring labor. Because women's labor is financially beneficial to global capitalism, gender is inseparable from class, regardless of the specific national or cultural contexts.

  1. Sequence variations of the locus-specific 5' untranslated regions of SLA class I genes and the development of a comprehensive genomic DNA-based high-resolution typing method for SLA-2.

    PubMed

    Choi, H; Le, M T; Lee, H; Choi, M-K; Cho, H-S; Nagasundarapandian, S; Kwon, O-J; Kim, J-H; Seo, K; Park, J-K; Lee, J-H; Ho, C-S; Park, C

    2015-10-01

    The genetic diversity of the major histocompatibility complex (MHC) class I molecules of pigs has not been well characterized. Therefore, the influence of MHC genetic diversity on the immune-related traits of pigs, including disease resistance and other MHC-dependent traits, is not well understood. Here, we attempted to develop an efficient method for systemic analysis of the polymorphisms in the epitope-binding region of swine leukocyte antigens (SLA) class I genes. We performed a comparative analysis of the last 92 bp of the 5' untranslated region (UTR) to the beginning of exon 4 of six SLA classical class I-related genes, SLA-1, -2, -3, -4, -5, and -9, from 36 different sequences. Based on this information, we developed a genomic polymerase chain reaction (PCR) and direct sequencing-based comprehensive typing method for SLA-2. We successfully typed SLA-2 from 400 pigs and 8 cell lines, consisting of 9 different pig breeds, and identified 49 SLA-2 alleles, including 31 previously reported alleles and 18 new alleles. We observed differences in the composition of SLA-2 alleles among different breeds. Our method can be used to study other SLA class I loci and to deepen our knowledge of MHC class I genes in pigs.

  2. Online, Bigger Classes May Be Better Classes

    ERIC Educational Resources Information Center

    Parry, Marc

    2010-01-01

    In his work as a professor, Stephen Downes used to feel that he was helping those who least needed it. His students at places like the University of Alberta already had a leg up in life and could afford the tuition. When a colleague suggested they co-teach an online class in learning theory at the University of Manitoba, in 2008, Downes welcomed…

  3. Limits to Open Class Performance?

    NASA Technical Reports Server (NTRS)

    Bowers, Albion H.

    2007-01-01

    This viewgraph presentation describes the limits to open class performance. The contents include: 1) Standard Class; 2) 15m/Racing Class; 3) Open Class; and 4) Design Solutions associated with assumptions, limiting parameters, airfoil performance, current trends, and analysis.

  4. Inhibition by chloroquine of the class II major histocompatibility complex-restricted presentation of endogenous antigens varies according to the cellular origin of the antigen-presenting cells, the nature of the T-cell epitope, and the responding T cell.

    PubMed Central

    Lombard-Platlet, S; Bertolino, P; Deng, H; Gerlier, D; Rabourdin-Combe, C

    1993-01-01

    Chloroquine treatment of antigen-presenting cells (APC) was explored as a tool to investigate the processing pathway for major histocompatibility complex (MHC) class II-restricted presentation of the endogenous secreted hen egg lysozyme (HEL) and transmembrane measles virus haemagglutinin (HA). A 72-hr pretreatment of the APC with 25 microM chloroquine blocked the presentation of the HEL(52-61) T-cell epitope generated from endogenous HEL to the I-Ak-restricted 3A9 T-cell hybridoma by MHC class II-transfected L cells expressing the invariant chain (Ii). The presentation of exogenously added HEL peptides was not affected. Under the same conditions, no inhibition of the presentation of HEL(106-116) to the I-Ed-restricted G28 high-avidity T-cell hybridoma, nor of HA when synthesized by L cells, was observed. When B-lymphoid APC were used, inhibition was observed in every case with a low number of B APC pretreated for 48 hr with chloroquine prior to the T-cell stimulation test. Moreover, addition of chloroquine to untreated B APC during the T-cell stimulation assay was sufficient to inhibit completely the presentation of HEL(106-116) to the B10.D24.42 low avidity T-cell hybridoma. Altogether these studies suggest that an apparent resistance of endogenous Ag presentation to chloroquine inhibition may not necessarily indicate the existence of a non-endosomal pathway but may be due to the nature of the T-cell epitope, to the use of 'non-professional' APC such as L cells, to the use of T cells of high avidity, and to high amounts of pre-existing MHC class II-peptide complexes expressed by the APC. We demonstrate here that, at least in conventional APC such as B cells, class II-restricted presentation of both endogenous secreted HEL and transmembrane HA involves an endosomal pathway. PMID:7508420

  5. The Last Class

    ERIC Educational Resources Information Center

    Uhl, Christopher

    2005-01-01

    The last class of the semester is like a goodbye. It can be cold and perfunctory or warm and heartfelt. For many years, I erred on the side of "cold and perfunctory." No more. Now my last classes are a time of celebration and ritual as I invite students to focus on qualities such as acceptance and gratitude.

  6. The Conversation Class

    ERIC Educational Resources Information Center

    Jackson, Acy L.

    2012-01-01

    The conversation class occupies a unique place in the process of learning English as a second or foreign language. From the author's own experience in conducting special conversation classes with Persian-speaking adults, he has drawn up a number of simple but important guidelines, some of which he hopes may provide helpful suggestions for the…

  7. Teaching Large Evening Classes

    ERIC Educational Resources Information Center

    Wambuguh, Oscar

    2008-01-01

    High enrollments, conflicting student work schedules, and the sheer convenience of once-a-week classes are pushing many colleges to schedule evening courses. Held from 6 to 9 pm or 7 to 10 pm, these classes are typically packed, sometimes with more than 150 students in a large lecture theater. How can faculty effectively teach, control, or even…

  8. The Class Size Debate.

    ERIC Educational Resources Information Center

    Mishel, Lawrence, Ed.; Rothstein, Richard, Ed.

    This collection of papers debates the merits of smaller class sizes and research methods used to evaluate the efficacy of this education reform measure. Four chapters focus on (1) "Understanding the Magnitude and Effect of Class Size on Student Achievement" (Alan B. Krueger), which discusses expenditures per student and economic criterion; (2)…

  9. Teaching Social Class

    ERIC Educational Resources Information Center

    Tablante, Courtney B.; Fiske, Susan T.

    2015-01-01

    Discussing socioeconomic status in college classes can be challenging. Both teachers and students feel uncomfortable, yet social class matters more than ever. This is especially true, given increased income inequality in the United States and indications that higher education does not reduce this inequality as much as many people hope. Resources…

  10. Molecular characterization by high-resolution isoelectric focusing of the products encoded by the class II region loci of the major histocompatibility complex in humans. I. DR and DQ gene variants.

    PubMed

    Rodriguez de Cordoba, S; Nunez-Roldan, A; Winchester, R; Marshall, P; Carrier, C; Mollen, N; Walker, M; Ginsberg-Fellner, F; Rubinstein, P

    1987-09-01

    We describe a new approach to the analysis of the structural polymorphism of the DR beta, DQ alpha, and DQ beta polypeptide chains of human histocompatibility class II antigens. In comparison to conventional two-dimensional gel studies, this method provides sharper definition of the protein bands and side-by-side comparisons within the same gel, thereby permitting the detection of minor differences in the isoelectric points of the protein chains. Using this methodology we have analyzed the IEF polymorphism and the variability in the number of the DR beta chains encoded by different DR haplotypes. Twenty DR beta chain variants, which include the products of no less than two separate DR beta loci, have been thus far identified. Alleles at one of these loci are assumed to code for DR beta chains carrying the DR alloespecificities DR1, DR2, DR3, DR4, DR5, DRw6, DR7, and DR8. Alleles at a second DR beta locus encode DR beta chains that may be shared by serologically DR-different haplotypes and carry supertypic serologic specificities (i.e., DRw52 and DRw53). We also demonstrate here that the structural polymorphisms of the DQ alpha and DQ beta chains are more extensive than previously thought, report the characterization of 14 DQ beta variants, and define their relationship to the previously described DQw serologic specificities. In addition, we describe the class II haplotype associations observed for the different DR and DQ variants characterized. PMID:3679903

  11. Major Histocompatibility Complex (MHC) Class I Processing of the NY-ESO-1 Antigen Is Regulated by Rpn10 and Rpn13 Proteins and Immunoproteasomes following Non-lysine Ubiquitination.

    PubMed

    Golnik, Richard; Lehmann, Andrea; Kloetzel, Peter-Michael; Ebstein, Frédéric

    2016-04-15

    The supply of MHC class I-restricted peptides is primarily ensured by the degradation of intracellular proteins via the ubiquitin-proteasome system. Depending on the target and the enzymes involved, ubiquitination is a process that may dramatically vary in terms of linkages, length, and attachment sites. Here we identified the unique lysine residue at position 124 of the NY-ESO-1 cancer/testis antigen as the acceptor site for the formation of canonical Lys-48-linkages. Interestingly, a lysine-less form of NY-ESO-1 was as efficient as its wild-type counterpart in supplying the HLA-A*0201-restricted NY-ESO-1157-165 antigenic peptide. In fact, we show that the regulation of NY-ESO-1 processing by the ubiquitin receptors Rpn10 and Rpn13 as a well as by the standard and immunoproteasome is governed by non-canonical ubiquitination on non-lysine sites. In summary, our data underscore the significance of atypical ubiquitination in the modulation of MHC class I antigen processing.

  12. MOLECULAR GENETICS OF THE SWINE MAJOR HISTOCOMPATIBILITY COMPLEX, THE SLA COMPLEX

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The swine major histocompatibility complex (MHC) or swine leukocyte antigen (SLA) complex is one of the most gene-dense regions in the swine genome. It consists of three major gene clusters, the SLA class I, class III and class II regions, that span ~1.1, 0.7 and 0.5 Mb, respectively, making the swi...

  13. Social Class Dialogues and the Fostering of Class Consciousness

    ERIC Educational Resources Information Center

    Madden, Meredith

    2015-01-01

    How do critical pedagogies promote undergraduate students' awareness of social class, social class identity, and social class inequalities in education? How do undergraduate students experience class consciousness-raising in the intergroup dialogue classroom? This qualitative study explores undergraduate students' class consciousness-raising in an…

  14. Debating Values: Race, Class and Academic Achievement

    ERIC Educational Resources Information Center

    Milton, Penny

    2008-01-01

    The relationships among race, class and academic achievement are complex, yet have been well documented in Canada for the last thirty years. Generations of students have experienced them--lowered expectations for achievement, gross generalizations about parents' backgrounds and aspirations, negative stereotypes of communities, and curricula that…

  15. On a Class of Real Integrals

    ERIC Educational Resources Information Center

    Capelas de Oliveira, E.; Rosa, M. A. F.; Vaz, J., Jr.

    2009-01-01

    We present a calculation involving a wide class of real integrals by means of integration in the complex plane. Some particular cases where Euler numbers and Bell polynomials appear are discussed and a generalisation of some previous results is also provided. (Contains 1 table and 1 figure.)

  16. Venture Class Launch Services

    NASA Technical Reports Server (NTRS)

    Wiese, Mark

    2016-01-01

    Provide an introduction to the Launch Services Program, and specifically the strategic initiative that drove the Venture Class Launch Services contracts. Provide information from the VCLS request for proposals, as well as the Agency's CubeSat Launch Initiative.

  17. Class, health and justice.

    PubMed

    Marchand, S; Wikler, D; Landesman, B

    1998-01-01

    Class inequalities in health are intuitively unjust. Although the link between social class and health status has been fully documented, the precise nature of the injustice has not been made clear. Four alternative views are presented, corresponding to four goals: (1) maximizing the sum total of health; (2) equalizing the health status of higher and lower social classes; (3) maximizing the health status of the lowest social class; and (4) maximizing the health status of the sickest individuals in society. The nature of the injustice is further obscured by several theoretical and empirical questions, like the degree and significance of personal responsibility for illness and the relation of the degree of economic inequality to sum total of health.

  18. Aerobic Conditioning Class.

    ERIC Educational Resources Information Center

    Johnson, Neil R.

    1980-01-01

    An aerobic exercise class that focuses on the conditioning of the cardiovascular and muscular systems is presented. Students complete data cards on heart rate, pulse, and exercises to be completed during the forty minute course. (CJ)

  19. Teaching Heterogeneous Classes.

    ERIC Educational Resources Information Center

    Millrood, Radislav

    2002-01-01

    Discusses an approach to teaching heterogeneous English-as-a-Second/Foreign-Language classes. Draws on classroom research data to describe the features of a success-building lesson context. (Author/VWL)

  20. Universality classes of inflation

    SciTech Connect

    Roest, Diederik

    2014-01-01

    We investigate all single-field, slow-roll inflationary models whose slow-roll parameters scale as 1/N in the limit of a large number of e-folds N. We proof that all such models belong to two universality classes, characterised by a single parameter. One class contains small field models like hilltop inflation, while the other class consists of large field models like chaotic inflation. We give the leading expressions for the spectral index and tensor-to-scalar ratio r, which are universal for each class, plus subleading corrections for a number of models. This predicts r either to be unobservably small, r < 0.01, or close to the present observational limit, r ≈ 0.07.

  1. A class in astrobiology

    NASA Astrophysics Data System (ADS)

    Airieau, S. A.

    1999-09-01

    The goal of this class is to provide basic astrobiology knowledge to upper division science students. The scope is broad and in-depth coverage is not possible in this introductory course. Instead, science students from various branches of academia can acquire a broad basis and understanding of the other fields: astronomy, biology, geology, biochemistry, planetary and space sciences. The class is highly modular and allows instructors to concentrate on or eliminate topics according to their priorities and preferences.

  2. Social-Class Identity and English Learning: Studies of Chinese Learners

    ERIC Educational Resources Information Center

    Gao, Feng

    2014-01-01

    This article first looks at the complex conceptualization of Chinese learners' social-class identities with respect to a shifting Chinese class stratification. It then examines the link between social class and second-language learning in the Chinese context by reviewing several studies on Chinese learners' social-class backgrounds and…

  3. Social class and heart disease mortality among African Americans.

    PubMed

    Barnett, Elizabeth; Williams, Carol R; Moore, Latetia; Chen, Fangfei

    2002-01-01

    The purpose of the present study was to examine variation in heart disease death rates by the social class of decedents. The term, "social class" refers to a complex set of phenomena such as control over economic resources, social status, and power relative to others in society. The target population for this study was African-American adults aged 35-74 years old who resided in the United States during the years 1996-1997. As a proxy for social class, we examined 5 levels of educational attainment: 0-8 years of school completed (Social Class I), 9-11 years of school completed (Social Class II), high school graduate/12 years of school completed (Social Class III), some college completed (Social Class IV), and college degree completed (Social Class V). Older age, male gender, and lower social class were all independently associated with higher heart disease death rates. For all ages, more disadvantaged social classes had a higher risk of heart disease mortality. The highest relative risks were found for Social Classes I and II among the younger age groups. Many of the "prerequisites" for the "heart healthy lifestyle" are predicated on the benefits of a privileged social class position. For African Americans, there are the additional stressors of segregation, exclusion, and discrimination to overcome, as well as the cumulative physiological toll of lifetime resistance to various forms of racism. For many African Americans in disadvantaged social class positions, the obstacles to reducing the risk for heart disease are very difficult to overcome.

  4. The peculiar distribution of class I and class II aldolases in diatoms and in red algae.

    PubMed

    Kroth, Peter G; Schroers, Yvonne; Kilian, Oliver

    2005-12-01

    Diatom plastids probably evolved by secondary endocytobiosis from a red alga that was up by a eukaryotic host cell. Apparently, this process increased the complexity of the intracellular distribution of metabolic enzymes. We identified genes encoding fructose-bisphosphate aldolases (FBA) in two centric (Odontella sinensis, Thalassiosira pseudonana) and one pennate (Phaeodactylum tricornutum) diatoms and found that four different aldolases are present in both groups: two plastid targeted class II enzymes (FBAC1 and FBAC2), one cytosolic class II (FBA3) and one cytosolic class I (FBA4) enzyme. The pennate Phaeodactylum possesses an additional plastidic class I enzyme (FBAC5). We verified the classification of the different aldolases in the diatoms by enzymatic characterization of isolated plastids and whole cell extracts. Interestingly, our results imply that in plastids of centric and pennate diatoms mainly either class I or class II aldolases are active. We also identified genes for both class I and class II aldolases in red algal EST databases, thus presenting a fascinating example of the reutilization and recompartmentalization of different aldolase isoenzymes during secondary endocytobiosis but as well demonstrating the limited use of metabolic enzymes as markers for the interpretation of phylogenetic histories in algae.

  5. Induction of a major histocompatibility complex class I-restricted cytotoxic T-lymphocyte response to a highly conserved region of human immunodeficiency virus type 1 (HIV-1) gp120 in seronegative humans immunized with a candidate HIV-1 vaccine.

    PubMed Central

    Johnson, R P; Hammond, S A; Trocha, A; Siliciano, R F; Walker, B D

    1994-01-01

    Efforts to induce broadly reactive immunity against human immunodeficiency virus type 1 (HIV-1) have been impaired by the extent of sequence variation exhibited by this lentivirus. Cytotoxic T lymphocytes (CTL) specific for other viruses such as influenza virus have been shown to mediate immunity against divergent viral strains, a property that is related to the ability of CTL to recognize processed antigen derived from conserved viral proteins. A recent candidate HIV-1 vaccine regimen has been described in which subjects receive a primary immunization with a recombinant vaccinia virus expressing gp160 and then a booster immunization with recombinant gp160. Volunteers immunized with this regimen have exhibited augmented humoral responses and have also developed CD4+ and CD8+ CTL specific for gp160. In this report, we have identified the epitopes recognized by CD4+ and CD8+ CTL obtained from two vaccines. An immunodominant CD8+ CTL response was HLA-A3.1 restricted and recognized a 10-amino-acid epitope (gp120/38-47) in a highly conserved region of gp120. CTL specific for the epitope gp120/38-47 were able to lyse targets sensitized with peptides corresponding to all known natural sequence variants in this region. In addition, other HLA class I-restricted CTL epitopes were identified in relatively conserved regions of gp120 and gp41, and CD4+ CTL were shown to recognize two different regions of gp120. Thus, in these two volunteers, immunization with a single strain of HIV-1 induced CD4+ and CD8+ CTL that are specific for multiple conserved regions of HIV-1 and would be expected to recognize a broad range of viral isolates. PMID:7908700

  6. Launching Complex Tasks

    ERIC Educational Resources Information Center

    Jackson, Kara J.; Shahan, Emily C.; Gibbons, Lynsey K.; Cobb, Paul A.

    2012-01-01

    Mathematics lessons can take a variety of formats. In this article, the authors discuss lessons organized around complex mathematical tasks. These lessons usually unfold in three phases. First, the task is introduced to students. Second, students work on solving the task. Third, the teacher "orchestrates" a concluding whole-class discussion in…

  7. Complexity in the Classroom.

    ERIC Educational Resources Information Center

    Doll, William E., Jr.

    1989-01-01

    Applies complexity theory, a movement in contemporary physics, to instruction of a sixth-grade math class. The mathematical chaos theory, embracing random and nonlinear patterning, contradicts the reductionist, particularist, and atomistic view commonly applied to science and teaching. Fractals and self-organization are similarly powerful,…

  8. "Emboldened Bodies": Social Class, School Health Policy and Obesity Discourse

    ERIC Educational Resources Information Center

    De Pian, Laura

    2012-01-01

    This paper examines the multiple ways in which health policy relating to obesity, diet and exercise is recontextualised and mediated by teachers and pupils in the context of social class in the UK. Drawing on a case study of a middle-class primary school in central England, the paper documents the complexity of the policy process, its uncertainty,…

  9. Coming out in Class

    ERIC Educational Resources Information Center

    McKinnon, Rachel

    2012-01-01

    This article shares how the author explained her trans status to her students. Everyone has been extremely supportive of her decision to come out in class and to completely mask the male secondary-sex characteristics, especially in the workplace. The department chair and the faculty in general have been willing to do whatever they can to assist…

  10. Shrinking Your Class

    ERIC Educational Resources Information Center

    Herron-Thorpe, Farren L.; Olson, Jo Clay; Davis, Denny

    2010-01-01

    Toys in the classroom was the result of a National Science Foundation grant that brought two engineering graduate students to a middle school math class. The graduate students and teachers collaborated in an effort to enhance students' mathematical learning. An engineering context was theorized as a way to further develop students' understanding…

  11. IQ and Social Class.

    ERIC Educational Resources Information Center

    Fischbein, Siv

    1980-01-01

    Swedish longitudinal studies of twins support Scarr-Salapatek's explanation of nature-nurture influences on intelligence. This model predicts more genetic variance in test results for advantaged than disadvantaged groups. Jensen's work, however, suggests equal amounts of variance among different social classes. (Author/CP)

  12. Financing Class Size Reduction

    ERIC Educational Resources Information Center

    Achilles, C. M.

    2005-01-01

    Class size reduction has been shown to, among other things, improve academic achievement for all students and particularly for low-income and minority students. With the No Child Left Behind Act's heavy emphasis on scientifically based research, adequate yearly progress, and disaggregated results, one wonders why all children aren't enrolled in…

  13. Virtual Classes, Real Policy

    ERIC Educational Resources Information Center

    Beem, Kate

    2010-01-01

    As Internet technology encroached on the public school classroom about a decade ago, Kim Ross, superintendent of the Houston School District in Houston, Minnesota, saw an opportunity. At first, he and his administrative team simply wanted to offer students in the district of 1,300 access to more classes via the web than what a district that size…

  14. Class D sucker rods

    SciTech Connect

    Woodings, R. T.

    1984-10-23

    It has been found that API Class D sucker rods can be made inexpensively from low-alloy, low-cost steel by following a suitable induction-normalizing process and using a suitable steel to which there has been added 0.07 to 0.15 percent of vanadium.

  15. Openers for Biology Classes.

    ERIC Educational Resources Information Center

    Gridley, C. Robert R.

    This teaching guide contains 200 activities that are suitable for openers and demonstrations in biology classes. Details are provided regarding the use of these activities. Some of the broad topics under which the activities are organized include algae, amphibians, bacteria, biologists, crustaceans, dinosaurs, ecology, evolution, flowering plants,…

  16. Microarrays for Undergraduate Classes

    ERIC Educational Resources Information Center

    Hancock, Dale; Nguyen, Lisa L.; Denyer, Gareth S.; Johnston, Jill M.

    2006-01-01

    A microarray experiment is presented that, in six laboratory sessions, takes undergraduate students from the tissue sample right through to data analysis. The model chosen, the murine erythroleukemia cell line, can be easily cultured in sufficient quantities for class use. Large changes in gene expression can be induced in these cells by…

  17. Class Attitudes among Dental Students.

    ERIC Educational Resources Information Center

    Gardiner, James F.; Lancaster, Diana M.

    Class attitudes among dental students were studied at Louisiana State University in spring 1986, with attention to attitudes toward leadership, faculty and administration, study habits, labs and clinics, information acquisition, social life, and class unification. Class attitudes became more uniform and deeply held as the classes progressed…

  18. The MHC class I genes of zebrafish.

    PubMed

    Dirscherl, Hayley; McConnell, Sean C; Yoder, Jeffrey A; de Jong, Jill L O

    2014-09-01

    Major histocompatibility complex (MHC) molecules play a central role in the immune response and in the recognition of non-self. Found in all jawed vertebrate species, including zebrafish and other teleosts, MHC genes are considered the most polymorphic of all genes. In this review we focus on the multi-faceted diversity of zebrafish MHC class I genes, which are classified into three sequence lineages: U, Z, and L. We examine the polygenic, polymorphic, and haplotypic diversity of the zebrafish MHC class I genes, discussing known and postulated functional differences between the different class I lineages. In addition, we provide the first comprehensive nomenclature for the L lineage genes in zebrafish, encompassing at least 15 genes, and characterize their sequence properties. Finally, we discuss how recent findings have shed new light on the remarkably diverse MHC loci of this species.

  19. Establishment of the reversible peptide-major histocompatibility complex (pMHC) class I Histamer technology: tool for visualization and selection of functionally active antigen-specific CD8(+) T lymphocytes.

    PubMed

    Tischer, Sabine; Kaireit, Till; Figueiredo, Constança; Hiller, Oliver; Maecker-Kolhoff, Britta; Geyeregger, Renè; Immenschuh, Stephan; Blasczyk, Rainer; Eiz-Vesper, Britta

    2012-09-01

    Multimers of soluble peptide-major histocompatibilty complex (pMHC) molecules are used in both basic and clinical immunology. They allow the specific visualization and isolation of antigen-specific T cells from ex vivo samples. Adoptive transfer of antigen-specific T cells sorted by pMHC multimers is an effective strategy for treatment of patients with malignancies or infectious diseases after transplantation. We developed a new reversible pMHC multimer called 'Histamer' to enable the specific detection and isolation of antiviral T cells from peripheral blood. HLA-A*02:01/CMVpp65 (495-503) Histamer (A02/CMV Histamer) was generated by coupling 6xHis-tagged pMHC molecules onto cobalt-based magnetic beads. The specificity of the Histamer was evaluated by flow cytometry. Sorting of antiviral CD8(+) cytotoxic T lymphocytes (CTLs) was performed by magnetic cell separation, followed by the monomerization of the Histamer after addition of the competitor L-histidine. Sorted T cells were analyzed for phenotype and function. The reversible pMHC Histamer proved to be highly specific and sensitive. CMV-specific T cells of up to 99.6% purity were isolated using the Histamer technology. Rapid and complete disassembly of the T-cell surface-bound A02/CMV Histamer followed by the subsequent dissociation of the pMHC monomers from CD8(+) CTL receptors was achieved using 100 mM L-histidine. The function of CMV-specific T cells enriched by Histamer staining did not differ from CTLs induced by standard T-cell assays. This reversible T-cell staining procedure preserves the functionality of antigen-specific T cells and can be adapted to good manufacturing practice conditions. The pMHC Histamer technology offers full flexibility and fulfills all requirements to generate clinical-grade T lymphocytes. PMID:22740564

  20. Amphotericin B Lipid Complex Injection

    MedlinePlus

    Amphotericin B lipid complex injection is used to treat serious, possibly life-threatening fungal infections in people who did not respond or are ... tolerate conventional amphotericin B therapy. Amphotericin B lipid complex injection is in a class of medications called ...

  1. Economy class syndrome.

    PubMed

    Sahiar, F; Mohler, S R

    1994-10-01

    A recent case of the "Economy Class Syndrome" is presented, emphasizing the syndrome's aeromedical implications and prevention. The clinical presentation, current modes of prophylaxis and therapy, plus a brief but pertinent historical background, are described. The syndrome is potentially fatal, and the authors stress that the condition needs to be recognized as a preventable hazard of air travel. Adoption of the preventive measures described herein can assist in promoting healthy air travel.

  2. Small-Space Analogues of Valiant's Classes

    NASA Astrophysics Data System (ADS)

    Mahajan, Meena; Rao, B. V. Raghavendra

    In the uniform circuit model of computation, the width of a boolean circuit exactly characterises the “space” complexity of the computed function. Looking for a similar relationship in Valiant’s algebraic model of computation, we propose width of an arithmetic circuit as a possible measure of space. We introduce the class VL as an algebraic variant of deterministic log-space L. In the uniform setting, we show that our definition coincides with that of VPSPACE at polynomial width.

  3. Contrasting patterns of selection acting on MHC class I and class II DRB genes in the Alpine marmot (Marmota marmota).

    PubMed

    Kuduk, K; Johanet, A; Allainé, D; Cohas, A; Radwan, J

    2012-08-01

    The major histocompatibility complex (MHC) genes code for proteins that play a critical role in the immune system response. The MHC genes are among the most polymorphic genes in vertebrates, presumably due to balancing selection. The two MHC classes appear to differ in the rate of evolution, but the reasons for this variation are not well understood. Here, we investigate the level of polymorphism and the evolution of sequences that code for the peptide-binding regions of MHC class I and class II DRB genes in the Alpine marmot (Marmota marmota). We found evidence for four expressed MHC class I loci and two expressed MHC class II loci. MHC genes in marmots were characterized by low polymorphism, as one to eight alleles per putative locus were detected in 38 individuals from three French Alps populations. The generally limited degree of polymorphism, which was more pronounced in class I genes, is likely due to bottleneck the populations undergone. Additionally, gene duplication within each class might have compensated for the loss of polymorphism at particular loci. The two gene classes showed different patterns of evolution. The most polymorphic of the putative loci, Mama-DRB1, showed clear evidence of historical positive selection for amino acid replacements. However, no signal of positive selection was evident in the MHC class I genes. These contrasting patterns of sequence evolution may reflect differences in selection pressures acting on class I and class II genes.

  4. Disordered cold atoms in different symmetry classes

    NASA Astrophysics Data System (ADS)

    Pinheiro, Fernanda; Larson, Jonas

    2015-08-01

    We consider an experimentally realizable model of noninteracting but randomly coupled atoms in a two-dimensional optical lattice. By choosing appropriate real or complex-valued random fields and species-dependent energy offsets, this system can be used to analyze effects of disorder in four different symmetry classes: the chiral BDI and AIII and the nonchiral A and AI. These chiral classes are known to support a metallic phase at zero energy, which here, due to the inevitable finite size of the system, should also persist in a neighborhood of nonzero energies. As we discuss, this is of particular interest for experiments involving quenches. Away from the center of the spectrum, we find that excitations appear as domain walls in the cases with time-reversal symmetry or as vortices in the cases where time-reversal symmetry is absent. Therefore, a quench in a system with uniform density would lead to the formation of either vortices or domain walls depending on the symmetry class. For the nonchiral models in classes A and AI, a population imbalance between the two atomic species naturally occurs. In these cases, one of the two species is seen to favor a more uniform density. We also study the onset of localization as the disorder strength is increased for the different classes, and by deriving an effective model for the nonchiral cases we show how their eigenstates remain extended for larger values of the coupling with the disorder when compared to the nonchiral ones.

  5. Class Participation: Promoting In-Class Student Engagement

    ERIC Educational Resources Information Center

    O'Connor, Kevin J.

    2013-01-01

    Class participation has long been valued by faculty members interested in engaging students in the learning process. This paper discusses class participation and shares participation techniques that promote active student engagement during class meetings. Emphasis is placed on techniques that invite a larger number of students into a course's…

  6. Class prediction for high-dimensional class-imbalanced data

    PubMed Central

    2010-01-01

    Background The goal of class prediction studies is to develop rules to accurately predict the class membership of new samples. The rules are derived using the values of the variables available for each subject: the main characteristic of high-dimensional data is that the number of variables greatly exceeds the number of samples. Frequently the classifiers are developed using class-imbalanced data, i.e., data sets where the number of samples in each class is not equal. Standard classification methods used on class-imbalanced data often produce classifiers that do not accurately predict the minority class; the prediction is biased towards the majority class. In this paper we investigate if the high-dimensionality poses additional challenges when dealing with class-imbalanced prediction. We evaluate the performance of six types of classifiers on class-imbalanced data, using simulated data and a publicly available data set from a breast cancer gene-expression microarray study. We also investigate the effectiveness of some strategies that are available to overcome the effect of class imbalance. Results Our results show that the evaluated classifiers are highly sensitive to class imbalance and that variable selection introduces an additional bias towards classification into the majority class. Most new samples are assigned to the majority class from the training set, unless the difference between the classes is very large. As a consequence, the class-specific predictive accuracies differ considerably. When the class imbalance is not too severe, down-sizing and asymmetric bagging embedding variable selection work well, while over-sampling does not. Variable normalization can further worsen the performance of the classifiers. Conclusions Our results show that matching the prevalence of the classes in training and test set does not guarantee good performance of classifiers and that the problems related to classification with class-imbalanced data are exacerbated when

  7. The Class of '34

    PubMed Central

    Cairney, Richard

    1995-01-01

    The Great Depression raged, governments were beleaguered, the unemployment rate stood at 30%, scurvy stalked the poor and no one was immune to contagious diseases such as scarlet fever, polio and measles when the University of Alberta School of Medicine's Class of '34 graduated. For four alumni who recently gathered in Edmonton—Drs. Morley Hodgson, Melvin Gaudin, John McLurg and Edmund Cairns—their 60th-anniversary reunion was a time to recall the changes they have witnessed in medicine, including the arrival of antibiotic drugs and the medicare system. Imagesp558-a

  8. Combination Classes and Educational Achievement

    ERIC Educational Resources Information Center

    Thomas, Jaime L.

    2012-01-01

    Using the ECLS-K and considering first graders in single-grade and K-1 and 1-2 combination classes, I discuss the mechanisms underlying the combination-class effect and address the systematic school-, teacher-, and student-level differences that confound estimates of this effect. I find evidence for positive selection into 1-2 classes, but using a…

  9. A Class Traitor in Academe

    ERIC Educational Resources Information Center

    Benton, Thomas H.

    2007-01-01

    In this article, the author reflects on his feelings as a working-class transplant into academic culture and the middle class. He draws on his feelings of alienation from the people who surround him and his observations of the cultural subordination necessary to succeed in the middle class world to explain his desire to do more to help other…

  10. Team Learning in Large Classes.

    ERIC Educational Resources Information Center

    Roueche, Suanne D., Ed.

    1984-01-01

    Information and suggestions are provided on the use of team learning in large college classes. Introductory material discusses the negative cycle of student-teacher interaction that may be provoked by large classes, and the use of permanent, heterogeneous, six- or seven-member student learning groups as the central focus of class activity as a…

  11. Multimethod latent class analysis

    PubMed Central

    Nussbeck, Fridtjof W.; Eid, Michael

    2015-01-01

    Correct and, hence, valid classifications of individuals are of high importance in the social sciences as these classifications are the basis for diagnoses and/or the assignment to a treatment. The via regia to inspect the validity of psychological ratings is the multitrait-multimethod (MTMM) approach. First, a latent variable model for the analysis of rater agreement (latent rater agreement model) will be presented that allows for the analysis of convergent validity between different measurement approaches (e.g., raters). Models of rater agreement are transferred to the level of latent variables. Second, the latent rater agreement model will be extended to a more informative MTMM latent class model. This model allows for estimating (i) the convergence of ratings, (ii) method biases in terms of differential latent distributions of raters and differential associations of categorizations within raters (specific rater bias), and (iii) the distinguishability of categories indicating if categories are satisfyingly distinct from each other. Finally, an empirical application is presented to exemplify the interpretation of the MTMM latent class model. PMID:26441714

  12. Social class and heart disease mortality among African Americans.

    PubMed

    Barnett, Elizabeth; Williams, Carol R; Moore, Latetia; Chen, Fangfei

    2002-01-01

    The purpose of the present study was to examine variation in heart disease death rates by the social class of decedents. The term, "social class" refers to a complex set of phenomena such as control over economic resources, social status, and power relative to others in society. The target population for this study was African-American adults aged 35-74 years old who resided in the United States during the years 1996-1997. As a proxy for social class, we examined 5 levels of educational attainment: 0-8 years of school completed (Social Class I), 9-11 years of school completed (Social Class II), high school graduate/12 years of school completed (Social Class III), some college completed (Social Class IV), and college degree completed (Social Class V). Older age, male gender, and lower social class were all independently associated with higher heart disease death rates. For all ages, more disadvantaged social classes had a higher risk of heart disease mortality. The highest relative risks were found for Social Classes I and II among the younger age groups. Many of the "prerequisites" for the "heart healthy lifestyle" are predicated on the benefits of a privileged social class position. For African Americans, there are the additional stressors of segregation, exclusion, and discrimination to overcome, as well as the cumulative physiological toll of lifetime resistance to various forms of racism. For many African Americans in disadvantaged social class positions, the obstacles to reducing the risk for heart disease are very difficult to overcome. PMID:12477160

  13. Luminescent macrocyclic lanthanide complexes

    DOEpatents

    Raymond, Kenneth N.; Corneillie, Todd M.; Xu, Jide

    2012-05-08

    The present invention provides a novel class of macrocyclic compounds as well as complexes formed between a metal (e.g., lanthanide) ion and the compounds of the invention. Preferred complexes exhibit high stability as well as high quantum yields of lanthanide ion luminescence in aqueous media without the need for secondary activating agents. Preferred compounds incorporate hydroxy-isophthalamide moieties within their macrocyclic structure and are characterized by surprisingly low, non-specific binding to a variety of polypeptides such as antibodies and proteins as well as high kinetic stability. These characteristics distinguish them from known, open-structured ligands.

  14. Luminescent macrocyclic lanthanide complexes

    DOEpatents

    Raymond, Kenneth N; Corneillie, Todd M; Xu, Jide

    2014-05-20

    The present invention provides a novel class of macrocyclic compounds as well as complexes formed between a metal (e.g., lanthanide) ion and the compounds of the invention. Preferred complexes exhibit high stability as well as high quantum yields of lanthanide ion luminescence in aqueous media without the need for secondary activating agents. Preferred compounds incorporate hydroxy-isophthalamide moieties within their macrocyclic structure and are characterized by surprisingly low, non-specific binding to a variety of polypeptides such as antibodies and proteins as well as high kinetic stability. These characteristics distinguish them from known, open-structured ligands.

  15. Designing an Ethics Class.

    ERIC Educational Resources Information Center

    Prager, Richard

    1993-01-01

    Describes a required ethics course designed for juniors and seniors at a small Connecticut boarding school. Students explore the ethics of care and justice, examine ethical assumptions behind the school's disciplinary system, consider a series of dilemmas, and discuss complex topics such as abortion, euthanasia, and racism. A sidebar outlines…

  16. Class IIc or Circular Bacteriocins

    NASA Astrophysics Data System (ADS)

    Martin-Visscher, Leah A.; van Belkum, Marco J.; Vederas, John C.

    The circular bacteriocins produced by Gram-positive bacteria represent a diverse class of antimicrobial peptides. These bacteriocins display enhanced stability compared to linear bacteriocins, which arises from their characteristic circular backbone. Currently, eight unique circular bacteriocins have been identified, and analysis of their gene clusters indicates that they likely utilize complex mechanisms for maturation and secretion, as well as for immunity. These bacteriocins target the cytoplasmic membrane of sensitive cells, leading to pore formation that results in loss of ions, dissipation of membrane potential, and ultimately, cell death. Structural studies suggest that despite variation in their sequences, most of these bacteriocins likely adopt a common three-dimensional architecture, consisting of four or five tightly packed helices encompassing a hydrophobic core. There are many mysteries surrounding the biosynthesis of these peptides, particularly in regard to the mechanism by which they are cyclized. Elucidation of such a mechanism may provide exciting new approaches to the bioengineering of new, stable, and antimicrobially active circular peptides.

  17. Functional classes and equivalence relations

    PubMed Central

    Sidman, Murray; Wynne, Constance K.; Maguire, Russell W.; Barnes, Thomas

    1989-01-01

    Three adult subjects were taught a set of two-choice simultaneous discriminations, with three positive and three negative stimuli; all possible combinations of positive and negative stimuli yielded nine different pairs. The discriminations were repeatedly reversed and rereversed, the former positive stimuli becoming negative and the former negative stimuli becoming positive. With all subjects, a reversal of the contingencies for one pair of stimuli became sufficient to change their responses to all of the other pairs. The reversals had produced functional stimulus classes. Then, all subjects showed conditional discriminations emerging between members of a functional class; given a sample from one class and comparisons from both classes, they selected the comparison that was in the same class as the sample. Next, 2 of the subjects showed that the within-class conditional relations possessed the symmetric and transitive properties of equivalence relations; after having been taught to relate new stimuli to existing class members, the subjects then matched other class members to the new stimuli. Subsequent tests of two-choice discriminations showed that the conditional discriminations had transferred functional class membership to the new stimuli. The 3rd subject, who did not show equivalence relations among functional class members, was also found to have lost the within-class conditional relations after the equivalence tests. PMID:16812597

  18. Class Differences in Cohabitation Processes

    PubMed Central

    Sassler, Sharon; Miller, Amanda J.

    2012-01-01

    Despite the burgeoning cohabitation literature, research has failed to examine social class variation in processes of forming and advancing such unions. Drawing upon in-depth interviews with 122 working- and middle-class cohabitors, we examine the duration between dating and moving in together, reasons for cohabiting, and subsequent plans. Transitions to cohabitation are more rapid among the working class. Respondents often cohabited for practical reasons—out of financial necessity, because it was convenient, or to meet a housing need. Regardless of social class status, few couples move in together as a “trial marriage.” Nonetheless, middle-class cohabitors were more likely to have become engaged than their working-class counterparts. Our findings indicate the need to reassess common beliefs regarding the role served by cohabitation and suggest that cohabitation has become another location where family outcomes are diverging by social class. PMID:23504506

  19. Class Differences in Cohabitation Processes.

    PubMed

    Sassler, Sharon; Miller, Amanda J

    2011-04-01

    Despite the burgeoning cohabitation literature, research has failed to examine social class variation in processes of forming and advancing such unions. Drawing upon in-depth interviews with 122 working- and middle-class cohabitors, we examine the duration between dating and moving in together, reasons for cohabiting, and subsequent plans. Transitions to cohabitation are more rapid among the working class. Respondents often cohabited for practical reasons-out of financial necessity, because it was convenient, or to meet a housing need. Regardless of social class status, few couples move in together as a "trial marriage." Nonetheless, middle-class cohabitors were more likely to have become engaged than their working-class counterparts. Our findings indicate the need to reassess common beliefs regarding the role served by cohabitation and suggest that cohabitation has become another location where family outcomes are diverging by social class.

  20. Pseudo Class III malocclusion

    PubMed Central

    Al-Hummayani, Fadia M.

    2016-01-01

    The treatment of deep anterior crossbite is technically challenging due to the difficulty of placing traditional brackets with fixed appliances. This case report represents a none traditional treatment modality to treat deep anterior crossbite in an adult pseudo class III malocclusion complicated by severely retruded, supraerupted upper and lower incisors. Treatment was carried out in 2 phases. Phase I treatment was performed by removable appliance “modified Hawley appliance with inverted labial bow,” some modifications were carried out to it to suit the presented case. Positive overbite and overjet was accomplished in one month, in this phase with minimal forces exerted on the lower incisors. Whereas, phase II treatment was performed with fixed appliances (braces) to align teeth and have proper over bite and overjet and to close posterior open bite, this phase was accomplished within 11 month. PMID:27052290

  1. Network Class Superposition Analyses

    PubMed Central

    Pearson, Carl A. B.; Zeng, Chen; Simha, Rahul

    2013-01-01

    Networks are often used to understand a whole system by modeling the interactions among its pieces. Examples include biomolecules in a cell interacting to provide some primary function, or species in an environment forming a stable community. However, these interactions are often unknown; instead, the pieces' dynamic states are known, and network structure must be inferred. Because observed function may be explained by many different networks (e.g., for the yeast cell cycle process [1]), considering dynamics beyond this primary function means picking a single network or suitable sample: measuring over all networks exhibiting the primary function is computationally infeasible. We circumvent that obstacle by calculating the network class ensemble. We represent the ensemble by a stochastic matrix , which is a transition-by-transition superposition of the system dynamics for each member of the class. We present concrete results for derived from Boolean time series dynamics on networks obeying the Strong Inhibition rule, by applying to several traditional questions about network dynamics. We show that the distribution of the number of point attractors can be accurately estimated with . We show how to generate Derrida plots based on . We show that -based Shannon entropy outperforms other methods at selecting experiments to further narrow the network structure. We also outline an experimental test of predictions based on . We motivate all of these results in terms of a popular molecular biology Boolean network model for the yeast cell cycle, but the methods and analyses we introduce are general. We conclude with open questions for , for example, application to other models, computational considerations when scaling up to larger systems, and other potential analyses. PMID:23565141

  2. Network class superposition analyses.

    PubMed

    Pearson, Carl A B; Zeng, Chen; Simha, Rahul

    2013-01-01

    Networks are often used to understand a whole system by modeling the interactions among its pieces. Examples include biomolecules in a cell interacting to provide some primary function, or species in an environment forming a stable community. However, these interactions are often unknown; instead, the pieces' dynamic states are known, and network structure must be inferred. Because observed function may be explained by many different networks (e.g., ≈ 10(30) for the yeast cell cycle process), considering dynamics beyond this primary function means picking a single network or suitable sample: measuring over all networks exhibiting the primary function is computationally infeasible. We circumvent that obstacle by calculating the network class ensemble. We represent the ensemble by a stochastic matrix T, which is a transition-by-transition superposition of the system dynamics for each member of the class. We present concrete results for T derived from boolean time series dynamics on networks obeying the Strong Inhibition rule, by applying T to several traditional questions about network dynamics. We show that the distribution of the number of point attractors can be accurately estimated with T. We show how to generate Derrida plots based on T. We show that T-based Shannon entropy outperforms other methods at selecting experiments to further narrow the network structure. We also outline an experimental test of predictions based on T. We motivate all of these results in terms of a popular molecular biology boolean network model for the yeast cell cycle, but the methods and analyses we introduce are general. We conclude with open questions for T, for example, application to other models, computational considerations when scaling up to larger systems, and other potential analyses. PMID:23565141

  3. From Atiyah Classes to Homotopy Leibniz Algebras

    NASA Astrophysics Data System (ADS)

    Chen, Zhuo; Stiénon, Mathieu; Xu, Ping

    2016-01-01

    A celebrated theorem of Kapranov states that the Atiyah class of the tangent bundle of a complex manifold X makes T X [-1] into a Lie algebra object in D + ( X), the bounded below derived category of coherent sheaves on X. Furthermore, Kapranov proved that, for a Kähler manifold X, the Dolbeault resolution {Ω^{bullet-1}(T_X^{1, 0})} of T X [-1] is an L ∞ algebra. In this paper, we prove that Kapranov's theorem holds in much wider generality for vector bundles over Lie pairs. Given a Lie pair ( L, A), i.e. a Lie algebroid L together with a Lie subalgebroid A, we define the Atiyah class α E of an A-module E as the obstruction to the existence of an A- compatible L-connection on E. We prove that the Atiyah classes α L/ A and α E respectively make L/ A[-1] and E[-1] into a Lie algebra and a Lie algebra module in the bounded below derived category {D^+(A)} , where {A} is the abelian category of left {U(A)} -modules and {U(A)} is the universal enveloping algebra of A. Moreover, we produce a homotopy Leibniz algebra and a homotopy Leibniz module stemming from the Atiyah classes of L/ A and E, and inducing the aforesaid Lie structures in {D^+(A)}.

  4. NLRC5/MHC class I transactivator is a target for immune evasion in cancer.

    PubMed

    Yoshihama, Sayuri; Roszik, Jason; Downs, Isaac; Meissner, Torsten B; Vijayan, Saptha; Chapuy, Bjoern; Sidiq, Tabasum; Shipp, Margaret A; Lizee, Gregory A; Kobayashi, Koichi S

    2016-05-24

    Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers. PMID:27162338

  5. Exploring social class: voices of inter-class couples.

    PubMed

    McDowell, Teresa; Melendez-Rhodes, Tatiana; Althusius, Erin; Hergic, Sara; Sleeman, Gillian; Ton, Nicky Kieu My; Zimpfer-Bak, A J

    2013-01-01

    Social class is not often discussed or examined in-depth in couple and family therapy research and literature even though social class shapes familial relationships and is considered an important variable in marital satisfaction. In this qualitative study, we explored the perceptions of eight couples who made lasting commitments across class lines by asking them about the impact of their social class backgrounds on their relationships. Three categories of themes emerged including: (a) differences and similarities in values and attitudes toward education, work, money, and class awareness/classism, (b) relationship issues involving families of origin, friends, and class-based couple conflict, and (c) differences in economic resources, social capital and privileges/opportunities. Implications for assessment and treatment of couples are included. PMID:25073843

  6. Intracellular Assembly and Trafficking of MHC Class I Molecules

    PubMed Central

    Donaldson, Julie G.; Williams, David B.

    2009-01-01

    The presentation of antigenic peptides by class I molecules of the major histocompatibility complex begins in the endoplasmic reticulum where the coordinated action of molecular chaperones, folding enzymes and class I-specific factors ensure that class I molecules are loaded with high affinity peptide ligands that will survive prolonged display at the cell surface. Once assembled, class I molecules are released from the quality control machinery of the ER for export to the plasma membrane where they undergo dynamic endocytic cycling and turnover. We review recent progress in our understanding of class I assembly, anterograde transport and endocytosis and highlight some of the events targeted by viruses as a means to evade detection by cytotoxic T cells and natural killer cells. PMID:19761542

  7. Spectrum of classes of point emitters of electromagnetic wave fields.

    PubMed

    Castañeda, Román

    2016-09-01

    The spectrum of classes of point emitters has been introduced as a numerical tool suitable for the design, analysis, and synthesis of non-paraxial optical fields in arbitrary states of spatial coherence. In this paper, the polarization state of planar electromagnetic wave fields is included in the spectrum of classes, thus increasing its modeling capabilities. In this context, optical processing is realized as a filtering on the spectrum of classes of point emitters, performed by the complex degree of spatial coherence and the two-point correlation of polarization, which could be implemented dynamically by using programmable optical devices. PMID:27607498

  8. Spectrum of classes of point emitters of electromagnetic wave fields.

    PubMed

    Castañeda, Román

    2016-09-01

    The spectrum of classes of point emitters has been introduced as a numerical tool suitable for the design, analysis, and synthesis of non-paraxial optical fields in arbitrary states of spatial coherence. In this paper, the polarization state of planar electromagnetic wave fields is included in the spectrum of classes, thus increasing its modeling capabilities. In this context, optical processing is realized as a filtering on the spectrum of classes of point emitters, performed by the complex degree of spatial coherence and the two-point correlation of polarization, which could be implemented dynamically by using programmable optical devices.

  9. Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

    NASA Technical Reports Server (NTRS)

    Armstrong, J. W.; Simske, S. J.; Beharka, A. A.; Balch, S.; Luttges, M. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

  10. 47 CFR 80.1053 - Prohibition on certification, manufacture, importation, sale or use of Class A, Class B, Class S...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Prohibition on certification, manufacture... certification, manufacture, importation, sale or use of Class A, Class B, Class S, and INMARSAT-E EPIRBs. The manufacture, importation, or sale in the United States of Class A, Class B, Class S, or INMARSAT-E EPIRBs...

  11. Class Matters in the Interview Setting? Positionality, Situatedness and Class

    ERIC Educational Resources Information Center

    Mellor, Jody; Ingram, Nicola; Abrahams, Jessie; Beedell, Phoebe

    2014-01-01

    In this article we argue that despite methodological and analytical advancements in the field of social class research, these developments have not led to a wholehearted discussion about class positionality and situatedness in relation to interviewer-participant dynamics. Despite--or perhaps due to--this methodological gap, there remains an…

  12. Class Counts: Education, Inequality, and the Shrinking Middle Class

    ERIC Educational Resources Information Center

    Ornstein, Allan

    2007-01-01

    Class differences and class warfare have existed since the beginning of western civilization, but the gap in income and wealth between the rich (top 10 percent) and the rest has increased steadily in the last twenty-five years. The U.S. is heading for a financial oligarchy much worse than the aristocratic old world that our Founding Fathers feared…

  13. Complexity in language acquisition.

    PubMed

    Clark, Alexander; Lappin, Shalom

    2013-01-01

    Learning theory has frequently been applied to language acquisition, but discussion has largely focused on information theoretic problems-in particular on the absence of direct negative evidence. Such arguments typically neglect the probabilistic nature of cognition and learning in general. We argue first that these arguments, and analyses based on them, suffer from a major flaw: they systematically conflate the hypothesis class and the learnable concept class. As a result, they do not allow one to draw significant conclusions about the learner. Second, we claim that the real problem for language learning is the computational complexity of constructing a hypothesis from input data. Studying this problem allows for a more direct approach to the object of study--the language acquisition device-rather than the learnable class of languages, which is epiphenomenal and possibly hard to characterize. The learnability results informed by complexity studies are much more insightful. They strongly suggest that target grammars need to be objective, in the sense that the primitive elements of these grammars are based on objectively definable properties of the language itself. These considerations support the view that language acquisition proceeds primarily through data-driven learning of some form.

  14. Search in weighted complex networks

    NASA Astrophysics Data System (ADS)

    Thadakamalla, Hari P.; Albert, R.; Kumara, S. R. T.

    2005-12-01

    We study trade-offs presented by local search algorithms in complex networks which are heterogeneous in edge weights and node degree. We show that search based on a network measure, local betweenness centrality (LBC), utilizes the heterogeneity of both node degrees and edge weights to perform the best in scale-free weighted networks. The search based on LBC is universal and performs well in a large class of complex networks.

  15. Supramolecular complexations of natural products.

    PubMed

    Schneider, Hans-Jörg; Agrawal, Pawan; Yatsimirsky, Anatoly K

    2013-08-21

    Complexations of natural products with synthetic receptors as well as the use of natural products as host compounds are reviewed, with an emphasis on possible practical uses or on biomedical significance. Applications such as separation, sensing, enzyme monitoring, and protection of natural drugs are first outlined. We then discuss examples of complexes with all important classes of natural compounds, such as amino acids, peptides, nucleosides/nucleotides, carbohydrates, catecholamines, flavonoids, terpenoids/steroids, alkaloids, antibiotics and toxins. PMID:23703643

  16. CAPEOPEN.NET CLASS LIBRARY

    EPA Science Inventory

    The Cape-Open for .Net class library is a collection of classes that implement the Cape-Open v.1.0 interfaces in the .Net framework. This is a tool to aid process modeling component (PMC) developers in producing CAPE-OPEN compliant objects using the latest version of the Visual S...

  17. Automatic discovery of optimal classes

    NASA Technical Reports Server (NTRS)

    Cheeseman, Peter; Stutz, John; Freeman, Don; Self, Matthew

    1986-01-01

    A criterion, based on Bayes' theorem, is described that defines the optimal set of classes (a classification) for a given set of examples. This criterion is transformed into an equivalent minimum message length criterion with an intuitive information interpretation. This criterion does not require that the number of classes be specified in advance, this is determined by the data. The minimum message length criterion includes the message length required to describe the classes, so there is a built in bias against adding new classes unless they lead to a reduction in the message length required to describe the data. Unfortunately, the search space of possible classifications is too large to search exhaustively, so heuristic search methods, such as simulated annealing, are applied. Tutored learning and probabilistic prediction in particular cases are an important indirect result of optimal class discovery. Extensions to the basic class induction program include the ability to combine category and real value data, hierarchical classes, independent classifications and deciding for each class which attributes are relevant.

  18. Class and SLA: Making Connections

    ERIC Educational Resources Information Center

    Block, David

    2012-01-01

    This article explores how class might be brought to the fore as an identity inscription in studies of second language learning, alongside other identity inscriptions such as gender, ethnicity and national identity, which have been the focus of rather more research. It begins by clarifying what is meant by class through a brief discussion of the…

  19. [Modified Class II tunnel preparation].

    PubMed

    Rimondini, L; Baroni, C

    1991-05-15

    Tunnel preparations for restoration of Class II carious lesions in primary molars preserve the marginal ridge and minimize sacrifice of healthy tooth substructure. Materials with improved bonding to tooth structure and increase potential for fluoride release allow Class II restorations without "extension for prevention". PMID:1864420

  20. Visions of the Special Class.

    ERIC Educational Resources Information Center

    Safford, Philip L.; Safford, Elizabeth J.

    1998-01-01

    Discusses how the advent of public school special day-classes for children with disabilities marked a major shift in the service model in the direction of educational and societal inclusion. The different visions of the classes as cluster, clinic, and clearinghouse are explained. (Author/CR)

  1. A Touch of...Class!

    ERIC Educational Resources Information Center

    Netten, Joan W., Ed.

    1984-01-01

    A collection of ideas for class activities in elementary and secondary language classes includes a vocabulary review exercise and games of memory, counting, vocabulary, flashcard tic-tac-toe, dice, trashcans, questioning, and spelling. Some are designed specifically for French. (MSE)

  2. Eustace Tilley Comes to Class

    ERIC Educational Resources Information Center

    Arin, Jennifer

    2009-01-01

    Of all the reasons to use "The New Yorker" in a college writing class, the most compelling may be that its articles go beyond--well beyond--the five-paragraph model. Why, oh why, did that paradigm become such a fixture in composition courses? Students in the author's writing classes invariably suppose they can compose a quick introduction, add…

  3. Class Differences in Cohabitation Processes

    ERIC Educational Resources Information Center

    Sassler, Sharon; Miller, Amanda J.

    2011-01-01

    Despite the burgeoning cohabitation literature, research has failed to examine social class variation in processes of forming and advancing such unions. Drawing upon in-depth interviews with 122 working- and middle-class cohabitors, we examine the duration between dating and moving in together, reasons for cohabiting, and subsequent plans.…

  4. Tucker2 Hierarchical Classes Analysis

    ERIC Educational Resources Information Center

    Ceulemans, Eva; Van Mechelen, Iven

    2004-01-01

    This paper presents a new hierarchical classes model, called Tucker2-HICLAS, for binary three-way three-mode data. As any three-way hierarchical classes model, the Tucker2-HICLAS model includes a representation of the association relation among the three modes and a hierarchical classification of the elements of each mode. A distinctive feature of…

  5. Translanguaging in a Reading Class

    ERIC Educational Resources Information Center

    Vaish, Viniti; Subhan, Aidil

    2015-01-01

    Using translanguaging as a theoretical foundation, this paper analyses findings from a Grade 2 reading class for low achieving students, where Malay was used as a scaffold to teach English. Data come from one class in one school in Singapore and its Learning Support Programme (LSP), which is part of a larger research project on biliteracy. The LSP…

  6. Student Engagement and Marketing Classes

    ERIC Educational Resources Information Center

    Taylor, Steven A.; Hunter, Gary L.; Melton, Horace; Goodwin, Stephen A.

    2011-01-01

    A study is reported that investigates the goals underlying undergraduate students' engagement in their major classes, nonmajor classes, and in extracurricular activities. The qualitative study employs both focus groups and goal-mapping exercises. The results suggest that students tend to focus on utilitarian, attribute-level considerations mainly…

  7. Complexity Survey.

    ERIC Educational Resources Information Center

    Gordon, Sandra L.; Anderson, Beth C.

    To determine whether consensus existed among teachers about the complexity of common classroom materials, a survey was administered to 66 pre-service and in-service kindergarten and prekindergarten teachers. Participants were asked to rate 14 common classroom materials as simple, complex, or super-complex. Simple materials have one obvious part,…

  8. Notes on the Comparison Class

    NASA Astrophysics Data System (ADS)

    Solt, Stephanie

    This paper investigates the role of comparison classes in the semantics of gradable adjectives in the positive form, focusing on the case where the comparison class is expressed overtly via a for-phrase (e.g. John is tall for a jockey). Two central questions are addressed: what information does the comparison class provide, and how is this information integrated compositionally? It is shown that the standard of comparison invoked by the positive form can be analyzed as a range of values whose width is based on the degree of dispersion in the comparison class. Compositionally, the comparison class can be analyzed as an argument of a null positive morpheme (contra Kennedy [13]), in parallel to recent proposals for the superlative (e.g. Heim [9]). The implications of the analysis for the choice between degree- and delineation-based analyses of gradable adjectives are discussed.

  9. Control Class Summaries and Control Class IV from April 1990

    SciTech Connect

    Wu, J.; /Fermilab

    1991-02-22

    The D0 cryogenic control system is a complicated system with many facets. Because of the large number and variety of features in the system, a series of ongoing control system training seminars, or control classes, were created in order to keep people up to date on the operation of the system. As of the writing of this engineering note, there have been four classes. The original lecture notes from each class can be found in the cryogenic control room at the D0 Assembly Building, or in the Co-op office. This note provides a summary of the first three control classes, and it includes the entire set of notes from the fourth class, which was held in April of 1990. This class was taught by Jeff Wendlandt and Dan Markley. Dan should be consulted for more complete explanations than those given in the notes. The notes are, in fact, more of a reference for someone who has some experience with the system, than they are a training manual. Most of the pages include pictures and printouts of different menus and functions, useful for finding details without searching through the actual program. In general, this note serves as a pointer to the existence of the control class lecture notes, and as an explanation of their overall contents and purpose.

  10. X-Windows Socket Widget Class

    NASA Technical Reports Server (NTRS)

    Barry, Matthew R.

    2006-01-01

    The X-Windows Socket Widget Class ("Class" is used here in the object-oriented-programming sense of the word) was devised to simplify the task of implementing network connections for graphical-user-interface (GUI) computer programs. UNIX Transmission Control Protocol/Internet Protocol (TCP/IP) socket programming libraries require many method calls to configure, operate, and destroy sockets. Most X Windows GUI programs use widget sets or toolkits to facilitate management of complex objects. The widget standards facilitate construction of toolkits and application programs. The X-Windows Socket Widget Class encapsulates UNIX TCP/IP socket-management tasks within the framework of an X Windows widget. Using the widget framework, X Windows GUI programs can treat one or more network socket instances in the same manner as that of other graphical widgets, making it easier to program sockets. Wrapping ISP socket programming libraries inside a widget framework enables a programmer to treat a network interface as though it were a GUI.

  11. A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo.

    PubMed Central

    Schlegel, P G; Aharoni, R; Chen, Y; Chen, J; Teitelbaum, D; Arnon, R; Sela, M; Chao, N J

    1996-01-01

    Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation. Images Fig. 1 Fig. 2 Fig. 4 PMID:8643529

  12. Mapping Lunar Chemistry with CLASS

    NASA Astrophysics Data System (ADS)

    Sreekumar, P.

    2012-07-01

    The Chandrayaan-2 Large Area Soft x-ray Spectrometer (CLASS) is planned to be flown on the second Indian lunar mission Chandrayaan-2. It aims to map elemental abundance on the lunar surface by measuring X-ray Fluorescence emission when solar x-rays are incident. The primary objective of CLASS is to quantitatively estimate the abundance of the major elements Mg, Al, Si, Ca, Ti and Fe on the lunar surface at a spatial resolution of 25 km. CLASS will be able to detect Mg, Al and Si signatures at this scale even during a low intensity A-class solar flare, quantify abundance from B-class flares and above, and obtain high Z elemental abundance during brighter flares (C-class and above). This instrument is a follow up to C1XS payload flown earlier on Chandrayaan-1, but with enhanced sensitivity and finer spatial resolution. CLASS will also study particle-induced x-ray emission in the lunar orbit. We will discuss the instrument configuration and developmental status.

  13. Effect of epidermal growth factor in HLA class I and class II transcription and protein expression in human breast adenocarcinoma cell lines.

    PubMed Central

    Bernard, D. J.; Courjal, F.; Maurizis, J. C.; Bignon, Y. J.; Chollet, P.; Plagne, R.

    1992-01-01

    The spontaneous expression of HLA class I and class II molecules in two human breast carcinoma cell lines (MCF7, T47D) and their modulation during epidermal growth factor treatment are reported. Transcription was analysed by Northern blot and hybridisation with HLA class II and class I cDNA specific probes. The expression of cell surface determinants was examined by internal protein labelling with 35s-methionine, immunoprecipitation with monoclonal antibodies specific for HLA class I or class II, followed by isolation of the immune complex on protein A-Sepharose; at least a quantification of glycoprotein was performed by chromatofocusing. Glycoprotein quantification showed a significant increase of HLA class I and class II (DR) antigen expression after stimulation by epidermal growth factor (0.02 microgram ml-1) in the two cell lines, when compared with untreated cell controls. However, with epidermal growth factor treatment of MCF7 and T47D cells, low increases in the amounts of HLA class I and class II RNA were obtained. These differences between expressed antigens and correspondent RNA amounts would be explained by the fact that EGF in these two cell lines acts more in post-transcription for HLA class I and class II antigens. Images Figure 1 PMID:1637682

  14. A class-chest for deriving transport protocols

    SciTech Connect

    Strayer, W.T.

    1996-10-01

    Development of new transport protocols or protocol algorithms suffers from the complexity of the environment in which they are intended to run. Modeling techniques attempt to avoid this by simulating the environment. Another approach to promoting rapid prototyping of protocols and protocol algorithms is to provide a pre-built infrastructure that is common to transport protocols, so that the focus is placed on the protocol-specific aspects. The Meta-Transport Library is a library of C++ base classes that implement or abstract out the mundane functions of a protocol, new protocol implementations are derived from base classes. The result is a fully viable user- level transport protocol implementation, with emphasis on modularity. The collection of base classes form a ``class-chest`` of tools .from which protocols can be developed and studied with as little change to a normal UNIX environment as possible.

  15. 7 CFR 1006.51 - Class I differential, adjustments to Class I prices, and Class I price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MILK IN THE FLORIDA MARKETING AREA Order Regulating Handling Class Prices § 1006.51 Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential, adjustments to Class I prices, and Class I price. 1006.51 Section 1006.51 Agriculture Regulations of the Department of...

  16. Supporting Struggling Readers in Secondary School Science Classes

    ERIC Educational Resources Information Center

    Roberts, Kelly D.; Takahashi, Kiriko; Park, Hye-Jin; Stodden, Robert A.

    2012-01-01

    Many secondary school students struggle to read complex expository text such as science textbooks. This article provides step-by-step guidance on how to foster expository reading for struggling readers in secondary school science classes. Two strategies are introduced: Text-to-Speech (TTS) Software as a reading compensatory strategy and the…

  17. HLA class II and autoimmunity: epitope selection vs differential expression.

    PubMed

    Müller-Hilke, Brigitte

    2009-01-01

    Autoimmune diseases like rheumatoid arthritis (RA), multiple sclerosis, psoriasis and insulin-dependent diabetes mellitus are subject to a complex pathogenesis controlled by multiple genes and numerous environmental factors. The strongest genetic association is with certain HLA class II haplotypes and we here summarize the evidence supporting differential expression as a mechanism supporting the autoimmune process. PMID:19118870

  18. Restructuring Heterogeneous Classes for Cognitive Development: Social Interactive Perspective.

    ERIC Educational Resources Information Center

    Ben-Ari, Rachel; Kedem-Friedrich, Peri

    2000-01-01

    Describes a study of students in grades three, four, and five that tried an educational application derived from the social constructivism view based on theories of Vygotsky and Piaget to improve cognitive development in a heterogeneous class. Path analysis showed that complex learning techniques are related to cognitive development. (Author/LRW)

  19. Legitimacy and Social Class in Catalan Language Education for Adults

    ERIC Educational Resources Information Center

    Frekko, Susan E.

    2013-01-01

    Adult students of Catalan are worthy of study because they reveal complexities underlying taken-for-granted assumptions about Catalan speakers and Castilian speakers. Far from fitting into neat bundles aligning language of origin, social class, and national orientation, the students in this study exemplify the breakdown of boundaries traditionally…

  20. Blocking MHC class II on human endothelium mitigates acute rejection

    PubMed Central

    Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G.; Bothwell, Alfred L.M.; Tellides, George; Saltzman, W. Mark; Pober, Jordan S.

    2016-01-01

    Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell–mediated destruction in vivo. We conclude that human CD8+ TEM–mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules. PMID:26900601

  1. Consumer Education in Any Class

    ERIC Educational Resources Information Center

    Wingo, Rosetta F.

    1977-01-01

    Examples are offered of how the classroom teacher can blend consumer education into typewriting, business English, business math, and other classes by intentionally focusing on principles and concepts or by including it incidentally when the opportunity arises. (TA)

  2. Integrals of the Ising Class

    SciTech Connect

    Bailey, David H.; Borwein, Jonathan M.; Crandall, Richard E.

    2006-06-01

    From an experimental-mathematical perspective we analyze"Ising-class" integrals. Our experimental results involvedextreme-precision, multidimensional quadrature on intricate integrands;thus, highly parallel computation was required.

  3. Wildflower Collecting: A Class Project

    ERIC Educational Resources Information Center

    Moore, Sheila V.

    1976-01-01

    Advocates wildflower collecting as a class project, citing instances of interest in studies of soil composition, growing wildflowers, and increased student motivation toward the subject of botany as basis for the activity. (CP)

  4. Class Sizes and Dissadvantaged Schools.

    ERIC Educational Resources Information Center

    Warner, David

    1978-01-01

    Describes a program in which smaller class groups for socially and culturally deprived children resulted in enhanced social attitudes and more responsive, mature behavior in interaction with both adults and peers. (Author/IRT)

  5. Statistical Descriptors of School Classes

    ERIC Educational Resources Information Center

    Lohnes, Paul R.

    1972-01-01

    It may be useful in evaluation research to employ the class as the unit of analysis, assessing its syntality by a vector of distribution cumulants or indices for each of several input tests administered. (Author)

  6. Whole Class Laboratories: More Examples

    NASA Astrophysics Data System (ADS)

    Kouh, Minjoon

    2016-03-01

    Typically, introductory physics courses are taught with a combination of lectures and laboratories in which students have opportunities to discover the natural laws through hands-on activities in small groups. This article reports the use of Google Drive, a free online document-sharing tool, in physics laboratories for pooling experimental data from the whole class. This pedagogical method was reported earlier, and the present article offers a few more examples of such "whole class" laboratories.

  7. Less than a Class Set

    ERIC Educational Resources Information Center

    Bennett, Kristin Redington

    2012-01-01

    The iPad holds amazing potential for classroom use. Just a few--or even only one--is enough to get results. Having a class set promotes traditional, whole-class instruction, but fewer iPads facilitate individualized and tailored instruction. In this article, the author discusses the potential of the iPad and suggests ways to put the iPad to use in…

  8. Two classes of speculative peaks

    NASA Astrophysics Data System (ADS)

    Roehner, Bertrand M.

    2001-10-01

    Speculation not only occurs in financial markets but also in numerous other markets, e.g. commodities, real estate, collectibles, and so on. Such speculative movements result in price peaks which share many common characteristics: same order of magnitude of duration with respect to amplitude, same shape (the so-called sharp-peak pattern). Such similarities suggest (at least as a first approximation) a common speculative behavior. However, a closer examination shows that in fact there are (at least) two distinct classes of speculative peaks. For the first, referred to as class U, (i) the amplitude of the peak is negatively correlated with the price at the start of the peak (ii) the ensemble coefficient of variation exhibits a trough. Opposite results are observed for the second class that we refer to as class S. Once these empirical observations have been made we try to understand how they should be interpreted. First, we show that the two properties are in fact related in the sense that the second is a consequence of the first. Secondly, by listing a number of cases belonging to each class we observe that the markets in the S-class offer collection of items from which investors can select those they prefer. On the contrary, U-markets consist of undifferentiated products for which a selection cannot be made in the same way. All prices considered in the paper are real (i.e., deflated) prices.

  9. School Class Size: Research and Policy

    ERIC Educational Resources Information Center

    Glass, Gene V.; And Others

    This book synthesizes research evidence to demonstrate that 1) class size is strongly related to pupil achievement; 2) smaller classes are more conducive to improved pupil performance than larger classes; 3) smaller classes provide more opportunities to adapt learning programs to individual needs; 4) pupils in smaller classes have more interest in…

  10. Complex derivatives

    NASA Astrophysics Data System (ADS)

    Battiston, Stefano; Caldarelli, Guido; Georg, Co-Pierre; May, Robert; Stiglitz, Joseph

    2013-03-01

    The intrinsic complexity of the financial derivatives market has emerged as both an incentive to engage in it, and a key source of its inherent instability. Regulators now faced with the challenge of taming this beast may find inspiration in the budding science of complex systems.

  11. Designing Complexity

    ERIC Educational Resources Information Center

    Glanville, Ranulph

    2007-01-01

    This article considers the nature of complexity and design, as well as relationships between the two, and suggests that design may have much potential as an approach to improving human performance in situations seen as complex. It is developed against two backgrounds. The first is a world view that derives from second order cybernetics and radical…

  12. Persistence to antihypertensive drug classes

    PubMed Central

    Qvarnström, Miriam; Kahan, Thomas; Kieler, Helle; Brandt, Lena; Hasselström, Jan; Boström, Kristina Bengtsson; Manhem, Karin; Hjerpe, Per; Wettermark, Björn

    2016-01-01

    Abstract The aim was to study persistence to, and switching between, antihypertensive drug classes and to determine factors associated with poor persistence. This was an observational cohort study. The Swedish Primary Care Cardiovascular Database includes data from medical records, socioeconomic data, filled prescriptions, and hospitalizations from national registries for 75,000 patients with hypertension. Patients included in the study were initiated on antihypertensive drug treatment in primary healthcare in 2006 to 2007. We defined class persistence as the proportion remaining on the initial drug class, including 30 days of gap. Patients with a filled prescription of another antihypertensive drug class after discontinuation of the initial drug, including 30 days of gap, were classified as switchers. Persistence to the various drug classes were compared with that for diuretics. We identified 4997 patients (mean age 60 ± 12 years in men and 63 ± 13 years in women). Out of these, 95 (2%) filled their first prescription for fixed combination therapy and 4902 (98%) for monotherapy, including angiotensin converting enzyme inhibitors (37%), angiotensin receptor blockers (4%), beta blockers (21%), calcium channel blockers (8%), and diuretics (28%). Persistence to the initial drug class was 57% after 1 year and 43% after 2 years. There were no differences in persistence between diuretics and any of the other antihypertensive drug classes, after adjustment for confounders. Discontinuation (all adjusted) was more common in men (P = 0.004), younger patients (P < 0.001), those with mild systolic blood pressure elevation (P < 0.001), and patients born outside the Nordic countries (P < 0.001). Among 1295 patients who switched drug class after their first prescription, only 21% had a blood pressure recorded before the switch occurred; and out them 69% still had high blood pressures. In conclusion, there appears to be no difference in drug class

  13. Association between hepatitis B virus and MHC class I polypeptide-related chain A in human hepatocytes derived from human-mouse chimeric mouse liver.

    PubMed

    Sasaki, Reina; Kanda, Tatsuo; Wu, Shuang; Nakamoto, Shingo; Haga, Yuki; Jiang, Xia; Nakamura, Masato; Shirasawa, Hiroshi; Yokosuka, Osamu

    2015-09-01

    Due to the lack of efficient hepatitis B virus (HBV) infection systems, progress in understanding the role of innate immunity in HBV infection has remained challenging. Here we used human hepatocytes from a humanized severe combined immunodeficiency albumin promoter/enhancer driven-urokinase-type plasminogen activator mouse model for HBV infection. HBV DNA levels in culture medium from these human hepatocytes were 4.8-5.7 log IU/mL between day 16 and day 66 post-infection by HBV genotype C inoculum. HBV surface antigen (HBsAg) was also detected by chemiluminescent immunoassay from day 7 to day 66 post-infection. Western blot analysis revealed that major histocompatibility complex class I-related chain A (MICA), which plays a role in the innate immune system, was induced in HBV-infected human hepatocytes 27 days after infection compared with the uninfected control. MICA was reduced at day 62 and undetectable at day 90. Of interest, MICA expression by human hepatocytes increased after HBV infection and decreased before HBsAg loss. Human hepatocytes derived from chimeric mice with hepatocyte-humanized liver could support HBV genome replication. Further studies of the association between HBV replication and MICA induction should be conducted.

  14. Complexity in Dynamical Systems

    NASA Astrophysics Data System (ADS)

    Moore, Cristopher David

    The study of chaos has shown us that deterministic systems can have a kind of unpredictability, based on a limited knowledge of their initial conditions; after a finite time, the motion appears essentially random. This observation has inspired a general interest in the subject of unpredictability, and more generally, complexity; how can we characterize how "complex" a dynamical system is?. In this thesis, we attempt to answer this question with a paradigm of complexity that comes from computer science, we extract sets of symbol sequences, or languages, from a dynamical system using standard methods of symbolic dynamics; we then ask what kinds of grammars or automata are needed a generate these languages. This places them in the Chomsky heirarchy, which in turn tells us something about how subtle and complex the dynamical system's behavior is. This gives us insight into the question of unpredictability, since these automata can also be thought of as computers attempting to predict the system. In the culmination of the thesis, we find a class of smooth, two-dimensional maps which are equivalent to the highest class in the Chomsky heirarchy, the turning machine; they are capable of universal computation. Therefore, these systems possess a kind of unpredictability qualitatively different from the usual "chaos": even if the initial conditions are known exactly, questions about the system's long-term dynamics are undecidable. No algorithm exists to answer them. Although this kind of unpredictability has been discussed in the context of distributed, many-degree-of -freedom systems (for instance, cellular automata) we believe this is the first example of such phenomena in a smooth, finite-degree-of-freedom system.

  15. Carney Complex

    MedlinePlus

    ... Screening guidelines may change over time as new technologies are developed and more is learned about Carney complex. It is important to talk with your doctor about appropriate screening tests. Learn more about what to expect when having ...

  16. A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization

    PubMed Central

    Goldstein, Leonard D.; Howarth, Mark; Cardelli, Luca; Emmott, Stephen; Elliott, Tim; Werner, Joern M.

    2011-01-01

    Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human

  17. Annelid L-Ornithine Carbamoyltransferase: A Class Project Using Substrate Analogues.

    ERIC Educational Resources Information Center

    Teal, A. R.; Alcock, R. S.

    1980-01-01

    Describes a biochemistry class project which allows students to investigate independently the separate aspects of a common complex problem. The basic experimental procedure is detailed for obtaining information about the structure and geometry of L-ornithine carbamoyltransferase. (CS)

  18. Limits to Open Class Performance?

    NASA Technical Reports Server (NTRS)

    Bowers, Albion H.

    2008-01-01

    This presentation discusses open or unlimited class aircraft performance limitations and design solutions. Limitations in this class of aircraft include slow climbing flight which requires low wing loading, high cruise speed which requires high wing loading, gains in induced or viscous drag alone which result in only half the gain overall and other structural problems (yaw inertia and spins, flutter and static loads integrity). Design solutions include introducing minimum induced drag for a given span (elliptical span load or winglets) and introducing minimum induced drag for a bell shaped span load. It is concluded that open class performance limits (under current rules and technologies) is very close to absolute limits, though some gains remain to be made from unexplored areas and new technologies.

  19. Universality class in conformal inflation

    SciTech Connect

    Kallosh, Renata; Linde, Andrei E-mail: alinde@stanford.edu

    2013-07-01

    We develop a new class of chaotic inflation models with spontaneously broken conformal invariance. Observational consequences of a broad class of such models are stable with respect to strong deformations of the scalar potential. This universality is a critical phenomenon near the point of enhanced symmetry, SO(1,1), in case of conformal inflation. It appears because of the exponential stretching of the moduli space and the resulting exponential flattening of scalar potentials upon switching from the Jordan frame to the Einstein frame in this class of models. This result resembles stretching and flattening of inhomogeneities during inflationary expansion. It has a simple interpretation in terms of velocity versus rapidity near the Kähler cone in the moduli space, similar to the light cone of special theory of relativity. This effect makes inflation possible even in the models with very steep potentials. We describe conformal and superconformal versions of this cosmological attractor mechanism.

  20. On the equivalence of a class of inverse decomposition algorithms for solving systems of linear equations

    NASA Technical Reports Server (NTRS)

    Tsao, Nai-Kuan

    1989-01-01

    A class of direct inverse decomposition algorithms for solving systems of linear equations is presented. Their behavior in the presence of round-off errors is analyzed. It is shown that under some mild restrictions on their implementation, the class of direct inverse decomposition algorithms presented are equivalent in terms of the error complexity measures.