Structure of a Pheromone Receptor-Associated Mhc Molecule With An Open And Empty Groove

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Olson, R.; Huey-Tubman, K.E.; Dulac, C.; Bjorkman, P.J.; /Caltech /Harvard U.

2006-10-06

Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

Structure of a pheromone receptor-associated MHC molecule with an open and empty groove.

Directory of Open Access Journals (Sweden)

2005-08-01

Full Text Available Neurons in the murine vomeronasal organ (VNO express a family of class Ib major histocompatibility complex (MHC proteins (M10s that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

Functional recombinant MHC class II molecules and high-throughput peptide-binding assays

DEFF Research Database (Denmark)

Justesen, Sune; Harndahl, Mikkel; Lamberth, Kasper

2009-01-01

BACKGROUND: Molecules of the class II major histocompability complex (MHC-II) specifically bind and present exogenously derived peptide epitopes to CD4+ T helper cells. The extreme polymorphism of the MHC-II hampers the complete analysis of peptide binding. It is also a significant hurdle......-II molecules and accompanying HTS peptide-binding assay were successfully developed for nine different MHC-II molecules including the DPA1*0103/DPB1*0401 (DP401) and DQA1*0501/DQB1*0201, where both alpha and beta chains are polymorphic, illustrating the advantages of producing the two chains separately....... CONCLUSION: We have successfully developed versatile MHC-II resources, which may assist in the generation of MHC class II -wide reagents, data, and tools....

MHCcluster, a method for functional clustering of MHC molecules

DEFF Research Database (Denmark)

Thomsen, Martin Christen Frølund; Lundegaard, Claus; Buus, Søren

2013-01-01

The identification of peptides binding to major histocompatibility complexes (MHC) is a critical step in the understanding of T cell immune responses. The human MHC genomic region (HLA) is extremely polymorphic comprising several thousand alleles, many encoding a distinct molecule. The potentially...... binding specificity. The method has a flexible web interface that allows the user to include any MHC of interest in the analysis. The output consists of a static heat map and graphical tree-based visualizations of the functional relationship between MHC variants and a dynamic TreeViewer interface where...

MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus.

Science.gov (United States)

Xie, Xuefang; Stadnisky, Michael D; Brown, Michael G

2009-06-01

Essential NK cell-mediated murine CMV (MCMV) resistance is under histocompatibility-2(k) (H-2(k)) control in MA/My mice. We generated a panel of intra-H2(k) recombinant strains from congenic C57L.M-H2(k/b) (MCMV resistant) mice for precise genetic mapping of the critical interval. Recombination breakpoint sites were precisely mapped and MCMV resistance/susceptibility traits were determined for each of the new lines to identify the MHC locus. Strains C57L.M-H2(k)(R7) (MCMV resistant) and C57L.M-H2(k)(R2) (MCMV susceptible) are especially informative; we found that allelic variation in a 0.3-megabase interval in the class I D locus confers substantial difference in MCMV control phenotypes. When NK cell subsets responding to MCMV were examined, we found that Ly49G2(+) NK cells rapidly expand and selectively acquire an enhanced capacity for cytolytic functions only in C57L.M-H2(k)(R7). We further show that depletion of Ly49G2(+) NK cells before infection abrogated MCMV resistance in C57L.M-H2(k)(R7). We conclude that the MHC class I D locus prompts expansion and activation of Ly49G2(+) NK cells that are needed in H-2(k) MCMV resistance.

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

DEFF Research Database (Denmark)

Pedersen, Lasse Eggers; Harndahl, Mikkel; Rasmussen, Michael

2011-01-01

a HLA-I molecule (HLA-A*11:01), thereby generating recombinant human/swine chimeric MHC-I molecules as well as the intact SLA-1*0401 molecule. Biochemical peptide-binding assays and positional scanning combinatorial peptide libraries were used to analyze the peptide-binding motifs of these molecules....... A pan-specific predictor of peptide–MHC-I binding, NetMHCpan, which was originally developed to cover the binding specificities of all known HLA-I molecules, was successfully used to predict the specificities of the SLA-1*0401 molecule as well as the porcine/human chimeric MHC-I molecules. These data......In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules. These are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating CTLs. The polymorphism of the MHC...

Generation of murine tumor cell lines deficient in MHC molecule surface expression using the CRISPR/Cas9 system.

Directory of Open Access Journals (Sweden)

Krishna Das

Full Text Available In this study, the CRISPR/Cas9 technology was used to establish murine tumor cell lines, devoid of MHC I or MHC II surface expression, respectively. The melanoma cell line B16F10 and the murine breast cancer cell line EO-771, the latter stably expressing the tumor antigen NY-BR-1 (EO-NY, were transfected with an expression plasmid encoding a β2m-specific single guide (sgRNA and Cas9. The resulting MHC I negative cells were sorted by flow cytometry to obtain single cell clones, and loss of susceptibility of peptide pulsed MHC I negative clones to peptide-specific CTL recognition was determined by IFNγ ELISpot assay. The β2m knockout (KO clones did not give rise to tumors in syngeneic mice (C57BL/6N, unless NK cells were depleted, suggesting that outgrowth of the β2m KO cell lines was controlled by NK cells. Using sgRNAs targeting the β-chain encoding locus of the IAb molecule we also generated several B16F10 MHC II KO clones. Peptide loaded B16F10 MHC II KO cells were insusceptible to recognition by OT-II cells and tumor growth was unaltered compared to parental B16F10 cells. Thus, in our hands the CRISPR/Cas9 system has proven to be an efficient straight forward strategy for the generation of MHC knockout cell lines. Such cell lines could serve as parental cells for co-transfection of compatible HLA alleles together with human tumor antigens of interest, thereby facilitating the generation of HLA matched transplantable tumor models, e.g. in HLAtg mouse strains of the newer generation, lacking cell surface expression of endogenous H2 molecules. In addition, our tumor cell lines established might offer a useful tool to investigate tumor reactive T cell responses that function independently from MHC molecule surface expression by the tumor.

Primordial linkage of β2-microglobulin to the MHC.

Science.gov (United States)

Ohta, Yuko; Shiina, Takashi; Lohr, Rebecca L; Hosomichi, Kazuyoshi; Pollin, Toni I; Heist, Edward J; Suzuki, Shingo; Inoko, Hidetoshi; Flajnik, Martin F

2011-03-15

β2-Microglobulin (β2M) is believed to have arisen in a basal jawed vertebrate (gnathostome) and is the essential L chain that associates with most MHC class I molecules. It contains a distinctive molecular structure called a constant-1 Ig superfamily domain, which is shared with other adaptive immune molecules including MHC class I and class II. Despite its structural similarity to class I and class II and its conserved function, β2M is encoded outside the MHC in all examined species from bony fish to mammals, but it is assumed to have translocated from its original location within the MHC early in gnathostome evolution. We screened a nurse shark bacterial artificial chromosome library and isolated clones containing β2M genes. A gene present in the MHC of all other vertebrates (ring3) was found in the bacterial artificial chromosome clone, and the close linkage of ring3 and β2M to MHC class I and class II genes was determined by single-strand conformational polymorphism and allele-specific PCR. This study satisfies the long-held conjecture that β2M was linked to the primordial MHC (Ur MHC); furthermore, the apparent stability of the shark genome may yield other genes predicted to have had a primordial association with the MHC specifically and with immunity in general.

The Ia.2 Epitope Defines a Subset of Lipid Raft Resident MHC Class II Molecules Crucial to Effective Antigen Presentation1

Science.gov (United States)

Busman-Sahay, Kathleen; Sargent, Elizabeth; Harton, Jonathan A.; Drake, James R.

2016-01-01

Previous work has established that binding of the 11-5.2 anti-I-Ak mAb, which recognizes the Ia.2 epitope on I-Ak class II molecules, elicits MHC class II signaling, whereas binding of two other anti-I-Ak mAb that recognize the Ia.17 epitope fail to elicit signaling. Using a biochemical approach, we establish that the Ia.2 epitope recognized by the widely used 11-5.2 mAb defines a subset of cell surface I-Ak molecules predominantly found within membrane lipid rafts. Functional studies demonstrate that the Ia.2 bearing subset of I-Ak class II molecules is critically necessary for effective B cell–T cell interactions especially at low antigen doses, a finding consistent with published studies on the role of raft-resident class II molecules in CD4 T cell activation. Interestingly, B cells expressing recombinant I-Ak class II molecules possessing a β chain-tethered HEL peptide lack the Ia.2 epitope and fail to partition into lipid rafts. Moreover, cells expressing Ia.2 negative tethered peptide-class II molecules are severely impaired in their ability to present both tethered peptide or peptide derived from exogenous antigen to CD4 T cells. These results establish the Ia.2 epitope as defining a lipid raft-resident MHC class II confomer vital to the initiation of MHC class II restricted B cell–T cell interactions. PMID:21543648

Peptide-binding motif prediction by using phage display library for SasaUBA*0301, a resistance haplotype of MHC class I molecule from Atlantic Salmon (Salmo salar)

DEFF Research Database (Denmark)

Zhao, Heng; Hermsen, Trudi; Stet, Rene J M

2008-01-01

The structure of the peptide-binding specificity of major histocompatibility complex (MHC) class I has been analyzed extensively in human and mouse. For fish, there are no crystallographic models of MHC molecules, neither are there data on the peptide-binding specificity. In this study, we descri...... and there is a significant association between MHC polymorphism and the disease resistance. Therefore, our study might contribute to designing a peptide vaccine against this viral disease....... class I molecule might have a very similar binding motif at the C-terminus compared with a known mouse class I molecule H2-Kb which has L, or I, V, M at p8. Previous work showed that Atlantic Salmon carrying the allele SasaUBA*0301 are resistant to infectious Salmon aneamia virus...

MHC motif viewer

DEFF Research Database (Denmark)

Rapin, Nicolas Philippe Jean-Pierre; Hoof, Ilka; Lund, Ole

2008-01-01

. Algorithms that predict which peptides MHC molecules bind have recently been developed and cover many different alleles, but the utility of these algorithms is hampered by the lack of tools for browsing and comparing the specificity of these molecules. We have, therefore, developed a web server, MHC motif....... A special viewing feature, MHC fight, allows for display of the specificity of two different MHC molecules side by side. We show how the web server can be used to discover and display surprising similarities as well as differences between MHC molecules within and between different species. The MHC motif...

Structural and Functional Characterization of a Single-chain Peptide-MHC Molecule that Modulates both Naive and Activated CD8plus T Cells

Energy Technology Data Exchange (ETDEWEB)

D Samanta; G Mukherjee; U Ramagopal; R Chaparro; S Nathenson; T DiLorenzo; S Almo

2011-12-31

Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8{sup +} T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8{sup +} T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK{sup d}.IGRP) by using the class I MHC molecule H-2K{sup d} and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP{sub 206-214}), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK{sup d}.IGRP tetramers bound specifically to cognate CD8{sup +} T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-{gamma} response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8{sup +} T cells makes them a potential intervention strategy in early and late stages of disease.

Quantum chemical analysis explains hemagglutinin peptide-MHC Class II molecule HLA-DRβ1*0101 interactions

International Nuclear Information System (INIS)

Cardenas, Constanza; Villaveces, Jose Luis; Bohorquez, Hugo; Llanos, Eugenio; Suarez, Carlos; Obregon, Mateo; Patarroyo, Manuel Elkin

2004-01-01

We present a new method to explore interactions between peptides and major histocompatibility complex (MHC) molecules using the resultant vector of the three principal multipole terms of the electrostatic field expansion. Being that molecular interactions are driven by electrostatic interactions, we applied quantum chemistry methods to better understand variations in the electrostatic field of the MHC Class II HLA-DRβ1*0101-HA complex. Multipole terms were studied, finding strong alterations of the field in Pocket 1 of this MHC molecule, and weak variations in other pockets, with Pocket 1 >> Pocket 4 > Pocket 9 ∼ Pocket 7 > Pocket 6. Variations produced by 'ideal' amino acids and by other occupying amino acids were compared. Two types of interactions were found in all pockets: a strong unspecific one (global interaction) and a weak specific interaction (differential interaction). Interactions in Pocket 1, the dominant pocket for this allele, are driven mainly by the quadrupole term, confirming the idea that aromatic rings are important in these interactions. Multipolar analysis is in agreement with experimental results, suggesting quantum chemistry methods as an adequate methodology to understand these interactions

Uncovering the Peptide-Binding Specificities of HLA-C: A General Strategy To Determine the Specificity of Any MHC Class I Molecule

DEFF Research Database (Denmark)

Rasmussen, Michael; Harndahl, Mikkel; Stryhn, Anette

2014-01-01

MHC class I molecules (HLA-I in humans) present peptides derived from endogenous proteins to CTLs. Whereas the peptide-binding specificities of HLA-A and -B molecules have been studied extensively, little is known about HLA-C specificities. Combining a positional scanning combinatorial peptide...... library approach with a peptide-HLA-I dissociation assay, in this study we present a general strategy to determine the peptide-binding specificity of any MHC class I molecule. We applied this novel strategy to 17 of the most common HLA-C molecules, and for 16 of these we successfully generated matrices...... representing their peptide-binding motifs. The motifs prominently shared a conserved C-terminal primary anchor with hydrophobic amino acid residues, as well as one or more diverse primary and auxiliary anchors at P1, P2, P3, and/or P7. Matrices were used to generate a large panel of HLA-C-specific peptide...

MHC-like molecules in some nonmammalian vertebrates can be detected by some cross-reactive xenoantisera

DEFF Research Database (Denmark)

Kaufman, J; Skjoedt, K; Salomonsen, J

1990-01-01

in the contact regions between the chains. These latter antibodies recognized biosynthetic intermediates and also a variety of unusual cell surface MHC-like molecules present in reptile and amphibian, but absent in the mammal and chicken cells tested. These included E homodimers whose relationship to chicken B......-G molecules is unknown. 5) MHC-like molecules were identified in a bird, three reptiles, and two amphibians, but no molecules with the expected properties were found with these reagents in any of the fish tested. Udgivelsesdato: 1990-Mar-15...

NK Cell Receptor/H2-Dk–Dependent Host Resistance to Viral Infection Is Quantitatively Modulated by H2 q Inhibitory Signals

Science.gov (United States)

Fodil-Cornu, Nassima; Loredo-Osti, J. Concepción; Vidal, Silvia M.

2011-01-01

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2k, we generated double congenic mice between MA/My and BALB.K mice and an F2 cross between FVB/N (H-2q) and BALB.K (H2k) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2k in conjunction with Cmv3MA/My or Cmv3FVB were resistant to MCMV infection. Subsequently, an F3 cross was carried out between transgenic FVB/H2-Dk and MHC-I deficient mice in which only the progeny expressing Cmv3FVB and a single H2-Dk class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell–dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2q alleles influence the expression level of H2q molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2q alleles. Our results support a model in which H-2q molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-Dk on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell–mediated control of viral load. PMID:21533075

pH dependence of the interaction between immunogenic peptides and MHC class II molecules. Evidence for an acidic intracellular compartment being the organelle of interaction

DEFF Research Database (Denmark)

Mouritsen, S; Buus, Anette Stryhn; Petersen, B L

1992-01-01

and most notably in the endosome-lysosome compartment in which Ag processing is thought to occur. Thus, Ag processing and interaction with MHC class II molecules can potentially happen in the very same compartment. This yet undefined acidic compartment would have to contain proteolytic enzymes and MHC...

NK cell receptor/H2-Dk-dependent host resistance to viral infection is quantitatively modulated by H2q inhibitory signals.

Science.gov (United States)

Fodil-Cornu, Nassima; Loredo-Osti, J Concepción; Vidal, Silvia M

2011-04-01

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2(k), we generated double congenic mice between MA/My and BALB.K mice and an F(2) cross between FVB/N (H-2(q)) and BALB.K (H2(k)) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2(k) in conjunction with Cmv3(MA/My) or Cmv3(FVB) were resistant to MCMV infection. Subsequently, an F(3) cross was carried out between transgenic FVB/H2-D(k) and MHC-I deficient mice in which only the progeny expressing Cmv3(FVB) and a single H2-D(k) class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell-dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2(q) alleles influence the expression level of H2(q) molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2(q) alleles. Our results support a model in which H-2(q) molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-D(k) on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell-mediated control of viral load.

ZAP-70 and p72syk are signaling response elements through MHC class II molecules

DEFF Research Database (Denmark)

Kanner, S B; Grosmaire, L S; Blake, J

1995-01-01

Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization...... of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA...... by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family...

MHC class II molecules and tumour immunotherapy

International Nuclear Information System (INIS)

Oven, I.

2005-01-01

Background. Tumour immunotherapy attempts to use the specificity and capability of the immune system to kill malignant cells with a minimum damage to normal tissue. Increasing knowledge of the identity of tumour antigens should help us design more effective therapeutic vaccines. Increasing evidence has demonstrated that MHC class II molecules and CD4+ T cells play important roles in generating and maintaining antitumour immune responses in animal models. These data suggest that it may be necessary to involve both CD4+ and CD8+ T cells for more effective antitumour therapy. Novel strategies have been developed for enhancing T cell responses against cancer by prolonging antigen presentation of dendritic cells to T cells, by the inclusion of MHC class II-restricted tumour antigens and by genetically modifying tumour cells to present antigen to T lymphocytes directly. Conclusions. Vaccines against cancers aim to induce tumour-specific effector T cells that can reduce tumour mass and induce development of tumour-specific T cell memory, that can control tumour relapse. (author)

The role of MHC haplotypes H2d/H2b in mouse resistance/susceptibility to cyst formation is influenced by the lineage of infective Toxoplasma gondii strain

Directory of Open Access Journals (Sweden)

Marianne G. Resende

2008-03-01

Full Text Available Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, weobserved that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii.Cepas de Toxoplasma gondii que apresentam o genótipo I/III são associadas a toxoplasmose ocular adquirida em humanos. No presente trabalho, nós utilizamos um modelo da doença em camundongos para caracterizar mecanismos imunológicos envolvidos na resistência do hospedeiro à infecção por aquelas cepas. Escolhemos as cepas D8, G2 e P-Br, que causam infecção crônica em camundongos, semelhante à toxoplasmose humana. Camundongos deficientes em MyD88, IFN-G e IL-12 foram susceptíveis a infecções com todas as três linhagens do parasita. Esses dados indicam a importância de mecanismos

Tests to determine the release of short-lived fission products from UO2 fuel operating at linear powers of 45 and 60 kW/m

International Nuclear Information System (INIS)

Hastings, I.J.; Hunt, C.E.L.; Lipsett, J.J.; MacDonald, R.D.

1985-09-01

Experiments have been carried out using a 'sweep gas' technique to determine the behaviour of short-lived fission products within operating, intact UO 2 fuel elements. The Zircaloy-4-clad elements were 600 mm long and contained fuel of density 10.65 - 10.71 Mg/m 3 . A He-2% H 2 carrier gas swept gaseous or volatile fission products out of the operating fuel element past a gamma spectrometer for measurement. We outline our loop model and give full details of calculational procedures. In tests at linear powers of 45 (FIO-122) and 60 kW/m (FIO-124) to a maximum burnup of 80 MW.h/kg U, the species measured directly at the spectrometer during normal operation were generally the short-lived xenons and kryptons. Iodines were not observed during normal operation. The behaviour of I-133 and I-135 was deduced from the decay of Xe-133 and Xe-135 during reactor shutdowns. Plots of R/B (released/born) against λ (decay constant) or effective λ for all isotopes observed at 45 and 60 kW/m show that a line of slope -0.5, corresponding with diffusion kinetics, is a good fit to the measured xenon and krypton data. The inferred release of iodine fits the same line. From this we can extrapolate to an R/B for I-131 of about 5 x 10 -4 at 45 kW/m, and 3 x 10 -3 at 60 kW/m. Both tests were terminated by defects. Under defect conditions, R/B dependence on λ was about 0.6. I-131 release under defect conditions was 5 Ci and 60 mCi for FIO-122 and FI0-124, respectively. 22 refs

Purification of correctly oxidized MHC class I heavy-chain molecules under denaturing conditions: a novel strategy exploiting disulfide assisted protein folding

DEFF Research Database (Denmark)

Ferré, Henrik; Ruffet, Emmanuel; Blicher, Thomas

2003-01-01

The aim of this study has been to develop a strategy for purifying correctly oxidized denatured major histocompability complex class I (MHC-I) heavy-chain molecules, which on dilution, fold efficiently and become functional. Expression of heavy-chain molecules in bacteria results in the formation...... of insoluble cellular inclusion bodies, which must be solubilized under denaturing conditions. Their subsequent purification and refolding is complicated by the fact that (1). correct folding can only take place in combined presence of beta(2)-microglobulin and a binding peptide; and (2). optimal in vitro...... conditions for disulfide bond formation ( approximately pH 8) and peptide binding ( approximately pH 6.6) are far from complementary. Here we present a two-step strategy, which relies on uncoupling the events of disulfide bond formation and peptide binding. In the first phase, heavy-chain molecules...

Purification of correctly oxidized MHC class I heavy-chain molecules under denaturing conditions: A novel strategy exploiting disulfide assisted protein folding

DEFF Research Database (Denmark)

Ferré, Henrik; Ruffet, E.; Blicher, T.

2003-01-01

The aim of this study has been to develop a strategy for purifying correctly oxidized denatured major histocompability complex class I (MHC-I) heavy-chain molecules, which on dilution, fold efficiently and become functional. Expression of heavy-chain molecules in bacteria results in the formation...... of insoluble cellular inclusion bodies, which must be solubilized under denaturing conditions. Their subsequent purification and refolding is complicated by the fact that (1) correct folding can only take place in combined presence of beta(2)-microglobulin and a binding peptide; and (2) optimal in vitro...... conditions for disulfide bond formation (similar topH 8) and peptide binding (similar topH 6.6) are far from complementary. Here we present a two-step strategy, which relies on uncoupling the events of disulfide bond formation and peptide binding. In the first phase, heavy-chain molecules with correct...

Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice

International Nuclear Information System (INIS)

Bix, M.; Nanshih Liao; Raulet, D.; Zijlstra, M.; Loring, J.; Jaenisch, R.

1991-01-01

Irradiated MHC-heterozygous mice often reject bone marrow cells transplanted from one of the homozygous parental strains, a phenomenon ('hybrid resistance') that appears to violate the laws of transplantation. Rejection of parental and allogeneic marrow cells also differs from conventional T cell-mediated rejection mechanisms as it is effected by NK1.1 + cells. To account for the unusual specificity of bone marrow rejection, it has been proposed that NK1.1 + cells destroy marrow cells that fail to express the full complement of self MHC class I (MHC-I) molecules. We show here that NK1.1 + cells in normal mice reject haemopoietic transplants from mice that are deficient for normal cell-surface MHC-I expression because of a targeted mutation in the β 2 -microglobulin gene. These findings demonstrate that deficient expression of MHC-I molecules renders marrow cells susceptible to rejection. (author)

Expression and characterization of recombinant single-chain salmon class I MHC fused with beta2-microglobulin with biological activity

DEFF Research Database (Denmark)

Zhao, Heng; Stet, René J M; Skjødt, Karsten

2008-01-01

Heterodimeric class I major histocompatibility complex (MHC) molecules consist of a putative 45-kDa heavy chain and a 12-kDa beta2-microglobulin (beta2m) light chain. The knowledge about MHC genes in Atlantic salmon accumulated during the last decade has allowed us to generate soluble and stable ...... MHC class I molecules with biological activity. We report here the use of a bacterial expression system to produce the recombinant single-chain MHC molecules based on a specific allele Sasa-UBA*0301. This particular allele was selected because previous work has shown its association...... antibodies were successfully produced against both the MHC class I heavy chain and beta(2)m, and showed binding to the recombinant molecule. The recombinant complex Sasabeta2mUBA*0301 was expressed and isolated; the production was scaled up by adjusting to its optimal conditions. Subsequently......, the recombinant proteins were purified by affinity chromatography using mAb against beta2m and alpha3. Eluates were analyzed by Western blot and refolded by the removal of denaturant. The correct folding was confirmed by measuring its binding capacity against mAb produced to recognize the native form of MHC...

Improved methods for predicting peptide binding affinity to MHC class II molecules

DEFF Research Database (Denmark)

Jensen, Kamilla Kjærgaard; Andreatta, Massimo; Marcatili, Paolo

2018-01-01

Major histocompatibility complex class II (MHC-II) molecules are expressed on the surface of professional antigen presenting cells where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. Understanding which peptides will be presented b...... are publicly available at www.cbs.dtu.dk/services/NetMHCII-2.3 and www.cbs.dtu.dk/services/NetMHCIIpan-3.2. This article is protected by copyright. All rights reserved....

Exploring the unbinding of Leishmania (L.) amazonensis CPB derived-epitopes from H2 MHC class I proteins.

Science.gov (United States)

Brandt, Artur M L; Batista, Paulo Ricardo; Souza-Silva, Franklin; Alves, Carlos Roberto; Caffarena, Ernesto Raul

2016-04-01

New strategies to control Leishmania disease demand an extensive knowledge about several aspects of infection including the understanding of its molecular events. In murine models, cysteine proteinase B from Leishmania amazonensis promotes regulation of immune response, and fragments from its C-terminus extension (cyspep) can play a decisive role in the host-parasite interaction. The interaction between cyspep-derived peptides and major histocompatibility complex (MHC) proteins is a crucial factor in Leishmania infections. Seven cyspep-derived peptides, previously identified as capable of interacting with H-2 (murine) MHC class I proteins, were studied in this work. We established a protocol to simulate the unbinding of these peptides from the cleft of H-2 receptors. From the simulations, we estimated the corresponding free energy of dissociation (ΔGd ) and described the molecular events that occur during the exit of peptides from the cleft. To test the reliability of this method, we first applied it to a calibration set of four crystallographic MHC/peptide complexes. Next, we explored the unbinding of the seven complexes mentioned above. Results were consistent with ΔGd values obtained from surface plasmon resonance (SPR) experiments. We also identified some of the primary interactions between peptides and H-2 receptors, and we detected three regions of influence for the interaction. This pattern was systematically observed for the peptides and helped determine a minimum distance for the real interaction between peptides and H-2 proteins occurring at ∼ 25 Å. © 2016 Wiley Periodicals, Inc.

The expression of B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in cord blood of healthy neonates.

Directory of Open Access Journals (Sweden)

S Radej

2011-04-01

Full Text Available The aim of our study was to estimate both B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in umbilical cord blood of healthy neonates in comparison with peripheral blood of healthy adults. Thirty nine healthy full-term neonates from physiological single pregnancies and 27 healthy adults were included in the study. The expression of B7-H1 and B7-H4 was revealed using the immunofluorescence method. Statistical analysis was performed using a non-parametric test (Mann-Whitney U-Test. The percentages of BDCA-1+ dendritic cells with B7-H1 and B7-H4 expressions were significantly higher in peripheral blood of healthy adults (p<0.00003. It was either observed that the percentage of BDCA-2+ dendritic cells with the expression of B7-H4 molecules was significantly higher in peripheral blood of healthy adults in comparison with umbilical cord blood (p<0.02. Decreased percentages of dendritic cells and co-stimulatory molecules indicate that neonates have immature immune system. Depletion of co-stimulatory B7-H1 and B7-H4 molecules enable appropriate development of immune response.

MHC class II molecules regulate growth in human T cells

DEFF Research Database (Denmark)

Nielsen, M; Odum, Niels; Bendtzen, K

1994-01-01

MHC-class-II-positive T cells are found in tissues involved in autoimmune disorders. Stimulation of class II molecules by monoclonal antibodies (mAbs) or bacterial superantigens induces protein tyrosine phosphorylation through activation of protein tyrosine kinases in T cells, and class II signals...... lines tested. Only one of three CD4+, CD45RAhigh, ROhigh T cells responded to class II costimulation. There was no correlation between T cell responsiveness to class II and the cytokine production profile of the T cell in question. Thus, T cell lines producing interferon (IFN)-gamma but not IL-4 (TH1...... modulate several T cell responses. Here, we studied further the role of class II molecules in the regulation of T cell growth. Costimulation of class II molecules by immobilized HLA-DR mAb significantly enhanced interleukin (IL)-2-supported T cell growth of the majority of CD4+, CD45RAlow, ROhigh T cell...

MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors

DEFF Research Database (Denmark)

Odum, Niels; Kanner, S B; Ledbetter, J A

1993-01-01

MHC class II-positive T cells are found in tissues involved in autoimmune and infectious disorders. Because stimulation of class II molecules by mAb or bacterial superantigens induces protein tyrosine phosphorylation through activation of PTK3 in T cells, we hypothesized that class II signals play...... tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation...... a regulatory function in T cell activation. Here, we show that cross-linking HLA-DR and -DP but not -DQ molecules by immobilized mAb enhanced proliferative T cell responses to IL-2. In contrast, class II stimulation had no effect on IL-4-induced proliferation. The costimulatory effect was most pronounced...

Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules

DEFF Research Database (Denmark)

Joosten, I; Wauben, M H; Holewijn, M C

1994-01-01

New strategies applied in the treatment of experimental autoimmune disease models involve blocking or modulation of MHC-peptide-TCR interactions either at the level of peptide-MHC interaction or, alternatively, at the level of T cell recognition. In order to identify useful competitor peptides one...... characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides...

Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer

DEFF Research Database (Denmark)

Siddle, Hannah V; Kreiss, Alexandre; Tovar, Cesar

2013-01-01

Contagious cancers that pass between individuals as an infectious cell line are highly unusual pathogens. Devil facial tumor disease (DFTD) is one such contagious cancer that emerged 16 y ago and is driving the Tasmanian devil to extinction. As both a pathogen and an allograft, DFTD cells should...... be rejected by the host-immune response, yet DFTD causes 100% mortality among infected devils with no apparent rejection of tumor cells. Why DFTD cells are not rejected has been a question of considerable confusion. Here, we show that DFTD cells do not express cell surface MHC molecules in vitro or in vivo......, MHC class I molecules can be restored to the surface of DFTD cells in vitro by using recombinant devil IFN-γ, which is associated with up-regulation of the MHC class II transactivator, a key transcription factor with deacetylase activity. Further, expression of MHC class I molecules by DFTD cells can...

Semi-empirical quantum evaluation of peptide - MHC class II binding

Science.gov (United States)

González, Ronald; Suárez, Carlos F.; Bohórquez, Hugo J.; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2017-01-01

Peptide presentation by the major histocompatibility complex (MHC) is a key process for triggering a specific immune response. Studying peptide-MHC (pMHC) binding from a structural-based approach has potential for reducing the costs of investigation into vaccine development. This study involved using two semi-empirical quantum chemistry methods (PM7 and FMO-DFTB) for computing the binding energies of peptides bonded to HLA-DR1 and HLA-DR2. We found that key stabilising water molecules involved in the peptide binding mechanism were required for finding high correlation with IC50 experimental values. Our proposal is computationally non-intensive, and is a reliable alternative for studying pMHC binding interactions.

MHC I stabilizing potential of computer-designed octapeptides.

Science.gov (United States)

Wisniewska, Joanna M; Jäger, Natalie; Freier, Anja; Losch, Florian O; Wiesmüller, Karl-Heinz; Walden, Peter; Wrede, Paul; Schneider, Gisbert; Hiss, Jan A

2010-01-01

Experimental results are presented for 180 in silico designed octapeptide sequences and their stabilizing effects on the major histocompatibility class I molecule H-2K(b). Peptide sequence design was accomplished by a combination of an ant colony optimization algorithm with artificial neural network classifiers. Experimental tests yielded nine H-2K(b) stabilizing and 171 nonstabilizing peptides. 28 among the nonstabilizing octapeptides contain canonical motif residues known to be favorable for MHC I stabilization. For characterization of the area covered by stabilizing and non-stabilizing octapeptides in sequence space, we visualized the distribution of 100,603 octapeptides using a self-organizing map. The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization.

MHC I Stabilizing Potential of Computer-Designed Octapeptides

Directory of Open Access Journals (Sweden)

Joanna M. Wisniewska

2010-01-01

Full Text Available Experimental results are presented for 180 in silico designed octapeptide sequences and their stabilizing effects on the major histocompatibility class I molecule H-2Kb. Peptide sequence design was accomplished by a combination of an ant colony optimization algorithm with artificial neural network classifiers. Experimental tests yielded nine H-2Kb stabilizing and 171 nonstabilizing peptides. 28 among the nonstabilizing octapeptides contain canonical motif residues known to be favorable for MHC I stabilization. For characterization of the area covered by stabilizing and non-stabilizing octapeptides in sequence space, we visualized the distribution of 100,603 octapeptides using a self-organizing map. The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization.

NetH2pan: A Computational Tool to Guide MHC peptide prediction on Murine Tumors

DEFF Research Database (Denmark)

DeVette, Christa I; Andreatta, Massimo; Bardet, Wilfried

2018-01-01

With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and mainta......With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated...... for evaluating antigen specificity in the murine FVB strain. Our study provides the first detailed molecular and immunoproteomic characterization of the FVB H-2q MHC Class I alleles, including >8500 unique peptide ligands, a multi-allele murine MHC peptide prediction tool, and in vivo validation of these data...

Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes.

Directory of Open Access Journals (Sweden)

Kasper Winther Jørgensen

2010-12-01

Full Text Available Major Histocompatibility class II (MHC-II molecules sample peptides from the extracellular space allowing the immune system to detect the presence of foreign microbes from this compartment. Prediction of MHC class II ligands is complicated by the open binding cleft of the MHC class II molecule, allowing binding of peptides extending out of the binding groove. Furthermore, only a few HLA-DR alleles have been characterized with a sufficient number of peptides (100-200 peptides per allele to derive accurate description of their binding motif. Little work has been performed characterizing structural properties of MHC class II ligands. Here, we perform one such large-scale analysis. A large set of SYFPEITHI MHC class II ligands covering more than 20 different HLA-DR molecules was analyzed in terms of their secondary structure and surface exposure characteristics in the context of the native structure of the corresponding source protein. We demonstrated that MHC class II ligands are significantly more exposed and have significantly more coil content than other peptides in the same protein with similar predicted binding affinity. We next exploited this observation to derive an improved prediction method for MHC class II ligands by integrating prediction of MHC- peptide binding with prediction of surface exposure and protein secondary structure. This combined prediction method was shown to significantly outperform the state-of-the-art MHC class II peptide binding prediction method when used to identify MHC class II ligands. We also tried to integrate N- and O-glycosylation in our prediction methods but this additional information was found not to improve prediction performance. In summary, these findings strongly suggest that local structural properties influence antigen processing and/or the accessibility of peptides to the MHC class II molecule.

Improved pan-specific MHC class I peptide-binding predictions using a novel representation of the MHC-binding cleft environment

DEFF Research Database (Denmark)

Carrasco Pro, S.; Zimic, M.; Nielsen, Morten

2014-01-01

of the current state-of-the-art methods for MHC class I is NetMHCpan, which has a core ingredient for the representation of the MHC class I molecule using a pseudo-sequence representation of the binding cleft amino acid environment. New and large MHC-peptide-binding data sets are constantly being made available...... of different MHC data sets including human leukocyte antigen (HLA), non-human primates (chimpanzee, macaque and gorilla) and other animal alleles (cattle, mouse and swine). From these constructs, we showed that by focusing on MHC sequence positions found to be polymorphic across the MHC molecules used to train...

Temperature dependence of third order ion molecule reactions. The reaction H+3 + 2H2 = H+5 + H2

International Nuclear Information System (INIS)

Hiraoka, K.; Kebarle, P.

1975-01-01

The rate constants k 1 for Reaction (1): H + 3 +2H 2 = H + 5 +H 2 were measured in the temperature range 100--300 degreeK. The temperature dependence of k 1 has the form k 1 proportionalT - /subn/, where n=2.3. Pierce and Porter have reported a much stronger negative temperature dependence with n=4.6. The difference arises from a determination of k 1 at 300 degreeK obtained by Arifov and used by Porter. The present k 1 (300 degreeK) =9times10 -30 (cm 6 molecules -2 center-dotsec -1 ). This is more than an order of magnitude larger than the Arifov value. The temperature dependence of third body dependent association reactions like (1) is examined on the basis of the energy transfer theory and the recently proposed trimolecular complex transition state theory by Meot-Ner, Solomon, Field, and Gershinowitz. The temperature dependence of the rate constant for the reverse reaction (-1) is obtained from k 1 and the previously determined temperature dependence of the equilibria (1). k/sub -//sub 1/ gives a good straight line Arrhenius plot leading to k/sub -//sub 1/ =8.7times10 -6 exp(-8.4/RT) cm 3 molecules -1 center-dotsec -1 . The activation energy is in kcal/mole. The preexponential factor is much larger than the rate constant for Langevin collisions. This is typical for pyrolysis of ions involving second order activation

H2 molecules and the intercloud medium

International Nuclear Information System (INIS)

Hill, J.K.; Hollenbach, D.J.

1976-01-01

We discuss expected column of densities of H 2 in the intercloud medium and the possible use of molecules as indicators of intercloud physical conditions. We treat molecule formation by the H - process and on graphite grains and show that the Barlow-Silk hypothesis of a 1 eV semichemical hydrogen-graphite bond leads to a large enhancement of the intercloud molecule formation rate. Rotational excitation calculations are presented for both cloud and intercloud conditions which show, in agreement with Jura, that the presently observed optically thin H 2 absorption components are more likely to originate in cold clouds than in the intercloud medium

The expression of B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in cord blood of healthy neonates

Directory of Open Access Journals (Sweden)

Kludka-Sternik M

2010-04-01

Full Text Available The aim of our study was to estimate both B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendriticcells in umbilical cord blood of healthy neonates in comparison with peripheral blood of healthy adults. Thirty ninehealthy full-term neonates from physiological single pregnancies and 27 healthy adults were included in the study. Theexpression of B7-H1 and B7-H4 was revealed using the immunofluorescence method. Statistical analysis was performedusing a non-parametric test (Mann-Whitney U-Test. The percentages of BDCA-1+ dendritic cells with B7-H1 and B7-H4expressions were significantly higher in peripheral blood of healthy adults (p<0.00003. It was either observed that the percentageof BDCA-2+ dendritic cells with the expression of B7-H4 molecules was significantly higher in peripheral blood ofhealthy adults in comparison with umbilical cord blood (p<0.02. Decreased percentages of dendritic cells and co-stimulatorymolecules indicate that neonates have immature immune system. Depletion of co-stimulatory B7-H1 and B7-H4 moleculesenable appropriate development of immune response.

Crystal structure of tetraaquabis(1,3-dimethyl-2,6-dioxo-7H-purin-7-ido-κN7cobalt(II

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Hicham El Hamdani

2017-09-01

Full Text Available The title complex, [Co(C7H7N4O22(H2O4], comprises mononuclear molecules consisting of a CoII ion, two deprotonated theophylline ligands (systematic name: 1,3-dimethyl-7H-purine-2,6-dione and four coordinating water molecules. The CoII atom lies on an inversion centre and has a slightly distorted octahedral coordination environment, with two N atoms of two trans-oriented theophylline ligands and the O atoms of four water molecules. An intramolecular hydrogen bond stabilizes this conformation. A three-dimensional supramolecular network structure is formed by intermolecular O—H...O and O—H...N hydrogen bonds.

Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens

DEFF Research Database (Denmark)

Wallny, Hans-Joachim; Avila, David; Hunt, Lawrence G.

2006-01-01

Compared with the MHC of typical mammals, the chicken MHC is smaller and simpler, with only two class I genes found in the B12 haplotype. We make five points to show that there is a single-dominantly expressed class I molecule that can have a strong effect on MHC function. First, we find only one...

Enhancement of MHC-I antigen presentation via architectural control of pH-responsive, endosomolytic polymer nanoparticles.

Science.gov (United States)

Wilson, John T; Postma, Almar; Keller, Salka; Convertine, Anthony J; Moad, Graeme; Rizzardo, Ezio; Meagher, Laurence; Chiefari, John; Stayton, Patrick S

2015-03-01

Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8(+) T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8(+) T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH ≤ 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8(+) T cell

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide

International Nuclear Information System (INIS)

Feng, Youjun; Qi, Jianxun; Zhang, Huimin; Wang, Jinzi; Liu, Jinhua; Jiang, Fan; Gao, Feng

2005-01-01

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β 2 m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide

Energy Technology Data Exchange (ETDEWEB)

Feng, Youjun [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Qi, Jianxun [Graduate School, Chinese Academy of Sciences, Beijing (China); Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Zhang, Huimin; Wang, Jinzi [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Liu, Jinhua [College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China); Jiang, Fan [Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Gao, Feng, E-mail: gaofeng@im.ac.cn [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China)

2006-01-01

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β{sub 2}m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides.

Anomalous absorption in H2CN and CH2CN molecules

Indian Academy of Sciences (India)

Abstract. Structures of H2CN and CH2CN molecules are similar to that of H2CO mole- cule. The H2CO has shown anomalous absorption for its transition 111 − 110 at 4.8 GHz in a number of cool molecular clouds. Though the molecules H2CN and CH2CN have been identified in TMC-1 and Sgr B2 through some ...

Identities of P2 and P3 Residues of H-2Kb-Bound Peptides Determine Mouse Ly49C Recognition.

Directory of Open Access Journals (Sweden)

Elsa A Marquez

Full Text Available Ly49 receptors can be peptide selective in their recognition of MHC-I-peptide complexes, affording them a level of discrimination beyond detecting the presence or absence of specific MHC-I allele products. Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others. Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity. If both are aliphatic residues, this is supportive. Whereas, small amino acids at P2 and aromatic amino acids at the P3 auxiliary anchor residue are detrimental to Ly49C recognition. These results resemble those with a rat Ly49 where the identity of a peptide anchor residue determines recognition, suggesting that dependence on specific peptide residues buried in the MHC-I peptide-binding groove may be fundamental to Ly49 peptide selectivity and recognition.

The MHC motif viewer: a visualization tool for MHC binding motifs

DEFF Research Database (Denmark)

Rapin, Nicolas; Hoof, Ilka; Lund, Ole

2010-01-01

is hampered by the lack of tools for browsing and comparing specificity of these molecules. We have developed a Web server, MHC Motif Viewer, which allows the display of the binding motif for MHC class I proteins for human, chimpanzee, rhesus monkey, mouse, and swine, as well as HLA-DR protein sequences...

The combination of major histocompatibility complex (MHC) and non-MHC genes influences murine lymphocytic choriomeningitis virus pathogenesis

DEFF Research Database (Denmark)

Eyler, Y L; Pfau, C J; Broomhall, K S

1989-01-01

with the recessive disease phenotype. In all cases, susceptibility was dominant. In backcross progeny obtained from matings of parental strains differing in both major histocompatibility complex (MHC) and non-MHC (SWR; C3H), 90% of the challenged mice died, indicating that at least three loci controlled...... susceptibility to the disease. When the parental strains carried similar MHC haplotypes but dissimilar background genes (B10.BR; CBA), 78% of the backcross mice succumbed, indicating that at least two non-MHC loci influenced disease susceptibility. It is unlikely, however, that the same two non-MHC loci...... are critical in all genetic combinations, since F1 produced from two H-2 identical, resistant strains (B10.BR; C3H) were found to be fully susceptible. When congenic mice, differing only in the D-end of the MHC region, were analysed, 50% of the backcross animals died, indicating that one gene in the MHC region...

MHC Class II and Non-MHC Class II Genes Differentially Influence Humoral Immunity to Bacillus anthracis Lethal Factor and Protective Antigen

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Judith A. James

2012-12-01

Full Text Available Anthrax Lethal Toxin consists of Protective Antigen (PA and Lethal Factor (LF, and current vaccination strategies focus on eliciting antibodies to PA. In human vaccination, the response to PA can vary greatly, and the response is often directed toward non-neutralizing epitopes. Variable vaccine responses have been shown to be due in part to genetic differences in individuals, with both MHC class II and other genes playing roles. Here, we investigated the relative contribution of MHC class II versus non-MHC class II genes in the humoral response to PA and LF immunization using three immunized strains of inbred mice: A/J (H-2k at the MHC class II locus, B6 (H-2b, and B6.H2k (H-2k. IgG antibody titers to LF were controlled primarily by the MHC class II locus, whereas IgG titers to PA were strongly influenced by the non-MHC class II genetic background. Conversely, the humoral fine specificity of reactivity to LF appeared to be controlled primarily through non-MHC class II genes, while the specificity of reactivity to PA was more dependent on MHC class II. Common epitopes, reactive in all strains, occurred in both LF and PA responses. These results demonstrate that MHC class II differentially influences humoral immune responses to LF and PA.

MPID-T2: a database for sequence-structure-function analyses of pMHC and TR/pMHC structures.

Science.gov (United States)

Khan, Javed Mohammed; Cheruku, Harish Reddy; Tong, Joo Chuan; Ranganathan, Shoba

2011-04-15

Sequence-structure-function information is critical in understanding the mechanism of pMHC and TR/pMHC binding and recognition. A database for sequence-structure-function information on pMHC and TR/pMHC interactions, MHC-Peptide Interaction Database-TR version 2 (MPID-T2), is now available augmented with the latest PDB and IMGT/3Dstructure-DB data, advanced features and new parameters for the analysis of pMHC and TR/pMHC structures. http://biolinfo.org/mpid-t2. shoba.ranganathan@mq.edu.au Supplementary data are available at Bioinformatics online.

NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets

DEFF Research Database (Denmark)

Nielsen, Morten; Andreatta, Massimo

2016-01-01

Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining informat...... specificities and ligand length scales, and demonstrated how this approach significantly improves the accuracy for prediction of peptide binding and identification of MHC ligands. The method is available at www.cbs.dtu.dk/services/NetMHCpan-3.0....

2-(7-Methyl-1H-indol-3-ylacetonitrile

Directory of Open Access Journals (Sweden)

Yu-Hua Ge

2012-01-01

Full Text Available In the title compound, C11H10N2, the carbonitrile group is twisted away from the indole plane [Ccy—Cme—Car—Car = 66.6 (2°; cy = cyanide, me = methylene and ar = aromatic]. In the crystal, N—H...N hydrogen bonds link the molecules into C(7 chains propagating in the [001] direction.

Behavior of ro-vibrationally excited H2 molecules and H atoms in a plasma expansion

International Nuclear Information System (INIS)

Vankan, P.; Schram, D.C.; Engeln, R.

2005-01-01

The behavior in a supersonic plasma expansion of H atom and H2 molecules, both ground-state and ro-vibrationally excited, is studied using various laser spectroscopic techniques. The ground-state H2 molecules expand like a normal gas. The behavior of H atoms and H 2 rv molecules, on the other hand, is considerably influenced, and to some extend even determined, by their reactivity. The H atoms diffuse out of the expansion due to surface association at the walls of the vacuum vessel. Moreover, by reducing the surface area of the nozzle by a factor of two, the amount of H atoms leaving the source is increased by one order of magnitude, due to a decreased surface association of H atoms in the nozzle. The evolution of the ro-vibrational distributions along the expansion axis shows the relaxation of the molecular hydrogen from the high temperature in the up-stream region to the low ambient temperature in the down-stream region. Whereas the vibrational distribution resembles a Boltzmann distribution, the rotational distribution is a non-equilibrium one, in which the high rotational levels (J > 7) are much more populated than what is expected from the low rotational levels (J <5). We observed overpopulations of up to seven orders of magnitude. The production of the high rotational levels is very probably connected to the surface association in the nozzle

Virus encoded MHC-like decoys diversify the inhibitory KIR repertoire.

Directory of Open Access Journals (Sweden)

Paola Carrillo-Bustamante

Full Text Available Natural killer (NK cells are circulating lymphocytes that play an important role in the control of viral infections and tumors. Their functions are regulated by several activating and inhibitory receptors. A subset of these receptors in human NK cells are the killer immunoglobulin-like receptors (KIRs, which interact with the highly polymorphic MHC class I molecules. One important function of NK cells is to detect cells that have down-regulated MHC expression (missing-self. Because MHC molecules have non polymorphic regions, their expression could have been monitored with a limited set of monomorphic receptors. Surprisingly, the KIR family has a remarkable genetic diversity, the function of which remains poorly understood. The mouse cytomegalovirus (MCMV is able to evade NK cell responses by coding "decoy" molecules that mimic MHC class I. This interaction was suggested to have driven the evolution of novel NK cell receptors. Inspired by the MCMV system, we develop an agent-based model of a host population infected with viruses that are able to evolve MHC down-regulation and decoy molecules. Our simulations show that specific recognition of MHC class I molecules by inhibitory KIRs provides excellent protection against viruses evolving decoys, and that the diversity of inhibitory KIRs will subsequently evolve as a result of the required discrimination between host MHC molecules and decoy molecules.

MHC Class II epitope predictive algorithms

DEFF Research Database (Denmark)

Nielsen, Morten; Lund, Ole; Buus, S

2010-01-01

Major histocompatibility complex class II (MHC-II) molecules sample peptides from the extracellular space, allowing the immune system to detect the presence of foreign microbes from this compartment. To be able to predict the immune response to given pathogens, a number of methods have been...... developed to predict peptide-MHC binding. However, few methods other than the pioneering TEPITOPE/ProPred method have been developed for MHC-II. Despite recent progress in method development, the predictive performance for MHC-II remains significantly lower than what can be obtained for MHC-I. One reason...

Molecules in strong laser fields. In depth study of H2 molecule

International Nuclear Information System (INIS)

Awasthi, Manohar

2009-01-01

A method for solving the time-dependent Schroedinger equation (TDSE) describing the electronic motion of the molecules exposed to very short intense laser pulses has been developed. The time-dependent electronic wavefunction is expanded in terms of a superposition of field-free eigenstates. The field-free eigenstates are calculated in two ways. In the first approach, which is applicable to two electron systems like H 2 , fully correlated field-free eigenstates are obtained in complete dimensionality using configuration-interaction calculation where the one-electron basis functions are built from B splines. In the second approach, which is even applicable to larger molecules, the field-free eigenstates are calculated within the single-active-electron (SAE) approximation using density functional theory. In general, the method can be divided into two parts, in the first part the field-free eigenstates are calculated and then in the second part a time propagation for the laser pulse parameters is performed. The H 2 molecule is the testing ground for the implementation of both the methods. The reliability of the configuration interaction (CI) based method for the solution of TDSE (CI-TDSE) is tested by comparing results in the low-intensity regime to the prediction of lowest-order perturbation theory. Another test for the CI-TDSE method is in the united atom limit for the H 2 molecule. By selecting a very small value of the internuclear distance close to zero for the H 2 molecule, Helium atom is obtained. Once the functionality and the reliability of the method is established, it is used for obtaining accurate results for molecular hydrogen exposed to intense laser fields. The results for the standard 800 nm Titanium-Sapphire laser and its harmonics at 400 nm and 266 nm are shown. The results for a scan over a wide range of incident photon energies as well as dependence on the internuclear distance are presented. The photoelectron spectra including above

A community resource benchmarking predictions of peptide binding to MHC-I molecules.

Science.gov (United States)

Peters, Bjoern; Bui, Huynh-Hoa; Frankild, Sune; Nielson, Morten; Lundegaard, Claus; Kostem, Emrah; Basch, Derek; Lamberth, Kasper; Harndahl, Mikkel; Fleri, Ward; Wilson, Stephen S; Sidney, John; Lund, Ole; Buus, Soren; Sette, Alessandro

2006-06-09

Recognition of peptides bound to major histocompatibility complex (MHC) class I molecules by T lymphocytes is an essential part of immune surveillance. Each MHC allele has a characteristic peptide binding preference, which can be captured in prediction algorithms, allowing for the rapid scan of entire pathogen proteomes for peptide likely to bind MHC. Here we make public a large set of 48,828 quantitative peptide-binding affinity measurements relating to 48 different mouse, human, macaque, and chimpanzee MHC class I alleles. We use this data to establish a set of benchmark predictions with one neural network method and two matrix-based prediction methods extensively utilized in our groups. In general, the neural network outperforms the matrix-based predictions mainly due to its ability to generalize even on a small amount of data. We also retrieved predictions from tools publicly available on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison of newly developed prediction methods. In addition, to generate and evaluate our own prediction methods, we have established an easily extensible web-based prediction framework that allows automated side-by-side comparisons of prediction methods implemented by experts. This is an advance over the current practice of tool developers having to generate reference predictions themselves, which can lead to underestimating the performance of prediction methods they are not as familiar with as their own. The overall goal of this effort is to provide a transparent prediction evaluation allowing bioinformaticians to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools.

MHC and Evolution in Teleosts

OpenAIRE

Grimholt, Unni

2016-01-01

Major histocompatibility complex (MHC) molecules are key players in initiating immune responses towards invading pathogens. Both MHC class I and class II genes are present in teleosts, and, using phylogenetic clustering, sequences from both classes have been classified into various lineages. The polymorphic and classical MHC class I and class II gene sequences belong to the U and A lineages, respectively. The remaining class I and class II lineages contain nonclassical gene sequences that, de...

Real-time, high-throughput measurements of peptide-MHC-I dissociation using a scintillation proximity assay

DEFF Research Database (Denmark)

Harndahl, Mikkel; Rasmussen, Michael; Røder, Gustav Andreas

2011-01-01

and it is well suited for high-throughput screening. To exemplify this, we screened a panel of 384 high-affinity peptides binding to the MHC class I molecule, HLA-A*02:01, and observed the rates of dissociation that ranged from 0.1h to 46h depending on the peptide used.......Efficient presentation of peptide-MHC class I complexes to immune T cells depends upon stable peptide-MHC class I interactions. Theoretically, determining the rate of dissociation of a peptide-MHC class I complexes is straightforward; in practical terms, however, generating the accurate and closely...... timed data needed to determine the rate of dissociation is not simple. Ideally, one should use a homogenous assay involving an inexhaustible and label-free assay principle. Here, we present a homogenous, high-throughput peptide-MHC class I dissociation assay, which by and large fulfill these ideal...

Dimeric MHC-peptides inserted into an immunoglobulin scaffold as new immunotherapeutic agents

Science.gov (United States)

Goldberg, Burt; Bona, Constantin

2011-01-01

Abstract The interactions of the T cell receptor (TCR) with cognate MHC-peptide and co-stimulatory molecules expressed at surface of antigen presenting cells (APC) leads to activation or tolerance of T cells. The development of molecular biological tools allowed for the preparation of soluble MHC-peptide molecules as surrogate for the APC. A decade ago a monomeric class II MHC molecule in which the peptide was covalently linked to β-chain of class II molecule was generated. This type of molecule had a low-binding affinity and did not cause the multimerization of TCR. The requirement of multimerization of TCR led to development of a new class of reagents, chimeric peptides covalently linked to MHC that was dimerized via Fc fragment of an immunoglobulin and linked to 3′ end of the β-chain of MHC class II molecule. These soluble dimerized MHC-peptide chimeric molecules display high affinity for the TCR and caused multimerization of TCR without processing by an APC. Because dimeric molecules are devoid of co-stimulatory molecules interacting with CD28, a second signal, they induce anergy rather the activation of T cells. In this review, we compare the human and murine dimerized MHC class II-peptides and their effect on CD4+ T cells, particularly the generation of T regulatory cells, which make these chimeric molecules an appealing approach for the treatment of autoimmune diseases. PMID:21435177

The C-terminal amino acid of the MHC-I heavy chain is critical for binding to Derlin-1 in human cytomegalovirus US11-induced MHC-I degradation.

Science.gov (United States)

Cho, Sunglim; Kim, Bo Young; Ahn, Kwangseog; Jun, Youngsoo

2013-01-01

Derlin-1 plays a critical role in endoplasmic reticulum-associated protein degradation (ERAD) of a particular subset of proteins. Although it is generally accepted that Derlin-1 mediates the export of ERAD substrates from the ER to the cytosol, little is known about how Derlin-1 interacts with these substrates. Human cytomegalovirus (HCMV) US11 exploits Derlin-1-dependent ERAD to degrade major histocompatibility complex class I (MHC-I) molecules and evade immune surveillance. US11 requires the cytosolic tail of the MHC-I heavy chain to divert MHC-I molecules into the ERAD pathway for degradation; however, the underlying mechanisms remain unknown. Here, we show that the cytosolic tail of the MHC-I heavy chain, although not required for interaction with US11, is required for tight binding to Derlin-1 and thus for US11-induced dislocation of the MHC-I heavy chain to the cytosol for proteasomal degradation. Surprisingly, deletion of a single C-terminal amino acid from the cytosolic tail disrupted the interaction between MHC-I molecules and Derlin-1, rendering mutant MHC-I molecules resistant to US11-induced degradation. Consistently, deleting the C-terminal cytosolic region of Derlin-1 prevented it from binding to MHC-I molecules. Taken together, these results suggest that the cytosolic region of Derlin-1 is involved in ERAD substrate binding and that this interaction is critical for the Derlin-1-mediated dislocation of the MHC-I heavy chain to the cytosol during US11-induced MHC-I degradation.

B7-H3 is a potent inhibitor of human T cell activation: No evidence for B7-H3 and TREML2 interaction

Science.gov (United States)

Leitner, Judith; Klauser, Christoph; Pickl, Winfried F.; Stöckl, Johannes; Majdic, Otto; Bardet, Anaïs F.; Kreil, David P.; Dong, Chen; Yamazaki, Tomohide; Zlabinger, Gerhard; Pfistershammer, Katharina; Steinberger, Peter

2010-01-01

B7-H3 belongs to the B7 superfamily, a group of molecules that costimulate or down-modulate T cell responses. Although it was shown that B7-H3 can inhibit T cell responses, several studies - most of them performed in murine systems - found B7-H3 to act in a costimulatory manner. In this study we have specifically addressed a potential functional dualism of human B7-H3 by assessing the effect of this molecule under varying experimental conditions as well as on different T cell subsets. We show that B7-H3 does not costimulate human T cells. In presence of strong activating signals, B7-H3 potently and consistently down-modulated human T cell responses. This inhibitory effect was evident when analyzing proliferation and cytokine production and affected naïve as well as pre-activated T cells. We furthermore demonstrate that B7-H3 - T cell interaction is characterized by an early suppression of IL-2 and that T cell inhibition can be reverted by exogenous IL-2. Since TREML2 has been recently described as costimulatory receptor of murine B7-H3 we have extensively analysed interaction of human B7-H3 with TREML2 (TLT2). In these experiments we found no evidence for such an interaction. Furthermore our data do not point to a role for murine TREML2 as a receptor for murine B7-H3. PMID:19544488

Molecules in strong laser fields. In depth study of H{sub 2} molecule

Energy Technology Data Exchange (ETDEWEB)

Awasthi, Manohar

2009-10-29

A method for solving the time-dependent Schroedinger equation (TDSE) describing the electronic motion of the molecules exposed to very short intense laser pulses has been developed. The time-dependent electronic wavefunction is expanded in terms of a superposition of field-free eigenstates. The field-free eigenstates are calculated in two ways. In the first approach, which is applicable to two electron systems like H{sub 2}, fully correlated field-free eigenstates are obtained in complete dimensionality using configuration-interaction calculation where the one-electron basis functions are built from B splines. In the second approach, which is even applicable to larger molecules, the field-free eigenstates are calculated within the single-active-electron (SAE) approximation using density functional theory. In general, the method can be divided into two parts, in the first part the field-free eigenstates are calculated and then in the second part a time propagation for the laser pulse parameters is performed. The H{sub 2} molecule is the testing ground for the implementation of both the methods. The reliability of the configuration interaction (CI) based method for the solution of TDSE (CI-TDSE) is tested by comparing results in the low-intensity regime to the prediction of lowest-order perturbation theory. Another test for the CI-TDSE method is in the united atom limit for the H{sub 2} molecule. By selecting a very small value of the internuclear distance close to zero for the H{sub 2} molecule, Helium atom is obtained. Once the functionality and the reliability of the method is established, it is used for obtaining accurate results for molecular hydrogen exposed to intense laser fields. The results for the standard 800 nm Titanium-Sapphire laser and its harmonics at 400 nm and 266 nm are shown. The results for a scan over a wide range of incident photon energies as well as dependence on the internuclear distance are presented. The photoelectron spectra including

New metal-organic frameworks of [M(C6H5O7)(C6H6O7)(C6H7O7)(H2O)] . H2O (M=La, Ce) and [Ce2(C2O4)(C6H6O7)2] . 4H2O

International Nuclear Information System (INIS)

Weng Shengfeng; Wang, Yun-Hsin; Lee, Chi-Shen

2012-01-01

Two novel materials, [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2), with a metal-organic framework (MOF) were prepared with hydrothermal reactions and characterized with photoluminescence, magnetic susceptibility, thermogravimetric analysis and X-ray powder diffraction in situ. The crystal structures were determined by single-crystal X-ray diffraction. Compound 1 crystallized in triclinic space group P1-bar (No. 2); compound 2 crystallized in monoclinic space group P2 1 /c (No. 14). The structure of 1 is built from a 1D MOF, composed of deprotonated citric ligands of three kinds. Compound 2 contains a 2D MOF structure consisting of citrate and oxalate ligands; the oxalate ligand arose from the decomposition in situ of citric acid in the presence of Cu II ions. Photoluminescence spectra of compounds 1b and 2 revealed transitions between the 5d 1 excited state and two levels of the 4f 1 ground state ( 2 F 5/2 and 2 F 7/2 ). Compounds 1b and 2 containing Ce III ion exhibit a paramagnetic property with weak antiferromagnetic interactions between the two adjacent magnetic centers. - Graphical Abstract: [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2)—with 1D and 2D structures were synthesized and characterized. Highlights: ► Two MOF – [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2) – with 1D and 2D structures. ► The adjacent chains of the 1D framework were correlated with each other through an oxalate ligand to form a 2D layer structure. ► The source of the oxalate ligand was the decomposition in situ of citric acid oxidized in the presence of Cu II ions.

Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity

Directory of Open Access Journals (Sweden)

Drew Michael GB

2006-03-01

Full Text Available Abstract Background MHC Class I molecules present antigenic peptides to cytotoxic T cells, which forms an integral part of the adaptive immune response. Peptides are bound within a groove formed by the MHC heavy chain. Previous approaches to MHC Class I-peptide binding prediction have largely concentrated on the peptide anchor residues located at the P2 and C-terminus positions. Results A large dataset comprising MHC-peptide structural complexes was created by re-modelling pre-determined x-ray crystallographic structures. Static energetic analysis, following energy minimisation, was performed on the dataset in order to characterise interactions between bound peptides and the MHC Class I molecule, partitioning the interactions within the groove into van der Waals, electrostatic and total non-bonded energy contributions. Conclusion The QSAR techniques of Genetic Function Approximation (GFA and Genetic Partial Least Squares (G/PLS algorithms were used to identify key interactions between the two molecules by comparing the calculated energy values with experimentally-determined BL50 data. Although the peptide termini binding interactions help ensure the stability of the MHC Class I-peptide complex, the central region of the peptide is also important in defining the specificity of the interaction. As thermodynamic studies indicate that peptide association and dissociation may be driven entropically, it may be necessary to incorporate entropic contributions into future calculations.

MHC class I cross-talk with CD2 and CD28 induces specific intracellular signalling and leads to growth retardation and apoptosis via a p56(lck)-dependent mechanism

DEFF Research Database (Denmark)

Ruhwald, M; Pedersen, Anders Elm; Claesson, M H

1999-01-01

Ligation of the major histocompatibility complex class I molecules (MHC-I) on human T lymphoma cells (Jurkat) initiates p56(lck)-dependent intracellular signalling events (phosphotyrosine kinase activity; [Ca(2+)](i)) and leads to augmented growth inhibition and apoptosis. MHC-I ligation in concert...... of apoptosis. In parallel experiments with the p56(lck)-negative Jurkat mutant cell, JCaM1.6, cross-linking neither influenced cell signalling nor cellular growth functions, indicating a cardinal role of the src kinases in signal transduction via MHC-I, CD2 and CD28 molecules. The results presented here...... with ligation of CD2 or CD28 augments, changes or modifies the pattern of activation. Ligation of MHC-I and CD2 alone resulted in growth inhibition, whereas CD28 ligation alone had no effect on cell proliferation. Ligation of MHC-I together with CD2 augmented growth inhibition and enhanced the level...

CD54/intercellular adhesion molecule 1 and major histocompatibility complex II signaling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation

DEFF Research Database (Denmark)

Poudrier, J; Owens, T

1994-01-01

We have examined signaling roles for CD54 intercellular adhesion molecule 1 and major histocompatibility complex (MHC) II as contact ligands during T help for B cell activation. We used a T helper 1 (Th1)-dependent helper system that was previously shown to be contact as well as interleukin 2 (IL-2......) dependent to demonstrate the relative roles of CD54, MHC II, and CD40 signaling in the events leading to the induction of B cell proliferation and responsiveness to IL-2. Paraformaldehyde-fixed activated Th1-induced expression of IL-2R alpha, IL-2R beta, and B7, and upregulated MHC II and CD54 on B cells...... resulted in the upregulated expression of MHC II and of CD54 and B7, respectively, analogous to the effect of fixed activated Th1 cells. B7 expression was further enhanced by co-cross-linking CD54 and MHC II. Cross-linking of CD40 achieved comparable effects. Strikingly, cross-linking ligation of CD54...

Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity.

Directory of Open Access Journals (Sweden)

Kevin D Pavelko

2012-02-01

Full Text Available Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2K(b gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the D(b transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of K(b but encoding the peptide binding domain of D(b, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric K(bα1α2D(b gene (low and D(b (high in the CNS of infected mice mirror expression levels of their endogenous H-2(q counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations.

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method.

Science.gov (United States)

Nielsen, Morten; Lundegaard, Claus; Lund, Ole

2007-07-04

Antigen presenting cells (APCs) sample the extra cellular space and present peptides from here to T helper cells, which can be activated if the peptides are of foreign origin. The peptides are presented on the surface of the cells in complex with major histocompatibility class II (MHC II) molecules. Identification of peptides that bind MHC II molecules is thus a key step in rational vaccine design and developing methods for accurate prediction of the peptide:MHC interactions play a central role in epitope discovery. The MHC class II binding groove is open at both ends making the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC) and three mouse H2-IA alleles. The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR), we demonstrate a consistent gain in predictive performance by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic amino acids at most anchor positions, whereas the SMM-align method identifies a preference for hydrophobic or neutral amino acids at the anchors. The SMM-align method was shown to outperform other

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

Directory of Open Access Journals (Sweden)

Lund Ole

2007-07-01

Full Text Available Abstract Background Antigen presenting cells (APCs sample the extra cellular space and present peptides from here to T helper cells, which can be activated if the peptides are of foreign origin. The peptides are presented on the surface of the cells in complex with major histocompatibility class II (MHC II molecules. Identification of peptides that bind MHC II molecules is thus a key step in rational vaccine design and developing methods for accurate prediction of the peptide:MHC interactions play a central role in epitope discovery. The MHC class II binding groove is open at both ends making the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC and three mouse H2-IA alleles. Results The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR, we demonstrate a consistent gain in predictive performance by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic amino acids at most anchor positions, whereas the SMM-align method identifies a preference for hydrophobic or neutral amino acids at the anchors. Conclusion

New design of MHC class II tetramers to accommodate fundamental principles of antigen presentation.

Science.gov (United States)

Landais, Elise; Romagnoli, Pablo A; Corper, Adam L; Shires, John; Altman, John D; Wilson, Ian A; Garcia, K Christopher; Teyton, Luc

2009-12-15

Direct identification and isolation of Ag-specific T cells became possible with the development of MHC tetramers, based on fluorescent avidins displaying biotinylated peptide-MHC complexes. This approach, extensively used for MHC class I-restricted T cells, has met very limited success with class II peptide-MHC complex tetramers (pMHCT-2) for the detection of CD4(+)-specific T cells. In addition, a very large number of these reagents, although capable of specifically activating T cells after being coated on solid support, is still unable to stain. To try to understand this puzzle and design usable tetramers, we examined each parameter critical for the production of pMHCT-2 using the I-A(d)-OVA system as a model. Through this process, the geometry of peptide-MHC display by avidin tetramers was examined, as well as the stability of rMHC molecules. However, we discovered that the most important factor limiting the reactivity of pMHCT-2 was the display of peptides. Indeed, long peptides, as presented by MHC class II molecules, can be bound to I-A/HLA-DQ molecules in more than one register, as suggested by structural studies. This mode of anchorless peptide binding allows the selection of a broader repertoire on single peptides and should favor anti-infectious immune responses. Thus, beyond the technical improvements that we propose, the redesign of pMHCT-2 will give us the tools to evaluate the real size of the CD4 T cell repertoire and help us in the production and testing of new vaccines.

A single-chain fusion molecule consisting of peptide, major histocompatibility gene complex class I heavy chain and beta2-microglobulin can fold partially correctly, but binds peptide inefficiently

DEFF Research Database (Denmark)

Sylvester-Hvid, C; Buus, S

1999-01-01

of a recombinant murine MHC-I molecule, which could be produced in large amounts in bacteria. The recombinant MHC-I protein was expressed as a single molecule (PepSc) consisting of the antigenic peptide linked to the MHC-I heavy chain and further linked to human beta2-microglobulin (hbeta2m). The PepSc molecule...... electrophoresis (SDS-PAGE). Serological analysis revealed the presence of some, but not all, MHC-I-specific epitopes. Biochemically, PepSc could bind peptide, however, rather ineffectively. We suggest that a partially correctly refolded MHC-I has been obtained....

A caspase-2-RFXANK interaction and its implication for MHC class II expression.

Science.gov (United States)

Forsberg, Jeremy; Li, Xinge; Akpinar, Birce; Salvatori, Roger; Ott, Martin; Zhivotovsky, Boris; Olsson, Magnus

2018-01-23

Despite recent achievements implicating caspase-2 in tumor suppression, the enzyme stands out from the apoptotic caspase family as a factor whose function requires further clarification. To specify enzyme characteristics through the definition of interacting proteins in apoptotic or non-apoptotic settings, a yeast 2-hybrid (Y2H) screen was performed using the full-length protein as bait. The current report describes the analysis of a captured prey and putative novel caspase-2 interacting factor, the regulatory factor X-associated ankyrin-containing protein (RFXANK), previously associated with CIITA, the transactivator regulating cell-type specificity and inducibility of MHC class II gene expression. The interaction between caspase-2 and RFXANK was verified by co-immunoprecipitations using both exogenous and endogenous proteins, where the latter approach suggested that binding of the components occurs in the cytoplasm. Cellular co-localization was confirmed by transfection of fluorescently conjugated proteins. Enhanced caspase-2 processing in RFXANK-overexpressing HEK293T cells treated with chemotherapeutic agents further supported Y2H data. Yet, no distinct differences with respect to MHC class II expression were observed in plasma membranes of antigen-presenting cells derived from wild type and caspase-2 -/- mice. In contrast, increased levels of the total MHC class II protein was evident in protein lysates from caspase-2 RNAi-silenced leukemia cell lines and B-cells isolated from gene-targeted mice. Together, these data identify a novel caspase-2-interacting factor, RFXANK, and indicate a potential non-apoptotic role for the enzyme in the control of MHC class II gene regulation.

Genes Outside the Major Histocompatibility Complex Locus Are Linked to the Development of Thyroid Autoantibodies and Thyroiditis in NOD.H2h4 Mice.

Science.gov (United States)

McLachlan, Sandra M; Lesage, Sylvie; Collin, Roxanne; Banuelos, Bianca; Aliesky, Holly A; Rapoport, Basil

2017-04-01

Thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) develop spontaneously in NOD.H2h4 mice, a phenotype enhanced by dietary iodine. NOD.H2h4 mice were derived by introducing the major histocompatibility class (MHC) molecule I-Ak from B10.A(4R) mice to nonobese diabetic (NOD) mice. Apart from I-Ak, the genes responsible for the NOD.H2h4 phenotype are unknown. Extending serendipitous observations from crossing BALB/c to NOD.H2h4 mice, thyroid autoimmunity was investigated in both genders of the F1, F2, and the second-generation backcross of F1 to NOD.H2h4 (N2). Medium-density linkage analysis was performed on thyroid autoimmunity traits in F2 and N2 progeny. TgAb develop before TPOAb and were measured after 8 and 16 weeks of iodide exposure; TPOAb and thyroiditis were studied at 16 weeks. TgAb, TPOAb, and thyroiditis, absent in BALB/c and F1 mice, developed in most NOD.H2h4 and in more N2 than F2 progeny. No linkages were observed in F2 progeny, probably because of the small number of autoantibody-positive mice. In N2 progeny (equal numbers of males and females), a chromosome 17 locus is linked to thyroiditis and TgAb and is suggestively linked to TPOAb. This locus includes MHC region genes from B10.A(4R) mice (such as I-Ak and Tnf, the latter involved in thyrocyte apoptosis) and genes from NOD mice such as Satb1, which most likely plays a role in immune tolerance. In conclusion, MHC and non-MHC genes, encoded within the chromosome 17 locus from both B10.A(4R) and NOD strains, are most likely responsible for the Hashimoto disease-like phenotype of NOD.H2h4 mice. Copyright © 2017 Endocrine Society.

DNA sequence of the Peromyscus leucopus MHC class II gene Aa (MhcPeleAa)

Energy Technology Data Exchange (ETDEWEB)

Crew, M.D.; Bates, L.M. [Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States)

1996-09-01

The genus Peromyscus has been extensively studied by populations biologists and ecologists for over eighty years, with P. leucopus (the white-footed mouse) being one of the most intensively investigated species. Polymorphic major histocompatibility complex (MHC) genes have proven useful in population genetic studies and might be helpful in understanding the population dynamics of Peromyscus species which are ubiquitously distributed over North and Central America. Polymorphism of P. leucopus MHC (MhcPele) class II genes was evident by restriction fragment length polymorphism (RFLP) analyses using human and mouse probes and Pele class II loci exhibited degrees of polymorphism similar to H2 class II genes (A-like>E-like). 8 refs., 2 figs.

A new polymorphic and multicopy MHC gene family related to nonmammalian class I

Energy Technology Data Exchange (ETDEWEB)

Leelayuwat, C.; Degli-Esposti, M.A.; Abraham, L.J. [Univ. of Western Australia, Perth (Australia); Townend, D.C. [Sir Charles Gairdner Hospital, Perth (Australia); Dawkins, R.L. [Royal Perth Hospital, Perth (Australia)]|[Univ. of Western Australia, Perth (Australia)]|[Sir Charles Gairdner Hospital, Perth (Australia)

1994-12-31

The authors have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning {approximately} 300 kilobases (kb) between TNF and HLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases such as myasthenia gravis (MG) and insulin dependent diabetes mellitus (IDDM). Genomic sequence was analyzed for coding potential, using two neural network programs, GRAIL and GeneParser. A genomic probe, JAB, containing putative coding sequences (PERB11) located 60 kb centromeric of HLA-B, was used for northern analysis of human tissues. Multiple transcripts were detected. Southern analysis of genomic DNA and overlapping YAC clones, covering the region from BAT1 to HLA-F, indicated that there are at least five copies of PERB11, four of which are located within this region of the MHC. The partial cDNA sequence of PERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative amino acid sequence of PERB11 shares {approximately} 30% identity to MHC class I molecules from various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FcR of the mouse and rat and the human Zn-{alpha}2-glycoprotein. From direct comparison of amino acid sequences, it is concluded that PERB11 is a distinct molecule more closely related to nonmammalian than known mammalian MHC class I molecules. Genomic sequence analysis of PERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is polymorphic at both DNA and protein level. The results suggest that the authors have identified a novel polymorphic gene family with multiple copies within the MHC. 48 refs., 10 figs., 2 tabs.

A combined prediction strategy increases identification of peptides bound with high affinity and stability to porcine MHC class I molecules SLA-1*04:01, SLA-2*04:01, and SLA-3*04:01

DEFF Research Database (Denmark)

Pedersen, Lasse Eggers; Rasmussen, Michael; Harndahl, Mikkel

2016-01-01

constitute an attractive protocol to select target peptides from the vast pool of viral proteome peptides. We have earlier reported the peptide binding motif of the porcine MHC-I molecules SLA-1*04:01 and SLA-2*04:01, identified by an ELISA affinity-based positional scanning combinatorial peptide library...

MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation

DEFF Research Database (Denmark)

Rosloniec, E F; Vitez, L J; Buus, S

1990-01-01

the alpha k-3 peptide binds slightly less well. These combined data, suggesting that class II-derived peptides can bind to MHC class II molecules, including the autologous molecule from which they are derived, have important implications for the molecular basis of alloreactivity and autoreactivity. Further...... found in the first and third polymorphic regions (PMR) of the A alpha k chain (alpha k-1 and alpha k-3) were capable of inhibiting the presentation of three different HEL-derived peptide antigens to their appropriate T cells. In addition, the alpha k-1 peptide inhibited the presentation of the OVA(323......-339) immunodominant peptide to the I-Ad-restricted T cell hybridomas specific for it. Prepulsing experiments demonstrated that the PMR peptides were interacting with the APC and not with the T cell hybridomas. These observations were confirmed and extended by the demonstration that the alpha k-1 and alpha k-3...

First-principles analysis of C2H2 molecule diffusion and its dissociation process on the ferromagnetic bcc-Fe(110) surface

International Nuclear Information System (INIS)

Ikeda, Minoru; Yamasaki, Takahiro; Kaneta, Chioko

2010-01-01

Using the projector-augmented plane wave method, we study diffusion and dissociation processes of C 2 H 2 molecules on the ferromagnetic bcc-Fe(110) surface and investigate the formation process of graphene created by C 2 H 2 molecules. The most stable site for C 2 H 2 on the Fe surface is a hollow site and its adsorption energy is - 3.5 eV. In order to study the diffusion process of the C 2 H 2 molecule, the barrier height energies for the C atom, C 2 -dimer and CH as well as the C 2 H 2 molecule are estimated using the nudged elastic band method. The barrier height energy for C 2 H 2 is 0.71 eV and this indicates that the C 2 H 2 diffuses easily on this FM bcc-Fe(110) surface. We further investigate the two step dissociation process of C 2 H 2 on Fe. The first step is the dissociation of C 2 H 2 into C 2 H and H, and the second step is that of C 2 H into C 2 and H. Their dissociation energies are 0.9 and 1.2 eV, respectively. These energies are relatively small compared to the dissociation energy 7.5 eV of C 2 H 2 into C 2 H and H in the vacuum. Thus, the Fe surface shows catalytic effects. We further investigate the initial formation process of graphene by increasing the coverage of C 2 H 2 . The formation process of the benzene molecule on the FM bcc(110) surface is also discussed. We find that there exists a critical coverage of C 2 H 2 which characterizes the beginning of the formation of the graphene.

First-principles analysis of C2H2 molecule diffusion and its dissociation process on the ferromagnetic bcc-Fe110 surface.

Science.gov (United States)

Ikeda, Minoru; Yamasaki, Takahiro; Kaneta, Chioko

2010-09-29

Using the projector-augmented plane wave method, we study diffusion and dissociation processes of C(2)H(2) molecules on the ferromagnetic bcc-Fe(110) surface and investigate the formation process of graphene created by C(2)H(2) molecules. The most stable site for C(2)H(2) on the Fe surface is a hollow site and its adsorption energy is - 3.5 eV. In order to study the diffusion process of the C(2)H(2) molecule, the barrier height energies for the C atom, C(2)-dimer and CH as well as the C(2)H(2) molecule are estimated using the nudged elastic band method. The barrier height energy for C(2)H(2) is 0.71 eV and this indicates that the C(2)H(2) diffuses easily on this FM bcc-Fe(110) surface. We further investigate the two step dissociation process of C(2)H(2) on Fe. The first step is the dissociation of C(2)H(2) into C(2)H and H, and the second step is that of C(2)H into C(2) and H. Their dissociation energies are 0.9 and 1.2 eV, respectively. These energies are relatively small compared to the dissociation energy 7.5 eV of C(2)H(2) into C(2)H and H in the vacuum. Thus, the Fe surface shows catalytic effects. We further investigate the initial formation process of graphene by increasing the coverage of C(2)H(2). The formation process of the benzene molecule on the FM bcc(110) surface is also discussed. We find that there exists a critical coverage of C(2)H(2) which characterizes the beginning of the formation of the graphene.

Exosomal cancer immunotherapy is independent of MHC molecules on exosomes.

Science.gov (United States)

Hiltbrunner, Stefanie; Larssen, Pia; Eldh, Maria; Martinez-Bravo, Maria-Jose; Wagner, Arnika K; Karlsson, Mikael C I; Gabrielsson, Susanne

2016-06-21

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans.

NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction

Directory of Open Access Journals (Sweden)

Lund Ole

2009-09-01

Full Text Available Abstract Background The major histocompatibility complex (MHC molecule plays a central role in controlling the adaptive immune response to infections. MHC class I molecules present peptides derived from intracellular proteins to cytotoxic T cells, whereas MHC class II molecules stimulate cellular and humoral immunity through presentation of extracellularly derived peptides to helper T cells. Identification of which peptides will bind a given MHC molecule is thus of great importance for the understanding of host-pathogen interactions, and large efforts have been placed in developing algorithms capable of predicting this binding event. Results Here, we present a novel artificial neural network-based method, NN-align that allows for simultaneous identification of the MHC class II binding core and binding affinity. NN-align is trained using a novel training algorithm that allows for correction of bias in the training data due to redundant binding core representation. Incorporation of information about the residues flanking the peptide-binding core is shown to significantly improve the prediction accuracy. The method is evaluated on a large-scale benchmark consisting of six independent data sets covering 14 human MHC class II alleles, and is demonstrated to outperform other state-of-the-art MHC class II prediction methods. Conclusion The NN-align method is competitive with the state-of-the-art MHC class II peptide binding prediction algorithms. The method is publicly available at http://www.cbs.dtu.dk/services/NetMHCII-2.0.

NetMHCpan, a method for MHC class I binding prediction beyond humans

DEFF Research Database (Denmark)

Hoof, Ilka; Peters, B; Sidney, J

2009-01-01

molecules. We show that the NetMHCpan-2.0 method can accurately predict binding to uncharacterized HLA molecules, including HLA-C and HLA-G. Moreover, NetMHCpan-2.0 is demonstrated to accurately predict peptide binding to chimpanzee and macaque MHC class I molecules. The power of NetMHCpan-2.0 to guide...

Innate lymphoid cells and the MHC.

Science.gov (United States)

Robinette, M L; Colonna, M

2016-01-01

Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ethanol oxidation reactions catalyzed by water molecules: CH3CH2OH+n H2O→ CH3CHO+ H2+n H2O (n=0,1,2)

Science.gov (United States)

Takahashi, H.; Hisaoka, S.; Nitta, T.

2002-09-01

Ab initio density functional theory calculations have been performed to investigate the catalytic role of water molecules in the oxidation reaction of ethanol: CH3CH2OH+n H2O→ CH3CHO+ H2+n H2O (n=0,1,2) . The results show that the potential energy barrier for the reaction is 88.0 kcal/mol in case of n=0, while it is reduced by ˜34 kcal/mol when two water molecules are involved ( n=2) in the reaction. As a result, the rate constant increases to 3.31×10 -4 s-1, which shows a significant catalytic role of water molecules in the ethanol oxidation reactions.

Specialities of the differentiation conditions for the memory cells - either initial or enriched secondary cytotoxic T lymphocyte precursors (pCTL-2) specific to the MHC molecule class 1

International Nuclear Information System (INIS)

Brondz, B.D.; Osipova, T.V.; Aptikaeva, G.F.; Kronin, V.V.

1989-01-01

The in vivo induced pCTL-2 with phenotype L3T4 - Lyt2 + , specific to the H-2K b molecule, turn into effector CTLs during 4 days in the mixed lymphocyte culture (with heat-treated donor stimulators) much more efficiency when donor and recipient are different from one another not only in MHC class 1 (anti-BIO, MBR BIO.AKM) but in 1+2 (K b +1 b ) anti-C57BL/6 BIAD2(R1O1). The initial pCTL-2 differentiation in enhanced as a result of synergistic effect between the K b alloantigen and rIL2. The anti-K b pCTL-2, being separated from helper T cells by means of absorption onto the macrophage donor monolayer and elution from it, give rise to pronounced differentiation in simplified conditions, irrespective of the stimulator presence and without external rIL2. It is supposed that these phenomena are roused to secrection of the CTL differentiation factor by the eluted pCTL-2 themselves, and besides, rIL2 may promote for secretion of this factor additionally

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Science.gov (United States)

Tai, Lee-Hwa; Goulet, Marie-Line; Belanger, Simon; Toyama-Sorimachi, Noriko; Fodil-Cornu, Nassima; Vidal, Silvia M.; Troke, Angela D.; McVicar, Daniel W.; Makrigiannis, Andrew P.

2008-01-01

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo. PMID:19075287

Fine-mapping analysis of the MHC region for vitiligo based on a new Han-MHC reference panel.

Science.gov (United States)

Yang, Chao; Wu, Juan; Zhang, Xuelei; Wen, Leilei; Sun, Jingying; Cheng, Yuyan; Tang, Xianfa; Liang, Bo; Chen, Gang; Zhou, Fusheng; Cui, Yong; Zhang, Anping; Zhang, Xuejun; Zheng, Xiaodong; Yang, Sen; Sun, Liangdan

2018-03-30

Vitiligo is an immune-related disease with patchy depigmentation of skin and hair caused by selective destruction of melanocytes. In recent decades, many studies have shown the association between vitiligo and HLA genes; however, the results of Han Chinese are scarce. In this study, we performed a fine-mapping analysis of the MHC region in 2818 Han Chinese subjects through a widely used HLA imputation method with a newly built large-scale Han-MHC reference panel. Three new four-digit HLA alleles (HLA-DQB1 ∗ 02:02, HLA-DQA1 ∗ 02:01 and HLA-DPB1 ∗ 17:01) were identified to be associated with the risk of vitiligo, and four previously reported alleles were confirmed. Further conditional analysis revealed that two important variants, HLA-DQβ1 amino acid position 135 (OR = 1.79, P = 1.87 × 10 -11 ) and HLA-B amino acid positions 45-46 (OR = 1.44, P = 5.61 × 10 -11 ), conferred most of the MHC associations. Three-dimension ribbon models showed that the former is located within the β2 domain of the HLA-DQβ1 molecule, and the latter lies in the α1 domain of the HLA-B molecule, while both are involved in specific antigen presenting process. Finally, we summarized all significant signals in the MHC region to clarify their complex relationships, and 8.60% of phenotypic variance could be explained based on all reported variants in Han Chinese so far. Our findings highlight the complex genetic architecture of the MHC region for vitiligo in Han Chinese population and expand our understanding of the roles of HLA coding variants in the etiology of vitiligo. Copyright © 2018. Published by Elsevier B.V.

Electron capture in collisions between O6+ ions and H2O molecules

NARCIS (Netherlands)

Bodewits, D.; Hoekstra, R.

By means of photon emission spectroscopy, state selective electron capture cross section for low energy (0.1-7.5 keV/amu) collisions of O6+ on H2O molecules have been measured. Over the range of interaction energies the state selective cross sections change strongly, i.e., by factors up to 5, while

Establishment of a quantitative ELISA capable of determining peptide - MHC class I interaction

DEFF Research Database (Denmark)

Sylvester-Hvid, C; Kristensen, N; Blicher, T

2002-01-01

dependent manner. Here, we exploit the availability of these molecules to generate a quantitative ELISA-based assay capable of measuring the affinity of the interaction between peptide and MHC-I. This assay is simple and sensitive, and one can easily envisage that the necessary reagents, standards......Many different assays for measuring peptide-MHC interactions have been suggested over the years. Yet, there is no generally accepted standard method available. We have recently generated preoxidized recombinant MHC class I molecules (MHC-I) which can be purified to homogeneity under denaturing...

Inhibition of MHC-I by Brucella abortus is an early event during infection and involves EGFR pathway.

Science.gov (United States)

Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Mercogliano, M Florencia; Pozner, Roberto G; Schillaci, Roxana; Elizalde, Patricia V; Giambartolomei, Guillermo H; Barrionuevo, Paula

2017-04-01

Brucella abortus is able to persist inside the host despite the development of potent CD8 + T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 - are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 + T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.

The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes

DEFF Research Database (Denmark)

Walker, Brian A; Hunt, Lawrence G; Sowa, Anna K

2011-01-01

In most mammals, the MHC class I molecules are polymorphic and determine the specificity of peptide presentation, whereas the transporter associated with antigen presentation (TAP) heterodimers are functionally monomorphic. In chickens, there are two classical class I genes but only one is expres...

MHC class I molecules with superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs

NARCIS (Netherlands)

L. Wooldridge (Linda); M. Clement (Mathew); A. Lissina (Anna); E.S.J. Edwards (Emily); K. Ladell (Kristin); J. Ekeruche (Julia); R.E. Hewitt (Rachel); B. Laugel (Bruno); E. Gostick (Emma); D.K. Cole (David); J.E.M.A. Debets (Reno); C.A. Berrevoets (Cor); J.J. Miles (John); S.R. Burrows (Scott); D.A. Price (David); A.K. Sewell (Andrew)

2010-01-01

textabstractCD8+CTLs are essential for effective immune defense against intracellular microbes and neoplasia. CTLs recognize short peptide fragments presented in association with MHC class I (MHCI) molecules on the surface of infected or dysregulated cells. Ag recognition involves the binding of

One-pot, mix-and-read peptide-MHC tetramers

DEFF Research Database (Denmark)

Leisner, Christian Valdemar Vinge; Loeth, Nina; Lamberth, Kasper

2008-01-01

BACKGROUND: Cytotoxic T Lymphocytes (CTL) recognize complexes of peptide ligands and Major Histocompatibility Complex (MHC) class I molecules presented at the surface of Antigen Presenting Cells (APC). Detection and isolation of CTL's are of importance for research on CTL immunity, and development...... molecules can be refolded in vitro, tetramerized with streptavidin, and used for specific T cell staining-all in a one-pot reaction without any intervening purification steps. CONCLUSIONS/SIGNIFICANCE: We have developed an efficient "one-pot, mix-and-read" strategy for peptide-MHC tetramer generation...

The systems biology of MHC class II antigen presentation

NARCIS (Netherlands)

Paul, Petra

2012-01-01

Major histocompatibility class II molecules (MHC class II) are one of the key regulators of adaptive immunity because of their specific expression by professional antigen presenting cells (APC). They present peptides derived from endocytosed material to T helper lymphocytes. Consequently, MHC class

The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex.

Science.gov (United States)

Elliott, Tim; Williams, Anthony

2005-10-01

Major histocompatibility complex (MHC) class I complexes present peptides from both self and foreign intracellular proteins on the surface of most nucleated cells. The assembled heterotrimeric complexes consist of a polymorphic glycosylated heavy chain, non-polymorphic beta(2) microglobulin, and a peptide of typically nine amino acids in length. Assembly of the class I complexes occurs in the endoplasmic reticulum and is assisted by a number of chaperone molecules. A multimolecular unit termed the peptide-loading complex (PLC) is integral to this process. The PLC contains a peptide transporter (transporter associated with antigen processing), a thiooxido-reductase (ERp57), a glycoprotein chaperone (calreticulin), and tapasin, a class I-specific chaperone. We suggest that class I assembly involves a process of optimization where the peptide cargo of the complex is edited by the PLC. Furthermore, this selective peptide loading is biased toward peptides that have a longer off-rate from the assembled complex. We suggest that tapasin is the key chaperone that directs this action of the PLC with secondary contributions from calreticulin and possibly ERp57. We provide a framework model for how this may operate at the molecular level and draw parallels with the proposed mechanism of action of human leukocyte antigen-DM for MHC class II complex optimization.

MHC class II expression in lung cancer.

Science.gov (United States)

He, Yayi; Rozeboom, Leslie; Rivard, Christopher J; Ellison, Kim; Dziadziuszko, Rafal; Yu, Hui; Zhou, Caicun; Hirsch, Fred R

2017-10-01

Immunotherapy is an exciting development in lung cancer research. In this study we described major histocompatibility complex (MHC) Class II protein expression in lung cancer cell lines and patient tissues. We studied MHC Class II (DP, DQ, DR) (CR3/43, Abcam) protein expression in 55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell lines and 278 lung cancer patient tissues by immunohistochemistry (IHC). Seven (12.7%) NSCLC cell lines were positive for MHC Class II. No SCLC cell lines were found to be MHC Class II positive. We assessed 139 lung cancer samples available in the Hirsch Lab for MHC Class II. There was no positive MHC Class II staining on SCLC tumor cells. MHC Class II expression on TILs in SCLC was significantly lower than that on TILs in NSCLC (P＜0.001). MHC Class II was also assessed in an additional 139 NSCLC tumor tissues from Medical University of Gdansk, Poland. Patients with positive staining of MHC Class II on TILs had longer regression-free survival (RFS) and overall survival (OS) than those whose TILs were MHC Class II negative (2.980 years, 95% CI 1.628-4.332 vs. 1.050 years, 95% CI 0.556-1.554, P=0.028) (3.230 years, 95% CI 2.617-3.843 vs. 1.390 years, 95% CI 0.629-2.151, P=0.014). MHC Class II was expressed both in NSCLC cell lines and tissues. However, MHC Class II was not detected in SCLC cell lines or tissue tumor cells. MHC Class II expression was lower on SCLC TILs than on NSCLC TILs. Loss of expression of MHC Class II on SCLC tumor cells and reduced expression on SCLC TILs may be a means of escaping anti-cancer immunity. Higher MHC Class II expression on TILs was correlated with better prognosis in patients with NSCLC. Copyright © 2017. Published by Elsevier B.V.

Crystallization and preliminary X-ray crystallographic analysis of the rhesus macaque MHC class I molecule Mamu-B*17 complexed with an immunodominant SIVmac239 Env epitope

International Nuclear Information System (INIS)

Gao, Feng; Bao, Jinku

2013-01-01

A primitive monoclinic crystal of the rhesus macaque MHC class I molecule Mamu-B*17 complexed with an SIVmac239 Env peptide was obtained and belonged to space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. The crystal diffracted to 2.55 Å resolution. Long-term nonprogression during simian immunodeficiency virus (SIV) infection has been strongly associated with the major histocompatibility complex (MHC) class I allele Mamu-B*17. Here, a complex of rhesus macaque Mamu-B*17 with rhesus macaque β 2 -microglobulin (β 2 m) and an immunodominant peptide (SIVmac239 Env241–251; LRCNDTNYSGF; Env LF11) derived from the SIV Env protein was crystallized by the hanging-drop method using PEG 3350 as a precipitating agent. The crystals belonged to the primitive monoclinic space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. Assuming the presence of one molecule in the asymmetric unit, the Matthews coefficient and solvent content were calculated to be 2.96 Å 3 Da −1 and 58.5%, respectively

Mamu-A*01/Kb transgenic and MHC Class I knockout mice as a tool for HIV vaccine development

International Nuclear Information System (INIS)

Li Jinliang; Srivastava, Tumul; Rawal, Ravindra; Manuel, Edwin; Isbell, Donna; Tsark, Walter; La Rosa, Corinna; Wang Zhongde; Li Zhongqi; Barry, Peter A.; Hagen, Katharine D.; Longmate, Jeffrey; Diamond, Don J.

2009-01-01

We have developed a murine model expressing the rhesus macaque (RM) Mamu-A*01 MHC allele to characterize immune responses and vaccines based on antigens of importance to human disease processes. Towards that goal, transgenic (Tg) mice expressing chimeric RM (α1 and α2 Mamu-A*01 domains) and murine (α3, transmembrane, and cytoplasmic H-2K b domains) MHC Class I molecules were derived by transgenesis of the H-2K b D b double MHC Class I knockout strain. After immunization of Mamu-A*01/K b Tg mice with rVV-SIVGag-Pol, the mice generated CD8 + T-cell IFN-γ responses to several known Mamu-A*01 restricted epitopes from the SIV Gag and Pol antigen sequence. Fusion peptides of highly recognized CTL epitopes from SIV Pol and Gag and a strong T-help epitope were shown to be immunogenic and capable of limiting an rVV-SIVGag-Pol challenge. Mamu-A*01/K b Tg mice provide a model system to study the Mamu-A*01 restricted T-cell response for various infectious diseases which are applicable to a study in RM.

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

DEFF Research Database (Denmark)

Boyle, Louise H; Hermann, Clemens; Boname, Jessica M

2013-01-01

Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled...... with β2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. β2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I...... occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR:MHC class I complex trafficks through the Golgi apparatus...

Charge transfer processes in collisions of H+ ions with H2, D2, CO, CO2 CH4, C2H2, C2H6 and C3H8 molecules below 10 keV

International Nuclear Information System (INIS)

Kusakabe, T.; Buenker, R.J.; Kimura, M.

2002-01-01

Charge transfer processes resulting from collisions of H + ions with H 2 , D 2 , CO, CO 2 CH 4 , C 2 H 2 , C 2 H 6 and C 3 H 8 molecules have been investigated in the energy range of 0.2 to 4.0 keV experimentally and theoretically. The initial growth rate method was employed in the experiment for studying the dynamics and cross sections. Theoretical analysis based on a molecular-orbital expansion method for H 2 , D 2 , CO, CH 4 and C 2 H 2 targets was also carried out. The present results for the H 2 , CO and CO 2 molecules by H + impact are found to be in excellent accord with most of previous measurements above 1 keV, but they show some differences below this energy where our result displays a stronger energy-dependence. For CH 4 , C 2 H 2 , C 2 H 6 and C 3 H 8 targets, both experimental and theoretical results indicate that if one assumes vibrationally excited molecular ions (CH 4 + , C 2 H 2 + , C 2 H 6 + and C 3 H 8 + ) formed in the exit channel, then charge transfer processes sometimes become more favorable since these vibrationally excited fragments meet an accidental resonant condition. This is a clear indication of the role of vibrational excited states for charge transfer, and is an important realization for general understanding. (author)

A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation

NARCIS (Netherlands)

Paul, Petra; van den Hoorn, Tineke; Jongsma, Marlieke L. M.; Bakker, Mark J.; Hengeveld, Rutger; Janssen, Lennert; Cresswell, Peter; Egan, David A.; van Ham, Marieke; ten Brinke, Anja; Ovaa, Huib; Beijersbergen, Roderick L.; Kuijl, Coenraad; Neefjes, Jacques

2011-01-01

MHC class II molecules (MHC-II) present peptides to T helper cells to facilitate immune responses and are strongly linked to autoimmune diseases. To unravel processes controlling MHC-II antigen presentation, we performed a genome-wide flow cytometry-based RNAi screen detecting MHC-II expression and

The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes-predisposing non-Aspbeta57 MHC class II molecules

DEFF Research Database (Denmark)

Quarsten, H; Paulsen, G; Johansen, B H

1998-01-01

Susceptibility and resistance to type 1 diabetes are associated with MHC class II alleles that carry non-Asp and Asp at residue 57 of their beta chain respectively. The effect of Asp or non-Aspbeta57 may relate to a differential ability of distinct class II molecules to bind specific immuno......-pathogenic peptides. Recent studies in man and mouse have revealed that some type 1 diabetes-predisposing non-Aspbeta57 class II molecules (i.e. DQ8, DR4Dw15 and I-Ag7) preferentially bind peptides with a negatively charged anchor residue at P9. It has been suggested that this is a common feature of type 1 diabetes......-predisposing class II molecules. The molecular explanation for such a phenomenon could be that class II beta chains with Aspbeta57 form a salt bridge between Aspbeta57 and a conserved Arg of the a chain, whereas in non-Aspbeta57 molecules the Arg is unopposed and free to interact with negatively charged P9 peptide...

Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies.

Science.gov (United States)

Wiendl, Heinz; Mitsdoerffer, Meike; Schneider, Dagmar; Chen, Lieping; Lochmüller, Hanns; Melms, Arthur; Weller, Michael

2003-10-01

B7-H1 is a novel B7 family protein attributed to costimulatory and immune regulatory functions. Here we report that human myoblasts cultured from control subjects and patients with inflammatory myopathies as well as TE671 muscle rhabdomyosarcoma cells express high levels of B7-H1 after stimulation with the inflammatory cytokine IFN-gamma. Coculture experiments of MHC class I/II-positive myoblasts with CD4 and CD8 T cells in the presence of antigen demonstrated the functional consequences of muscle-related B7-H1 expression: production of inflammatory cytokines, IFN-gamma and IL-2, by CD4 as well CD8 T cells was markedly enhanced in the presence of a neutralizing anti-B7-H1 antibody. This observation was paralleled by an augmented expression of the T cell activation markers CD25, ICOS, and CD69, thus showing B7-H1-mediated inhibition of T cell activation. Further, we investigated 23 muscle biopsy specimens from patients with polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM), and nonmyopathic controls for B7-H1 expression by immunohistochemistry: B7-H1 was expressed in PM, IBM, and DM specimens but not in noninflammatory and nonmyopathic controls. Staining was predominantly localized to areas of strong inflammation and to muscle cells as well as mononuclear cells. These data highlight the immune regulatory properties of muscle cells and suggest that B7-H1 expression represents an inhibitory mechanism induced upon inflammatory stimuli and aimed at protecting muscle fibers from immune aggression.

NLRC5: a key regulator of MHC class I-dependent immune responses.

Science.gov (United States)

Kobayashi, Koichi S; van den Elsen, Peter J

2012-12-01

The expression of MHC class I molecules is crucial for the initiation and regulation of adaptive immune responses against pathogens. NOD-, LRR- and CARD-containing 5 (NLRC5) was recently identified as a specific transactivator of MHC class I genes (CITA). NLRC5 and the master regulator for MHC class II genes, class II transactivator (CIITA), interact with similar MHC promoter-bound factors. Here, we provide a broad overview of the molecular mechanisms behind MHC class I transcription and the role of the class I transactivator NLRC5 in MHC class I-dependent immune responses.

Modified human beta 2-microglobulin (desLys(58)) displays decreased affinity for the heavy chain of MHC class I and induces nitric oxide production and apoptosis

DEFF Research Database (Denmark)

Wang, M; Harhaji, L; Lamberth, K

2009-01-01

Beta2-microglobulin (beta2m) is the light chain of major histocompatibility complex class I (MHC-I) molecules, and is a prerequisite for the binding of peptides to the heavy chain and their presentation to CD8+ T cells. beta2m can be modified in vivo and in vitro by proteolytic cleavage...... by complement C1 and subsequent carboxypeptidase B-like activity--processes that lead to the generation of desLys(58) beta2m (dbeta2m). This work aims to study the effect of dbeta2m on peptide binding to MHC-I, the influence of dbeta2m on the binding of beta2m to the MHC-I heavy chain and the biological...... activity of dbeta2m. Both beta2m and dbeta2m are able to support the generation of MHC-I/peptide complexes at 18 degrees C, but complexes formed in the presence of dbeta2m destabilize at 37 degrees C. Moreover, a 250 times higher concentration of dbeta2m than of beta2m is needed to displace MHC...

The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators

Science.gov (United States)

Forlani, Greta; Abdallah, Rawan; Accolla, Roberto S.; Tosi, Giovanna

2013-01-01

The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution. PMID:23986750

Neuronal MHC Class I Expression Is Regulated by Activity Driven Calcium Signaling.

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Dan Lv

Full Text Available MHC class I (MHC-I molecules are important components of the immune system. Recently MHC-I have been reported to also play important roles in brain development and synaptic plasticity. In this study, we examine the molecular mechanism(s underlying activity-dependent MHC-I expression using hippocampal neurons. Here we report that neuronal expression level of MHC-I is dynamically regulated during hippocampal development after birth in vivo. Kainic acid (KA treatment significantly increases the expression of MHC-I in cultured hippocampal neurons in vitro, suggesting that MHC-I expression is regulated by neuronal activity. In addition, KA stimulation decreased the expression of pre- and post-synaptic proteins. This down-regulation is prevented by addition of an MHC-I antibody to KA treated neurons. Further studies demonstrate that calcium-dependent protein kinase C (PKC is important in relaying KA simulation activation signals to up-regulated MHC-I expression. This signaling cascade relies on activation of the MAPK pathway, which leads to increased phosphorylation of CREB and NF-κB p65 while also enhancing the expression of IRF-1. Together, these results suggest that expression of MHC-I in hippocampal neurons is driven by Ca2+ regulated activation of the MAPK signaling transduction cascade.

Zoledronate complexes. III. Two zoledronate complexes with alkaline earth metals: [Mg(C(5)H(9)N(2)O(7)P(2))(2)(H(2)O)(2)] and [Ca(C(5)H(8)N(2)O(7)P(2))(H(2)O)](n).

Science.gov (United States)

Freire, Eleonora; Vega, Daniel R; Baggio, Ricardo

2010-06-01

Diaquabis[dihydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonato-kappa(2)O,O']magnesium(II), [Mg(C(5)H(9)N(2)O(7)P(2))(2)(H(2)O)(2)], consists of isolated dimeric units built up around an inversion centre and tightly interconnected by hydrogen bonding. The Mg(II) cation resides at the symmetry centre, surrounded in a rather regular octahedral geometry by two chelating zwitterionic zoledronate(1-) [or dihydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonate] anions and two water molecules, in a pattern already found in a few reported isologues where the anion is bound to transition metals (Co, Zn and Ni). catena-Poly[[aquacalcium(II)]-mu(3)-[hydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonato]-kappa(5)O:O,O':O',O''], [Ca(C(5)H(8)N(2)O(7)P(2))(H(2)O)](n), consists instead of a Ca(II) cation in a general position, a zwitterionic zoledronate(2-) anion and a coordinated water molecule. The geometry around the Ca(II) atom, provided by six bisphosphonate O atoms and one water ligand, is that of a pentagonal bipyramid with the Ca(II) atom displaced by 0.19 A out of the equatorial plane. These Ca(II) coordination polyhedra are ;threaded' by the 2(1) axis so that successive polyhedra share edges of their pentagonal basal planes. This results in a strongly coupled rhomboidal Ca(2)-O(2) chain which runs along [010]. These chains are in turn linked by an apical O atom from a -PO(3) group in a neighbouring chain. This O-atom, shared between chains, generates strong covalently bonded planar arrays parallel to (100). Finally, these sheets are linked by hydrogen bonds into a three-dimensional structure. Owing to the extreme affinity of zoledronic acid for bone tissue, in general, and with calcium as one of the major constituents of bone, it is expected that this structure will be useful in modelling some of the biologically interesting processes in which the drug takes part.

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule.

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Chen, B P; Madrigal, A; Parham, P

1990-09-01

Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.

The Tunable Bandgap of AB-Stacked Bilayer Graphene on SiO2 with H2O Molecule Adsorption

International Nuclear Information System (INIS)

Wang Tao; Guo Qing; Liu Yan; Wang Wen-Bo; Sheng Kuang; Ao Zhi-Min; Yu Bin

2011-01-01

The atomic and electronic structures of AB-stacking bilayer graphene (BLG) in the presence of H 2 O molecules are investigated by density functional theory calculations. For free-standing BLG, the bandgap is opened to 0.101 eV with a single H 2 O molecule adsorbed on its surface. The perfectly suspended BLG is sensitive to H 2 O adsorbates, which break the BLG lattice symmetry and open an energy gap. While a single H 2 O molecule is adsorbed on the BLG surface with a SiO 2 substrate, the bandgap widens to 0.363 eV. Both the H 2 O molecule adsorption and the oxide substrate contribute to the BLG bandgap opening. The phenomenon is interpreted with the charge transfer process in 2D carbon nanostructures. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

Peptide binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes, and include HLA-B27-like alleles

OpenAIRE

Mothé, Bianca R.; Southwood, Scott; Sidney, John; English, A. Michelle; Wriston, Amanda; Hoof, Ilka; Shabanowitz, Jeffrey; Hunt, Donald F.; Sette, Alessandro

2013-01-01

Chinese rhesus macaques are of particular interest in SIV/HIV research as these animals have prolonged kinetics of disease progression to AIDS, compared to their Indian counterparts, suggesting that they may be a better model for HIV. Nevertheless, the specific mechanism(s) accounting for these kinetics remains unclear. The study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide binding motifs, provides valuable information for measuring cellular immune response...

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

DEFF Research Database (Denmark)

Solomon, C.; Southwood, S.; Hoof, Ilka

2010-01-01

Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus.......3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide...

ER stress affects processing of MHC class I-associated peptides

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Meloche Sylvain

2009-02-01

Full Text Available Abstract Background Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR. The UPR regulates the two key processes that control major histocompatibility complex class I (MHC I-peptide presentation: protein synthesis and degradation. We therefore asked whether and how the UPR impinges on MHC I-peptide presentation. Results We evaluated the impact of the UPR on global MHC I expression and on presentation of the H2Kb-associated SIINFEKL peptide. EL4 cells stably transfected with vectors coding hen egg lysozyme (HEL-SIINFEKL protein variants were stressed with palmitate or exposed to glucose deprivation. UPR decreased surface expression of MHC I but did not affect MHC I mRNA level nor the total amount of intracellular MHC I proteins. Impaired MHC I-peptide presentation was due mainly to reduced supply of peptides owing to an inhibition of overall protein synthesis. Consequently, generation of H2Kb-SIINFEKL complexes was curtailed during ER stress, illustrating how generation of MHC I peptide ligands is tightly coupled to ongoing protein synthesis. Notably, the UPR-induced decline of MHC I-peptide presentation was more severe when the protein source of peptides was localized in the cytosol than in the ER. This difference was not due to changes in the translation rates of the precursor proteins but to increased stability of the cytosolic protein during ER stress. Conclusion Our results demonstrate that ER stress impairs MHC I-peptide presentation, and that it differentially regulates expression of ER- vs. cytosol-derived peptides. Furthermore, this work illustrates how ER stress, a typical feature of infected and malignant cells, can impinge on cues for adaptive immune recognition.

A cell-based MHC stabilization assay for the detection of peptide binding to the canine classical class I molecule, DLA-88.

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Ross, Peter; Holmes, Jennifer C; Gojanovich, Gregory S; Hess, Paul R

2012-12-15

Identifying immunodominant CTL epitopes is essential for studying CD8+ T-cell responses in populations, but remains difficult, as peptides within antigens typically are too numerous for all to be synthesized and screened. Instead, to facilitate discovery, in silico scanning of proteins for sequences that match the motif, or binding preferences, of the restricting MHC class I allele - the largest determinant of immunodominance - can be used to predict likely candidates. The high false positive rate with this analysis ideally requires binding confirmation, which is obtained routinely by an assay using cell lines such as RMA-S that have defective transporter associated with antigen processing (TAP) machinery, and consequently, few surface class I molecules. The stabilization and resultant increased life-span of peptide-MHC complexes on the cell surface by the addition of true binders validates their identity. To determine whether a similar assay could be developed for dogs, we transfected a prevalent class I allele, DLA-88*50801, into RMA-S. In the BARC3 clone, the recombinant heavy chain was associated with murine β2-microglobulin, and importantly, could differentiate motif-matched and -mismatched peptides by surface MHC stabilization. This work demonstrates the potential to use RMA-S cells transfected with canine alleles as a tool for CTL epitope discovery in this species. Copyright © 2012 Elsevier B.V. All rights reserved.

Fast metastable hydrogen atoms from H2 molecules: twin atoms

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Trimèche A.

2015-01-01

Full Text Available It is a difficult task to obtain “twin atoms”, i.e. pairs of massive particles such that one can perform experiments in the same fashion that is routinely done with “twin photons”. One possible route to obtain such pairs is by dissociating homonuclear diatomic molecules. We address this possibility by investigating the production of metastable H(2s atoms coming from the dissociation of cold H2 molecules produced in a Campargue nozzle beam crossing an electron beam from a high intensity pulsed electron gun. Dissociation by electron impact was chosen to avoid limitations of target molecular excited states due to selection rules. Detectors placed several centimeters away from the collision center, and aligned with respect to possible common molecular dissociation channel, analyze the neutral fragments as a function of their time-of-flight (TOF through Lyman-α detection. Evidence for the first time observed coincidence of pairs of H(2s atoms obtained this way is presented.

Adsorption of H2S molecule on TiO2/Au nanocomposites: A density functional theory study

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Amirali Abbasi

2017-01-01

Full Text Available The adsorption of hydrogen sulfide molecule on undoped and N-doped TiO2/Au nanocomposites was investigated by density functional theory (DFT calculations. The results showed that the adsorption energies of H2S on the nanocomposites follow the order of 2N doped (Ti site>N-doped (Ti site>Undoped (Ti site. The structural properties including bond lengths, angles and adsorption energies and electronic properties in view of the projected density of states (PDOSs and molecular orbitals (MOs were analyzed in detail. The results indicated that the interaction between H2S molecule and N-doped TiO2/Au nanocomposite is stronger than that between H2S and undoped nanocomposite, suggesting that N-doping helps to strengthen the interaction of H2S with TiO2/Au nanocomposite. Mulliken population analysis was conducted to analyze the charge transfer between the nanocomposite and H2S molecule. Although H2S molecule has no significant interaction with undoped nanocomposite, it tends to be strongly adsorbed on the N-doped nanocomposite. The results also suggest that the two doped nitrogen atoms in TiO2 greatly strengthen the adsorption process, being a helpful procedure to help in the design and development of improved sensor devices for H2S detection.

Systems Li2B4O7 (Na2B4O7, K2B4O7)-N2H3H4OH-H2O at 25 deg C

International Nuclear Information System (INIS)

Skvortsov, V.G.; Sadetdinov, Sh.V.; Akimov, V.M.; Mitrasov, Yu.N.; Petrova, O.V.; Klopov, Yu.N.

1994-01-01

Phase equilibriums in the Li 2 B 4 O 7 (Na 2 B 4 O 7 , K 2 B 4 O 7 )-N 2 H 3 H 4 OH-H 2 O systems were investigated by methods of isothermal solubility, refractometry and PH-metry at 25 deg C for the first time. Lithium and sodium tetraborates was established to form phases of changed composition mM 2 B 4 O 7 ·nN 2 H 3 C 2 H 4 OH·XH 2 O, where M=Li, Na with hydrazine ethanol. K 2 B 4 O 7 ·4H 2 O precipitates in solid phase in the case of potassium salt. Formation of isomorphous mixtures was supported by X-ray diffraction and IR spectroscopy methods

Pan-specific prediction of peptide-MHC Class I complex stability, a correlate of T cell immunogenicity

DEFF Research Database (Denmark)

Rasmussen, Michael; Fenoy, Emilio; Harndahl, Mikkel

2016-01-01

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 b...

NKG2H-Expressing T Cells Negatively Regulate Immune Responses

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Daniela Dukovska

2018-03-01

Full Text Available The biology and function of NKG2H receptor, unlike the better characterized members of the NKG2 family NKG2A, NKG2C, and NKG2D, remains largely unclear. Here, we show that NKG2H is able to associate with the signaling adapter molecules DAP12 and DAP10 suggesting that this receptor can signal for cell activation. Using a recently described NKG2H-specific monoclonal antibody (mAb, we have characterized the expression and function of lymphocytes that express this receptor. NKG2H is expressed at the cell surface of a small percentage of peripheral blood mononuclear cell (PBMC and is found more frequently on T cells, rather than NK cells. Moreover, although NKG2H is likely to trigger activation, co-cross-linking of this receptor with an NKG2H-specific mAb led to decreased T cell activation and proliferation in polyclonal PBMC cultures stimulated by anti-CD3 mAbs. This negative regulatory activity was seen only after cross-linking with NKG2H, but not NKG2A- or NKG2C-specific monoclonal antibodies. The mechanism underlying this negative effect is as yet unclear, but did not depend on the release of soluble factors or recognition of MHC class I molecules. These observations raise the intriguing possibility that NKG2H may be a novel marker for T cells able to negatively regulate T cell responses.

Cross Talk between H2O2 and Interacting Signal Molecules under Plant Stress Response

Science.gov (United States)

Saxena, Ina; Srikanth, Sandhya; Chen, Zhong

2016-01-01

It is well established that oxidative stress is an important cause of cellular damage. During stress conditions, plants have evolved regulatory mechanisms to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of reactive oxygen species, which is subsequently converted to H2O2. H2O2 is continuously produced as the byproduct of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 immerges as an important factor during many biological processes. It has been established that it acts as a secondary messenger in signal transduction networks. In this review, we discuss potential roles of H2O2 and other signaling molecules during various stress responses. PMID:27200043

B7-H3 in tumors: friend or foe for tumor immunity?

Science.gov (United States)

Li, Gen; Quan, Yanchun; Che, Fengyuan; Wang, Lijuan

2018-02-01

B7-H3 is a type I transmembrane co-stimulatory molecule of the B7 family. B7-H3 mRNA is widely distributed in most tissues; however, B7-H3 protein is not constitutively expressed. Few molecules have been shown to mediate the regulation of B7-H3 expression, and their regulatory mechanisms remain unexplored. Recently, TREM-like transcript 2 (TLT-2) has been identified as a potential receptor of B7-H3. However, TLT-2 may not be the only receptor of B7-H3, as B7-H3 has many contradictory roles. As a co-stimulatory molecule, B7-H3 increases the proliferation of both CD4+ and CD8+ T-cells and enhances cytotoxic T-cell activity. However, greatly increased T-cell proliferation and IL-2 levels have been observed in the absence of B7-H3. Thus far, it has been shown that various tumors test positive for B7-H3 expression and that B7-H3 levels correlate with tumor growth, invasion, metastasis, malignant stage, and recurrence rate. Furthermore, transfection of cells with a B7-H3 plasmid and treatment with monoclonal antibodies to block B7-H3 are the main immunotherapeutic strategies for cancer treatment. Several groups have generated anti-B7-H3 antibodies and observed tumor growth suppression in vitro and in vivo. Therefore, it is likely that B7-H3 plays an important role in cancer diagnosis and treatment, aside from its role as a co-stimulatory molecule.

Sibling rivalry: competition between MHC class II family members inhibits immunity.

Science.gov (United States)

Denzin, Lisa K; Cresswell, Peter

2013-01-01

Peptide loading of major histocompatibility complex (MHC) class II molecules in the endosomes and lysosomes of antigen-presenting cells is catalyzed by human leukocyte antigen-DM (HLA-DM) and modulated by HLA-DO. In a structural study in this issue, Guce et al. show that HLA-DO is an MHC class II mimic and functions as a competitive and essentially irreversible inhibitor of HLA-DM activity, thereby inhibiting MHC class II antigen presentation.

The SysteMHC Atlas project.

Science.gov (United States)

Shao, Wenguang; Pedrioli, Patrick G A; Wolski, Witold; Scurtescu, Cristian; Schmid, Emanuel; Vizcaíno, Juan A; Courcelles, Mathieu; Schuster, Heiko; Kowalewski, Daniel; Marino, Fabio; Arlehamn, Cecilia S L; Vaughan, Kerrie; Peters, Bjoern; Sette, Alessandro; Ottenhoff, Tom H M; Meijgaarden, Krista E; Nieuwenhuizen, Natalie; Kaufmann, Stefan H E; Schlapbach, Ralph; Castle, John C; Nesvizhskii, Alexey I; Nielsen, Morten; Deutsch, Eric W; Campbell, David S; Moritz, Robert L; Zubarev, Roman A; Ytterberg, Anders Jimmy; Purcell, Anthony W; Marcilla, Miguel; Paradela, Alberto; Wang, Qi; Costello, Catherine E; Ternette, Nicola; van Veelen, Peter A; van Els, Cécile A C M; Heck, Albert J R; de Souza, Gustavo A; Sollid, Ludvig M; Admon, Arie; Stevanovic, Stefan; Rammensee, Hans-Georg; Thibault, Pierre; Perreault, Claude; Bassani-Sternberg, Michal; Aebersold, Ruedi; Caron, Etienne

2018-01-04

Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and recent developments in MS-based peptide analysis technologies now support the generation of the required data. Importantly, the availability of diverse immunopeptidomic datasets has resulted in an increasing need to standardize, store and exchange this type of data to enable better collaborations among researchers, to advance the field more efficiently and to establish quality measures required for the meaningful comparison of datasets. Here we present the SysteMHC Atlas (https://systemhcatlas.org), a public database that aims at collecting, organizing, sharing, visualizing and exploring immunopeptidomic data generated by MS. The Atlas includes raw mass spectrometer output files collected from several laboratories around the globe, a catalog of context-specific datasets of MHC class I and class II peptides, standardized MHC allele-specific peptide spectral libraries consisting of consensus spectra calculated from repeat measurements of the same peptide sequence, and links to other proteomics and immunology databases. The SysteMHC Atlas project was created and will be further expanded using a uniform and open computational pipeline that controls the quality of peptide identifications and peptide annotations. Thus, the SysteMHC Atlas disseminates quality controlled immunopeptidomic information to the public domain and serves as a community resource toward the generation of a high-quality comprehensive map of the human immunopeptidome and the support of consistent measurement of immunopeptidomic sample cohorts. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

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.

Science.gov (United States)

Quinn, Laura L; Williams, Luke R; White, Claire; Forrest, Calum; Zuo, Jianmin; Rowe, Martin

2016-01-01

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. 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

Circumvention of MHC class II restriction by genetic immunization.

Science.gov (United States)

Schuler, K; Lu, C; Chang, H D; Croft, M; Zanetti, M; Gerloni, M

2001-11-12

The fate of T cell responses to peptide-based vaccination is subject to constraints by the major histocompatibility complex (MHC), MHC restriction. Using as a model system of T and B cell epitopes from the circumsporozoite protein of Plasmodium falciparum malaria parasite, we show that vaccination by somatic transgene immunization readily primes Balb/c mice (H-2(d)) a strain previously reported to be non-responder to immunization with a synthetic peptide vaccine encompassing these epitopes. Following genetic vaccination Balb/c mice developed a primary T cell response comparable to that of the responder strain C57Bl/6 (H-2(b)). Following booster immunization on day 45 Balb/c mice responded with a typical T cell memory response. Priming induced the formation of specific antibodies, which rose sharply after booster immunization. These findings suggests that genetic immunization can circumvent MHC class II restriction.

NetMHCpan 4.0: Improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data

OpenAIRE

Jurtz, Vanessa; Paul, Sinu; Andreatta, Massimo; Marcatili, Paolo; Peters, Bjoern; Nielsen, Morten

2017-01-01

Cytotoxic T cells are of central importance in the immune systems response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC (major histocompatibility complex) class I molecules. Peptide binding to MHC molecules is the single most selective step in the antigen presentation pathway. On the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has therefore attracted large attention. In the past, predictors of peptide-...

Peptide-binding motifs of two common equine class I MHC molecules in Thoroughbred horses.

Science.gov (United States)

Bergmann, Tobias; Lindvall, Mikaela; Moore, Erin; Moore, Eugene; Sidney, John; Miller, Donald; Tallmadge, Rebecca L; Myers, Paisley T; Malaker, Stacy A; Shabanowitz, Jeffrey; Osterrieder, Nikolaus; Peters, Bjoern; Hunt, Donald F; Antczak, Douglas F; Sette, Alessandro

2017-05-01

Quantitative peptide-binding motifs of MHC class I alleles provide a valuable tool to efficiently identify putative T cell epitopes. Detailed information on equine MHC class I alleles is still very limited, and to date, only a single equine MHC class I allele, Eqca-1*00101 (ELA-A3 haplotype), has been characterized. The present study extends the number of characterized ELA class I specificities in two additional haplotypes found commonly in the Thoroughbred breed. Accordingly, we here report quantitative binding motifs for the ELA-A2 allele Eqca-16*00101 and the ELA-A9 allele Eqca-1*00201. Utilizing analyses of endogenously bound and eluted ligands and the screening of positional scanning combinatorial libraries, detailed and quantitative peptide-binding motifs were derived for both alleles. Eqca-16*00101 preferentially binds peptides with aliphatic/hydrophobic residues in position 2 and at the C-terminus, and Eqca-1*00201 has a preference for peptides with arginine in position 2 and hydrophobic/aliphatic residues at the C-terminus. Interestingly, the Eqca-16*00101 motif resembles that of the human HLA A02-supertype, while the Eqca-1*00201 motif resembles that of the HLA B27-supertype and two macaque class I alleles. It is expected that the identified motifs will facilitate the selection of candidate epitopes for the study of immune responses in horses.

A comparative analysis of viral peptides presented by contemporary human and chimpanzee MHC class I molecules

NARCIS (Netherlands)

van Deutekom, Hanneke W. M.; Hoof, Ilka; Bontrop, Ronald E.; Keşmir, Can

2011-01-01

Genetic factors such as the MHC influence the immunocompetence of an individual. MHC genes are the most polymorphic genes in primates, which is often interpreted as an adaptation to establish good T cell responses to a wide range of (evolving) pathogens. Chimpanzee MHC (Patr) genes are less

Repression of MHC class I transcription by HPV16E7 through interaction with a putative RXRβ motif and NF-κB cytoplasmic sequestration

International Nuclear Information System (INIS)

Li, Hui; Zhan, TaiLan; Li, Chang; Liu, Mugen; Wang, Qing K.

2009-01-01

Down-regulation of transcription of the MHC class I genes in HPV16 tumorigenic cells is partly due to HPV16E7 associated with the MHC class I promoter and repressed chromatin activation. In this study, we further demonstrated that HPV16E7 is physically associated with a putative RXRβ binding motif (GGTCA) of the proximal promoter of the MHC class I genes by using reporter transcriptional assays and chromatin immunoprecipitation assays. Our data also provide evidence that HPV16E7 inhibits TNF-α-induced up-regulation of MHC class I transcription by impaired nuclear translocation of NF-κB. More importantly, CaSki tumor cells treated with TSA and transfected with the constitutively active mutant form of IKK-α (which can activate NF-κB directly) showed a maximal level of up-regulation of MHC-I expression. Taken together, our results suggest that HPV16E7 may employ two independent mechanisms to ensure that either the constitutive or inducible transcription of MHC class I genes is down-regulated.

MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel

DEFF Research Database (Denmark)

Thomsen, Allan Randrup; Marker, O

1989-01-01

with regard to all three parameters was recessive, indicating that natural tolerance is not the mechanism explaining non-MHC dependent low responsiveness in this system. The implications of these findings are discussed with specific reference to the role of MHC genes in controlling resistance to infectious......, indicating that both H-2 and non-H-2 genes may influence the elimination of this virus. Differences in virus spread prior to appearance of the immune response could not explain the observed differences in clearance rate. On the other hand, inefficient clearance always correlated with low T cell...

MHC-I affects infection intensity but not infection status with a frequent avian malaria parasite in blue tits.

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Helena Westerdahl

Full Text Available Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load and infection status (infected or not. It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.

MHC-I affects infection intensity but not infection status with a frequent avian malaria parasite in blue tits.

Science.gov (United States)

Westerdahl, Helena; Stjernman, Martin; Råberg, Lars; Lannefors, Mimi; Nilsson, Jan-Åke

2013-01-01

Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC) molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load) and infection status (infected or not). It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.

Effect of conformational propensity of peptide antigens in their interaction with MHC class II molecules. Failure to document the importance of regular secondary structures

DEFF Research Database (Denmark)

Sette, A; Lamont, A; Buus, S

1989-01-01

the binding capacity, but no correlation was found between their effect and their alpha-helical, beta-sheet, or beta-turn conformational propensity as calculated by the Chou and Fasman algorithm. In summary, all the data presented herein suggest that, at least in the case of OVA 323-336 and IAd......, the propensity of the antigen molecule to form secondary structures such as alpha-helices, beta-sheets, or beta-turns does not correlate with its capacity to bind MHC molecules....

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data

DEFF Research Database (Denmark)

Jurtz, Vanessa Isabell; Paul, Sinu; Andreatta, Massimo

2017-01-01

by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging......Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway....... Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified...

Observing electron localization in a dissociating H2+ molecule in real time.

Science.gov (United States)

Xu, H; Li, Zhichao; He, Feng; Wang, X; Atia-Tul-Noor, A; Kielpinski, D; Sang, R T; Litvinyuk, I V

2017-06-16

Dissociation of diatomic molecules with odd number of electrons always causes the unpaired electron to localize on one of the two resulting atomic fragments. In the simplest diatomic molecule H 2 + dissociation yields a hydrogen atom and a proton with the sole electron ending up on one of the two nuclei. That is equivalent to breaking of a chemical bond-the most fundamental chemical process. Here we observe such electron localization in real time by performing a pump-probe experiment. We demonstrate that in H 2 + electron localization is complete in just 15 fs when the molecule's internuclear distance reaches 8 atomic units. The measurement is supported by a theoretical simulation based on numerical solution of the time-dependent Schrödinger equation. This observation advances our understanding of detailed dynamics of molecular dissociation.

rac-Ethyl 2-hydroxy-2,7,7-trimethyl-4-(4-nitrophenyl-5-oxo-3,4,5,6,7,8-hexahydro-2H-chromene-3-carboxylate

Directory of Open Access Journals (Sweden)

Konstantin A. Potekhin

2013-01-01

Full Text Available The title molecule, C21H25NO7, has four stereogenic centres and crystallized as a racemate. It consists of enantiomeric pairs with the relative configuration rac-(1R*,2S*,3R*. The cyclohexenone ring adopts an envelope conformation; the dimethyl-substituted C atom lies 0.640 (1 Å out of the mean plane formed by the rest of the ring atoms (r.m.s. deviation = 0.016 Å. The oxacyclohexene ring adopts a half-chair conformation, the hydroxy- and carboxyl-substituted C atoms lying −0.336 (1 and 0.419 (1 Å, respectively, out of the mean plane formed by the rest of the ring atoms (r.m.s. deviation = 0.002 Å. In the crystal, O—H...O hydrogen bonds link the molecules into a chain along the c-axis direction.

TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation

NARCIS (Netherlands)

Nair-Gupta, Priyanka; Baccarini, Alessia; Tung, Navpreet; Seyffer, Fabian; Florey, Oliver; Huang, Yunjie; Banerjee, Meenakshi; Overholtzer, Michael; Roche, Paul A.; Tampé, Robert; Brown, Brian D.; Amsen, Derk; Whiteheart, Sidney W.; Blander, J. Magarian

2014-01-01

Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly

Binding of human beta 2-microglobulin to murine EL4 thymoma cells upregulates MHC class I heavy-chain epitopes, inhibits IL-2 secretion and induces resistance to killing by natural killer cells

DEFF Research Database (Denmark)

Claësson, M H; Nissen, Mogens Holst

1994-01-01

line (ABLS-8), X63 B-lymphoma cells and YAC cells did not bind h beta 2m. In two of the T lymphomas, EL4 and BW5147, binding of h beta 2m led to an increase in major histocompatibility complex class I (MHC-I) heavy-chain epitope expression as measured by anti-H-2K/D antibody binding and FACS analysis....... EL4 cells which had bound h beta 2m decreased their rate of constitutive IL-2 secretion and became resistant to activated natural killer (NK) cell killing. The present data suggest the binding of h beta 2m to mouse T cells leads to conformational changes of MHC-I heavy chains which influence both...

Cell surface appearance of unexpected host MHC determinants on thymocytes from radiation bone marrow chimeras

International Nuclear Information System (INIS)

Sharrow, S.O.; Mathieson, B.J.; Singer, A.

1981-01-01

The phenotypic appearance of cell surface antigens on murine thymocytes from long-term radiation bone marrow chimeras was analyzed using indirect immunofluorescence and flow microfluorometry. Cells maturing in the thymi of these mice were typed for MHC (Kk, I-Ak, H-2b, Kb, and Ib) and non-MHC (Lty 1, Ly 9, and TL) determinants. All cells were of donor origin as determined by non-MHC (Ly) phenotype in P1 leads to P2, P1 x P2 leads to P1, and P1 leads to P2 radiation chimeras. In contrast, the MHC phenotypes of these thymocytes were markedly affected by the host environment. Specifically, H-2 and I-A determinants of both parental phenotypes were detected on thymocytes from P1 leads to P1 x P2 chimeras; I-A determinants of host phenotype were present, whereas I-A determinants of donor phenotype were reduced on thymocytes from P1 x P2 leads to P1 chimeras; and thymocytes from P1 leads to P2 chimeras possessed H-2 and I-A determinants of host phenotype but showed reduction of donor I-A phenotype determinants. The appearance of host cell surface H-2 and I-A determinants on thymocytes from chimeras closely parallels the functional recognition of MHC determinants by T cells from chimeric mice and thus may be significantly related to the development of the self-recognition repertoire by maturing T cells

Selective loss of mouse embryos due to the expression of transgenic major histocompatibility class I molecules early in embryogenesis.

Science.gov (United States)

Aït-Azzouzene, D; Langkopf, A; Cohen, J; Bleux, C; Gendron, M C; Kanellopoulos-Langevin, C

1998-05-01

Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regulation of expression of the polymorphic major histocompatibility complex (MHC) at the fetal-maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation, the absence of polymorphic MHC molecules on the early embryo, as well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class la gene H-2Kb under the control of a housekeeping gene promoter, the hydroxy-methyl-glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H-2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one-cell stage with the pHMG-Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal-maternal interface and in various transgenic mouse models.

MHC class II deficiency: Report of a novel mutation and special review.

Science.gov (United States)

Farrokhi, S; Shabani, M; Aryan, Z; Zoghi, S; Krolo, A; Boztug, K; Rezaei, N

The MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper. Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Detection of new MHC mutations in mice by skin grafting, tumor transplantation and monoclonal antibodies: a comparison

International Nuclear Information System (INIS)

Egorov, I.K.; Egorov, O.S.

1988-01-01

Two mechanisms of major histocompatibility complex (MHC) mutations have been described in mice: gene conversion and homologous but unequal recombination. However, the knowledge of mutations in MHC is incomplete because studies have been limited almost exclusively to two haplotypes, H-2/sup b/ and H-2/sup d/, while hundreds of haplotypes exist in nature; it has been biased by the use of only one procedure of screening for mutation, skin grafting. The authors used three procedures to screen for MHC mutations: (1) conventional techniques of skin grafting, (2) syngeneic tumor transplantation and (3) typing with monoclonal anti-MHC antibodies (mAbs) and complement. The faster technique of tumor transplantation detected mutants similar to those discovered by skin grafting technique. Screening with mAbs allowed us to detect both mutants that are capable of rejecting standard skin grafts and those that are silent in skin grafting tests, and which therefore resulted in a higher apparent mutation frequency. Two mutants of the H-2/sup a/ haplotype were found that carry concomitant class I and class II antigenic alterations. Both MHC mutants silent in skin grafting tests and mutants carrying concomitant class I and class II alterations have never been studied before and are expected to reveal new mechanisms of generating MHC mutations. 1-Ethyl-1-nitrosourea (ENU) failed to induce de novo MHC mutations in our skin grafting series

Tris[2-(2H-indazol-2-ylethyl]amine

Directory of Open Access Journals (Sweden)

Saúl Ovalle

2012-06-01

Full Text Available The title tertiary amine, C27H27N7, a potential tripodal ligand for coordination chemistry, crystallizes with the central N atom located on a threefold axis of a trigonal cell. The gauche conformation of the N(amime—CH2—CH2—N(indazole chain [torsion angle = −64.2 (2°] places the pendant 2H-indazole heterocycles surrounding the symmetry axis, affording a claw-like shaped molecule. Two symmetry-related indazole planes in the molecule make an acute angle of 60.39 (4°. The lone pair of the tertiary N atom is located inside the cavity, and should thus be inactive (as a ligand. In the crystal, neither significant π–π nor C—H...π interactions between molecules are found.

Analytic cross sections for collisions of H, H2, He and Li atoms and ions with atoms and molecules, 1

International Nuclear Information System (INIS)

Ito, Rinsuke; Tabata, Tatsuo; Shirai, Toshizo; Phaneuf, R.A.

1993-06-01

Analytic expressions fitted to Barnett's recommended data are given for the cross sections of the following reactions: (1) electron capture by H, H + , H 2 + , He + , and He 2+ colliding with atoms, molecules, and ions and (2) electron capture into excited states by H + , He + , and He 2+ colliding with atoms and molecules. The latter category includes cross sections for photon emission due to electron capture. The expressions use the semiempirical functional forms proposed by Green and McNeal and some modified forms to make it possible not only to interpolate but also to extrapolate the recommended data. (author)

Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity

Science.gov (United States)

Dunn, Steven M.; Rizkallah, Pierre J.; Baston, Emma; Mahon, Tara; Cameron, Brian; Moysey, Ruth; Gao, Feng; Sami, Malkit; Boulter, Jonathan; Li, Yi; Jakobsen, Bent K.

2006-01-01

The mammalian α/β T cell receptor (TCR) repertoire plays a pivotal role in adaptive immunity by recognizing short, processed, peptide antigens bound in the context of a highly diverse family of cell-surface major histocompatibility complexes (pMHCs). Despite the extensive TCR–MHC interaction surface, peptide-independent cross-reactivity of native TCRs is generally avoided through cell-mediated selection of molecules with low inherent affinity for MHC. Here we show that, contrary to expectations, the germ line-encoded complementarity determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to contact only the MHC surface and not the bound peptide, can be engineered to yield soluble low nanomolar affinity ligands that retain a surprisingly high degree of specificity for the cognate pMHC target. Structural investigation of one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact interfaces as being a key determinant of the increased affinity. Our results suggest that manipulation of germ line CDR2 loops may provide a useful route to the production of high-affinity TCRs with therapeutic and diagnostic potential. PMID:16600963

Ion-Molecule Reaction of Gas-Phase Chromium Oxyanions: CrxOyHz- + H2O

International Nuclear Information System (INIS)

Gianotto, Anita Kay; Hodges, Brittany DM; Benson, Michael Timothy; Harrington, Peter Boves; Appelhans, Anthony David; Olson, John Eric; Groenewold, Gary Steven

2003-01-01

Chromium oxyanions having the general formula CrxOyHz- play a key role in many industrial, environmental, and analytical processes, which motivated investigations of their intrinsic reactivity. Reactions with water are perhaps the most significant, and were studied by generating CrxOyHz- in the gas phase using a quadrupole ion trap secondary ion mass spectrometer. Of the ions in the Cr1OyHz envelope (y = 2, 3, 4; z = 0, 1), only CrO2- was observed to react with H2O, producing the hydrated CrO3H2- at a slow rate (∼0.07% of the ion-molecule collision constant at 310 K). CrO3-, CrO4-, and CrO4H- were unreactive. In contrast, Cr2O4-, Cr2O5-, and Cr2O5H2- displayed a considerable tendency to react with H2O. Cr2O4- underwent sequential reactions with H2O, initially producing Cr2O5H2- at a rate that was ∼7% efficient. Cr2O5H2- then reacted with a second H2O by addition to form Cr2O6H4- (1.8% efficient) and by OH abstraction to form Cr2O6H3- (0.6% efficient). The reactions of Cr2O5- were similar to those of Cr2O5H2-: Cr2O5- underwent addition to form Cr2O6H2- (3% efficient) and OH abstraction to form Cr2O6H- (<1% efficient). By comparison, Cr2O6- was unreactive with H2O, and in fact, no further H2O addition could be observed for any of the Cr2O6Hz- anions. Hartree-Fock ab initio calculations showed that reactive CrxOyHz- species underwent nucleophilic attack by the incoming H2O molecules, which produced an initially formed adduct in which the water O was bound to a Cr center. The experimental and computational studies suggested that Cr2OyHz- species that have bi- or tricoordinated Cr centers are susceptible to attack by H2O; however, when the metal becomes tetracoordinate, reactivity stops. For the Cr2OyHz- anions the lowest energy structures all contained rhombic Cr2O2 rings with pendant O atoms and/or OH groups. The initially formed [Cr2Oy- + H2O] adducts underwent H rearrangement to a gem O atom to produce stable dihydroxy structures. The calculations indicated that

7-Diethylamino-2-oxo-2H-chromene-3-carbohydrazide

Directory of Open Access Journals (Sweden)

Li-Jun Zhang

2011-05-01

Full Text Available The asymmetric unit of the title compound, C14H17N3O3, contains two independent molecules with different conformations of the ethyl groups. In the crystal, intermolecular N—H...O hydrogen bonds link the molecules into ribbons extending along the a axis.

Vibrational and cascade dissociation of H{sub 2}{sup +} ions by collision with gas molecules; Dissociation vibrationnelle et dissociation en cascade d'ions H{sub 2}{sup +} par collisions avec les molecules d'un gaz

Energy Technology Data Exchange (ETDEWEB)

Verveer, P [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires

1966-07-01

Protons produced by collisional dissociation of H{sub 2}{sup +} ions have an energy spectrum with a narrow central peak. For a part the protons in this peak are produced by vibrational dissociation and for another part by a cascade of two collisions. For H{sub 2}{sup +} ions of 50 to 150 keV the cross section for vibrational dissociation is about 4.1 10{sup -19} cm{sup 2}/molecule in hydrogen and 1.1 10{sup -18} cm{sup 2}/molecule in argon. (author) [French] Les protons resultant de la dissociation par collisions d'ions H{sub 2}{sup +} dans un gaz ont un spectre d'energie qui presente un pic central tres etroit. Les protons dans ce pic proviennent, pour une part de la dissociation vibrationnelle et pour l'autre part d'une suite de deux collisions. Dans le domaine d'energie des ions H{sub 2}{sup +} de 50 a 150 keV la section efficace de dissociation vibrationnel vaut 4.1 10{sup -19} cm{sup 2}/molecule pour l'hydrogene et 1,1 10{sup -18} cm{sup 2}/molecule pour l'argon.

Patterns of predicted T-cell epitopes associated with antigenic drift in influenza H3N2 hemagglutinin.

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E Jane Homan

Full Text Available Antigenic drift allowing escape from neutralizing antibodies is an important feature of transmission and survival of influenza viruses in host populations. Antigenic drift has been studied in particular detail for influenza A H3N2 and well defined antigenic clusters of this virus documented. We examine how host immunogenetics contributes to determination of the antibody spectrum, and hence the immune pressure bringing about antigenic drift. Using uTOPE™ bioinformatics analysis of predicted MHC binding, based on amino acid physical property principal components, we examined the binding affinity of all 9-mer and 15-mer peptides within the hemagglutinin 1 (HA1 of 447 H3N2 virus isolates to 35 MHC-I and 14 MHC-II alleles. We provide a comprehensive map of predicted MHC-I and MHC-II binding affinity for a broad array of HLA alleles for the H3N2 influenza HA1 protein. Each HLA allele exhibited a characteristic predicted binding pattern. Cluster analysis for each HLA allele shows that patterns based on predicted MHC binding mirror those described based on antibody binding. A single amino acid mutation or position displacement can result in a marked difference in MHC binding and hence potential T-helper function. We assessed the impact of individual amino acid changes in HA1 sequences between 10 virus isolates from 1968-2002, representative of antigenic clusters, to understand the changes in MHC binding over time. Gain and loss of predicted high affinity MHC-II binding sites with cluster transitions were documented. Predicted high affinity MHC-II binding sites were adjacent to antibody binding sites. We conclude that host MHC diversity may have a major determinant role in the antigenic drift of influenza A H3N2.

Gene transfer, expression, and sarcomeric incorporation of a headless myosin molecule in cardiac myocytes: evidence for a reserve in myofilament motor function

Science.gov (United States)

Vandenboom, Rene; Herron, Todd; Favre, Elizabeth; Albayya, Faris P.

2011-01-01

The purpose of this study was to implement a living myocyte in vitro model system to test whether a motor domain-deleted headless myosin construct could be incorporated into the sarcomere and affect contractility. To this end we used gene transfer to express a “headless” myosin heavy chain (headless-MHC) in complement with the native full-length myosin motors in the cardiac sarcomere. An NH2-terminal Flag epitope was used for unique detection of the motor domain-deleted headless-MHC. Total MHC content (i.e., headless-MHC + endogenous MHC) remained constant, while expression of the headless-MHC in transduced myocytes increased from 24 to 72 h after gene transfer until values leveled off at 96 h after gene transfer, at which time the headless-MHC comprised ∼20% of total MHC. Moreover, immunofluorescence labeling and confocal imaging confirmed expression and demonstrated incorporation of the headless-MHC in the A band of the cardiac sarcomere. Functional measurements in intact myocytes showed that headless-MHC modestly reduced amplitude of dynamic twitch contractions compared with controls (P < 0.05). In chemically permeabilized myocytes, maximum steady-state isometric force and the tension-pCa relationship were unaltered by the headless-MHC. These data suggest that headless-MHC can express to 20% of total myosin and incorporate into the sarcomere yet have modest to no effects on dynamic and steady-state contractile function. This would indicate a degree of functional tolerance in the sarcomere for nonfunctional myosin molecules. PMID:21112946

Predicted MHC peptide binding promiscuity explains MHC class I 'hotspots' of antigen presentation defined by mass spectrometry eluted ligand data.

Science.gov (United States)

Jappe, Emma Christine; Kringelum, Jens; Trolle, Thomas; Nielsen, Morten

2018-02-15

Peptides that bind to and are presented by MHC class I and class II molecules collectively make up the immunopeptidome. In the context of vaccine development, an understanding of the immunopeptidome is essential, and much effort has been dedicated to its accurate and cost-effective identification. Current state-of-the-art methods mainly comprise in silico tools for predicting MHC binding, which is strongly correlated with peptide immunogenicity. However, only a small proportion of the peptides that bind to MHC molecules are, in fact, immunogenic, and substantial work has been dedicated to uncovering additional determinants of peptide immunogenicity. In this context, and in light of recent advancements in mass spectrometry (MS), the existence of immunological hotspots has been given new life, inciting the hypothesis that hotspots are associated with MHC class I peptide immunogenicity. We here introduce a precise terminology for defining these hotspots and carry out a systematic analysis of MS and in silico predicted hotspots. We find that hotspots defined from MS data are largely captured by peptide binding predictions, enabling their replication in silico. This leads us to conclude that hotspots, to a great degree, are simply a result of promiscuous HLA binding, which disproves the hypothesis that the identification of hotspots provides novel information in the context of immunogenic peptide prediction. Furthermore, our analyses demonstrate that the signal of ligand processing, although present in the MS data, has very low predictive power to discriminate between MS and in silico defined hotspots. © 2018 John Wiley & Sons Ltd.

pKWmEB: integration of Kruskal-Wallis test with empirical Bayes under polygenic background control for multi-locus genome-wide association study.

Science.gov (United States)

Ren, Wen-Long; Wen, Yang-Jun; Dunwell, Jim M; Zhang, Yuan-Ming

2018-03-01

Although nonparametric methods in genome-wide association studies (GWAS) are robust in quantitative trait nucleotide (QTN) detection, the absence of polygenic background control in single-marker association in genome-wide scans results in a high false positive rate. To overcome this issue, we proposed an integrated nonparametric method for multi-locus GWAS. First, a new model transformation was used to whiten the covariance matrix of polygenic matrix K and environmental noise. Using the transferred model, Kruskal-Wallis test along with least angle regression was then used to select all the markers that were potentially associated with the trait. Finally, all the selected markers were placed into multi-locus model, these effects were estimated by empirical Bayes, and all the nonzero effects were further identified by a likelihood ratio test for true QTN detection. This method, named pKWmEB, was validated by a series of Monte Carlo simulation studies. As a result, pKWmEB effectively controlled false positive rate, although a less stringent significance criterion was adopted. More importantly, pKWmEB retained the high power of Kruskal-Wallis test, and provided QTN effect estimates. To further validate pKWmEB, we re-analyzed four flowering time related traits in Arabidopsis thaliana, and detected some previously reported genes that were not identified by the other methods.

Syntheses and Thermal Behaviors of Rb(FOX-7)·H2O and Cs(FOX-7)·H2O

International Nuclear Information System (INIS)

Luo, Jinan; Xu, Kangzhen; Wang, Min; Ren, Xiaolei; Chen, Yongshun; Song, Jirong; Zhao, Fengqi

2010-01-01

Two new energetic organic alkali metal salts, 1,1-diamino-2,2-dinitroethylene rubidium salt [Rb(FOX-7)·H 2 O] and 1,1- diamino-2,2-dinitroethylene cesium salt [Cs(FOX-7)·H 2 O], were synthesized by reacting of 1,1-diamino-2,2-dinitroethylene (FOX-7) and rubidium chloride or cesium chloride in alkali methanol aqueous solution, respectively. The thermal behaviors of Rb(FOX-7)·H 2 O and Cs(FOX-7)·H 2 O were studied with DSC and TG methods. The critical temperatures of thermal explosion of the two compounds are 216.22 and 223.73 .deg. C, respectively. Specific heat capacities of the two compounds were determined with a micro-DSC method, and the molar heat capacities are 217.46 and 199.47 J mol -1 K -1 at 298.15 K, respectively. The adiabatic times-to-explosion were also calculated to be a certain value of 5.81 - 6.36 s for Rb(FOX-7)·H 2 O, and 9.92 - 10.54 s for Cs(FOX-7)·H 2 O. After FOX-7 becoming alkali metal salts, thermal decomposition temperatures of the compounds heighten with the rise of element period, but thermal decomposition processes become intense

4-Methyl-2-oxo-2H-chromen-7-yl 4-methoxybenzenesulfonate

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Suman Sinha

2011-12-01

Full Text Available In the title compound, C17H14O6S, the 2H-chromene ring is essentially planar, with a maximum deviation of 0.016 (1 Å. The dihedral angle between the 2H-chromene and the benzene rings is 54.61 (5°. The C atom of the methoxy group is close to coplanar with its attached ring [deviation = 0.082 (2 Å]. In the crystal, molecules are connected via C—H...O hydrogen bonds, forming sheets lying parallel to the bc plane. Weak C—H...π interactions are also observed.

Ethyl (E)-2-(2,7-dimethyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-4-ylidene)acetate

OpenAIRE

Oulemda Bassou; Hakima Chicha; Latifa Bouissane; El Mostapha Rakib; Mohamed Saadi; Lahcen El Ammari

2017-01-01

In the title compound, C14H14O5, the two heterocyclic rings are coplanar (r.m.s. deviation = 0.008 Å), with the largest deviation from the mean plane being 0.012 (1) Å. The mean plane through the acetate group is inclined slightly with respect to the oxopyrano[4,3-b]pyran-4-yl system, as indicated by the dihedral angle of 1.70 (7)° between them. Two intramolecular hydrogen bonds, completing S(6) ring motifs, are observed in the molecule. In the crystal, molecules are linked by weak C—H...O hy...

It's the peptide-MHC affinity, stupid.

Science.gov (United States)

Kammertoens, Thomas; Blankenstein, Thomas

2013-04-15

Adoptively transferred T cells can reject large established tumors, but recurrence due to escape variants frequently occurs. In this issue of Cancer Cell, Engels et al. demonstrate that the affinity of the target peptide to the MHC molecule determines whether large tumors will relapse following adoptive T cell therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Patterns of MHC-G-Like and MHC-B Diversification in New World Monkeys.

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Juan S Lugo

Full Text Available The MHC class I (MHC-I region in New World monkeys (Platyrrhini has remained relatively understudied. To evaluate the diversification patterns and transcription behavior of MHC-I in Platyrrhini, we first analyzed public genomic sequences from the MHC-G-like subregion in Saimiri boliviensis, Ateles geoffroyi and Callicebus moloch, and from the MHC-B subregion in Saimiri boliviensis. While S. boliviensis showed multiple copies of both MHC-G-like (10 and -B (15 loci, A. geoffroyi and C. moloch had only three and four MHC-G-like genes, respectively, indicating that not all Platyrrhini species have expanded their MHC-I loci. We then sequenced MHC-G-like and -B cDNAs from nine Platyrrhini species, recovering two to five unique cDNAs per individual for both loci classes. In two Saguinus species, however, no MHC-B cDNAs were found. In phylogenetic trees, MHC-G-like cDNAs formed genus-specific clusters whereas the MHC-B cDNAs grouped by Platyrrhini families, suggesting a more rapid diversification of the former. Furthermore, cDNA sequencing in 12 capuchin monkeys showed that they transcribe at least four MHC-G-like and five MHC-B polymorphic genes, showing haplotypic diversity for gene copy number and signatures of positive natural selection at the peptide binding region. Finally, a quantitative index for MHC:KIR affinity was proposed and tested to predict putative interacting pairs. Altogether, our data indicate that i MHC-I genes has expanded differentially among Platyrrhini species, ii Callitrichinae (tamarins and marmosets MHC-B loci have limited or tissue-specific expression, iii MHC-G-like genes have diversified more rapidly than MHC-B genes, and iv the MHC-I diversity is generated mainly by genetic polymorphism and gene copy number variation, likely promoted by natural selection for ligand binding.

Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?

NARCIS (Netherlands)

Carrillo-Bustamante, Paola; Kesmir, Can; de Boer, Rob J

2015-01-01

Natural killer (NK) cells express inhibiting receptors (iNKRs), which specifically bind MHC-I molecules on the surface of healthy cells. When the expression of MHC-I on the cell surface decreases, which might occur during certain viral infections and cancer, iNKRs lose inhibiting signals and the

Signal transduction by the major histocompatibility complex class I molecule

DEFF Research Database (Denmark)

Pedersen, A E; Skov, Svend; Bregenholt, S

1999-01-01

Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....

Public epitopes and the antigenic structure of the HLA molecules.

Science.gov (United States)

Rodey, G E; Fuller, T C

1987-01-01

Simplified procedures for determining amino acid sequences in proteins and nucleotide sequences in DNA have rapidly expanded the number of MHC molecules for which primary amino acid structure is known. These molecules will be especially valuable as tools to study the structure-function relationships of globular proteins because of the extensive polymorphism of genes coding the MHC genes products. The general three-dimensional structure of class I MHC molecules was recently deduced, but the more subtle topographical microconformations are still undefined. Definition and topographical mapping of epitopes, defined by serological or cellular immune effector products, will be critical probes for these three-dimensional studies. Comparative studies of amino acid sequences among various MHC and molecules have revealed distinct regions of hypervariability in the alpha-1 and -2 domains of class I heavy chains and the alpha-1 and beta-1 domains of most class II molecules. Mutant MHC molecules that differ from each other by no more than one to three amino acids can have structural changes which may result in a loss of the private epitopes that defined the allelic gene product. On the basis of these studies, the private epitopes are thought to be determined by one or more of the hypervariable regions. Similar studies of the relationships between specific regions of the molecule and public epitopes are not fully explored. Because public epitopes are partially conserved structures, one might expect that their structure is not principally determined by hypervariable region. In fact, however, some public epitopes, such as A2/B17 and BW4/Bw6, do map to diversity regions. Epitope mapping as a means of identifying specific topographic sites and relating these sites to specific functional regions of the molecule will be difficult unless the epitopes themselves are better defined. Thus, the capacity to distinguish spatially distinct public epitopes from cross-reactive homologous

5HT(4) agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes

NARCIS (Netherlands)

Zeinstra, Esther M.; Wilczak, Nadine; Wilschut, Jan C.; Glazenburg, Lisa; Chesik, Daniel; Kroese, Frans G. M.; De Keyser, Jacques

2006-01-01

A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT4 serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced

Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

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Sofia Johansson

Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

A Novel Therapeutic Vaccine for Metastatic Mammary Carcinoma: Focusing MHC/Peptide Complexes to Lipid Rafts

Science.gov (United States)

2006-11-01

reportable outcomes). Briefly, the T cell lymphoma EL4 and the immortalized fibroblast cell line DAP (both expressing ova) were used to measure...and Use Committee. Cells , transfections, and antibodies B16.BL6 8.2, A20, EL4 and EL4 /ova were cultured as described (20-22). NIH3T3 cells were...types can donate MHC class I molecules to DC. To determine if the levels of MHC class I on the donor cell affected the efficiency of transfer, EL4 /ova

Theoretical study of the interaction of N2 with water molecules. (H2O)/sub n/:N2, n = 1--8

International Nuclear Information System (INIS)

Curtiss, L.A.; Eisgruber, C.L.

1984-01-01

Ab initio molecular orbital calculations including correlation energy have been carried out on the interaction of a single H 2 O molecule with N 2 . The potential energy surface for H 2 O:N 2 is found to have a minimum corresponding to a HOH xxx N 2 structure with a weak ( -1 ) hydrogen bond. A second, less stable, configuration corresponding to a H 2 O xxx N 2 structure with N 2 bonded side on to the oxygen of H 2 O was found to be either a minimum or a saddle point in the potential energy surface depending on the level of calculation. The minimal STO-3G basis set was used to investigate the interaction of up to eight H 2 O molecules with N 2 . Two types of clusters, one containing only HOH xxx N 2 interactions and the other containing both HOH xxxN 2 and H 2 O xxx N 2 interactions, were investigated for [N 2 :(H 2 O)/sub n/, n = 2--8

Increased antigen presentation but impaired T cells priming after upregulation of interferon-beta induced by lipopolysaccharides is mediated by upregulation of B7H1 and GITRL.

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Fang Wang

Full Text Available Dendritic cells are able to present Ag-derived peptides on MHC class I and II molecules and induce T cells priming. Lipopolysaccharides (LPS, an activator of Toll-like 4 receptor (TLR4 signaling, has been demonstrated to facilitate Ag-presentation, up-regulate surface molecules expression but impair T cells priming. In this study, we investigated the effect of LPS on nicotine-enhanced DCs-dependent T cells priming and the mechanisms of LPS orchestrating the immunosuppressive program. We could demonstrate that the treatment with LPS resulted in increased surface molecules expression, enhanced Ag-presentation, up-regulated release of TGF-beta, TNF-alpha, IL-6, and IFN-beta. Concomititantly, the upregulation of IFN-beta in DCs induces the up-regulation of coinhibitory molecules B7H1 and GITRL, which cause an impaired activation of naïve Ag-specific T cells and the induction of T cell tolerance by enhancing B7H1-PD-1 interactions and promoting GITRL-GITL facilitated Treg generation, respectively. These data provide a mechanistic basis for the immunomodulatory action of IFN-beta which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune response and persistent infection.

Peptide specific expansion of CD8(+) T cells by recombinant plate bound MHC/peptide complexes

DEFF Research Database (Denmark)

Schmidt, Esben G W; Buus, Soren; Thorn, Mette

2009-01-01

to in vitro T cell stimulation was investigated. By use of an antigenic peptide derived from the cytomegalovirus (CMVp) we tested the stimulatory efficacy of recombinant plate bound MHC molecules (PB-MHC), being immobilized in culture plates. A single stimulation of non-adherent peripheral blood mononuclear...

Systematic Characterisation of Cellular Localisation and Expression Profiles of Proteins Containing MHC Ligands

DEFF Research Database (Denmark)

Juncker, Agnieszka; Larsen, Mette Voldby; Weinhold, Nils

2009-01-01

Background: Presentation of peptides on Major Histocompatibility Complex (MHC) molecules is the cornerstone in immune system activation and increased knowledge of the characteristics of MHC ligands and their source proteins is highly desirable. Methodology/Principal Finding: In the present large......-scale study, we used a large data set of proteins containing experimentally identified MHC class I or II ligands and examined the proteins according to their expression profiles at the mRNA level and their Gene Ontology (GO) classification within the cellular component ontology. Proteins encoded by highly...

Channels with ordered water and bipyridine molecules in the porous coordination polymer {[Cu(SiF6(C10H8N22]·2C10N2H8·5H2O}n

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Emmanuel Aubert

2016-11-01

Full Text Available The coordination polymer {[Cu(SiF6(C10H8N22]·2C10H8N2·5H2O}n, systematic name: poly[[bis(μ2-4,4′-bipyridine(μ2-hexafluoridosilicatocopper(II] 4,4′-bipyridine disolvate pentahydrate], contains pores which are filled with water and 4,4′-bipyridine molecules. As a result of the presence of these ordered species, the framework changes its symmetry from P4/mmm to P21/c. The 4,4′-bipyridine guest molecules form chains inside the 6.5 × 6.9 Å pores parallel to [100] in which the molecules interact through π–π stacking. Ordered water molecules form infinite hydrogen-bonded chains inside a second pore system (1.6 × 5.3 Å free aperture perpendicular to the 4,4′-bipyridine channels.

Design of Peptide Immunotherapies for MHC Class-II-Associated Autoimmune Disorders

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Masha Fridkis-Hareli

2013-01-01

Full Text Available Autoimmune disorders, that occur when autoreactive immune cells are induced to activate their responses against self-tissues, affect one percent of the world population and represent one of the top 10 leading causes of death. The major histocompatibility complex (MHC is a principal susceptibility locus for many human autoimmune diseases, in which self-tissue antigens providing targets for pathogenic lymphocytes are bound to HLA molecules encoded by disease-associated alleles. In spite of the attempts to design strategies for inhibition of antigen presentation targeting the MHC-peptide/TCR complex via generation of blocking antibodies, altered peptide ligands (APL, or inhibitors of costimulatory molecules, potent therapies with minimal side effects have yet to be developed. Copaxone (glatiramer acetate, GA is a random synthetic amino acid copolymer that reduces the relapse rate by about 30% in relapsing-remitting multiple sclerosis (MS patients. Based on the elucidated binding motifs of Copaxone and of the anchor residues of the immunogenic myelin basic protein (MBP peptide to HLA-DR molecules, novel copolymers have been designed and proved to be more effective in suppressing MS-like disease in mice. In this report, we describe the rationale for design of second-generation synthetic random copolymers as candidate drugs for a number of MHC class-II-associated autoimmune disorders.

4-(4-Bromophenyl-7,7-dimethyl-2-methylamino-3-nitro-7,8-dihydro-4H-chromen-5(6H-one including an unknown solvate

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S. Antony Inglebert

2014-05-01

Full Text Available In the title compound, C18H19BrN2O4, the chromene unit is not quite planar (r.m.s. deviation = 0.199 Å, with the methyl C atoms lying 0.027 (4 and 1.929 (4 Å from the mean plane of the chromene unit. The six-membered carbocyclic ring of the chromene moiety adopts an envelope conformation, with the dimethyl-substituted C atom as the flap. The methylamine and nitro groups are slightly twisted from the chromene moiety, with C—N—C—O and O—N—C—C torsion angles of 2.7 (4 and −0.4 (4°, respectively. The dihedral angle between the mean plane of the chromene unit and the benzene ring is 85.61 (13°. An intramolecular N—H...O hydrogen bond generates an S(6 ring motif, which stabilizes the molecular conformation. In the crystal, molecules are linked via N—H...O hydrogen bonds, forming hexagonal rings lying parallel to the ab plane. A region of disordered electron density, most probably disordered ethanol solvent molecules, occupying voids of ca 432 Å3 for an electron count of 158, was treated using the SQUEEZE routine in PLATON [Spek (2009. Acta Cryst. D65, 148–155]. Their formula mass and unit-cell characteristics were not taken into account during refinement.

Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.

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Channakeshava Sokke Umeshappa

Full Text Available Involvement of CD4(+ helper T (Th cells is crucial for CD8(+ cytotoxic T lymphocyte (CTL-mediated immunity. However, CD4(+ Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA-pulsed dendritic cell (DCova. CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I complex signaling, CD4(+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2 and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7 molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.

Science.gov (United States)

Umeshappa, Channakeshava Sokke; Xie, Yufeng; Xu, Shulin; Nanjundappa, Roopa Hebbandi; Freywald, Andrew; Deng, Yulin; Ma, Hong; Xiang, Jim

2013-01-01

Involvement of CD4(+) helper T (Th) cells is crucial for CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4(+) Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+) Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+) T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b)/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4(+) Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+) Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+) Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

Features of target cell lysis by class I and class II MHC restricted cytolytic T lymphocytes

International Nuclear Information System (INIS)

Maimone, M.M.; Morrison, L.A.; Braciale, V.L.; Braciale, T.J.

1986-01-01

The lytic activity of influenza virus-specific muvine cytolytic T lymphocyte (CTL) clones that are restricted by either H-2K/D (class I) or H-2I (class II) major histocompatibility (MHC) locus products was compared on an influenza virus-infected target cell expressing both K/D and I locus products. With the use of two in vitro measurements of cytotoxicity, conventional 51 Cr release, and detergent-releasable radiolabeled DNA (as a measure of nuclear disintegration in the early post-lethal hit period), the authors found no difference between class I and class II MHC-restricted CTL in the kinetics of target cell destruction. In addition, class II MHC-restricted antiviral CTL failed to show any lysis of radiolabeled bystander cells. Killing of labeled specific targets by these class II MHC-restricted CTL was also efficiently inhibited by unlabeled specific competitor cells in a cold target inhibition assay. In sum, these data suggest that class I and class II MHC-restricted CTL mediate target cell destruction by an essentially similar direct mechanism

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

Science.gov (United States)

Jurtz, Vanessa; Paul, Sinu; Andreatta, Massimo; Marcatili, Paolo; Peters, Bjoern; Nielsen, Morten

2017-11-01

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes. Copyright © 2017 by The American Association of Immunologists, Inc.

Analytic cross sections for collisions of H, H2, He and Li Atoms and ions with atoms and molecules. 2

International Nuclear Information System (INIS)

Ito, Rinsuke; Tabata, Tatsuo; Shirai, Toshizo; Phaneuf, R.A.

1994-07-01

Analytic expressions fitted to Barnett's recommended data are given for the cross sections of excitation and spectral line emission by H, H + , He + , He, and He 2+ colliding with atoms and molecules. The expressions use the semiempirical functional forms proposed by Green and McNeal and some modified forms to make it possible not only to interpolate but also to extrapolate the recommended data. (author)

Horse cDNA clones encoding two MHC class I genes

Energy Technology Data Exchange (ETDEWEB)

Barbis, D.P.; Maher, J.K.; Stanek, J.; Klaunberg, B.A.; Antczak, D.F.

1994-12-31

Two full-length clones encoding MHC class I genes were isolated by screening a horse cDNA library, using a probe encoding in human HLA-A2.2Y allele. The library was made in the pcDNA1 vector (Invitrogen, San Diego, CA), using mRNA from peripheral blood lymphocytes obtained from a Thoroughbred stallion (No. 0834) homozygous for a common horse MHC haplotype (ELA-A2, -B2, -D2; Antczak et al. 1984; Donaldson et al. 1988). The clones were sequenced, using SP6 and T7 universal primers and horse-specific oligonucleotides designed to extend previously determined sequences.

Mixed Quantum/Classical Theory for Molecule-Molecule Inelastic Scattering: Derivations of Equations and Application to N2 + H2 System.

Science.gov (United States)

Semenov, Alexander; Babikov, Dmitri

2015-12-17

The mixed quantum classical theory, MQCT, for inelastic scattering of two molecules is developed, in which the internal (rotational, vibrational) motion of both collision partners is treated with quantum mechanics, and the molecule-molecule scattering (translational motion) is described by classical trajectories. The resultant MQCT formalism includes a system of coupled differential equations for quantum probability amplitudes, and the classical equations of motion in the mean-field potential. Numerical tests of this theory are carried out for several most important rotational state-to-state transitions in the N2 + H2 system, in a broad range of collision energies. Besides scattering resonances (at low collision energies) excellent agreement with full-quantum results is obtained, including the excitation thresholds, the maxima of cross sections, and even some smaller features, such as slight oscillations of energy dependencies. Most importantly, at higher energies the results of MQCT are nearly identical to the full quantum results, which makes this approach a good alternative to the full-quantum calculations that become computationally expensive at higher collision energies and for heavier collision partners. Extensions of this theory to include vibrational transitions or general asymmetric-top rotor (polyatomic) molecules are relatively straightforward.

Crystal structure of (Z-ethyl 3-[2-(5-methyl-7-nitro-1H-indole-2-carbonylhydrazinylidene]butanoate

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Amal Errossafi

2015-09-01

Full Text Available The reaction of 5-methyl-7-nitro-1H-indole-2-carbohydrazide with ethyl acetoacetate yielded the title molecule, C16H18N4O5, in which the indole ring is almost planar, with the greatest deviation from the mean plane being 0.006 (2 Å. The nine atoms of the indole ring are almost perpendicular to the mean plane through the ethyl acetate group, as indicated by the dihedral angle of 87.02 (4° between them. In the crystal, centrosymmetric supramolecular dimers are formed via N—H...O hydrogen bonds and eight-membered amide {...HNCO}2 synthons. These are consolidated into a three-dimensional architecture by C—H...O contacts, and by π–π interactions between six-membered rings [inter-centroid distance = 3.499 (2 Å].

MHC class II polymorphisms, autoreactive T-cells and autoimmunity

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Sue eTsai

2013-10-01

Full Text Available Major histocompatibility complex (MHC genes, also known as human leukocyte antigen genes (HLA in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D, Multiple Sclerosis (MS, and Rheumatoid arthritis (RA, among others (Todd and Wicker, 2001;MacKay et al., 2002;Hafler et al., 2007. Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T cell repertoires of the host towards autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development towards a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development towards non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

Liquefaction of H2 molecules upon exterior surfaces of carbon nanotube bundles

International Nuclear Information System (INIS)

Han, Sang Soo; Kang, Jeung Ku; Lee, Hyuck Mo; Duin, Adri C.T. van; Goddard, William A. III

2005-01-01

We have used molecular dynamics simulations to investigate interaction of H 2 molecules on the exterior surfaces of carbon nanotubes (CNTs): single and bundle types. At 80 K and 10 MPa, it is found that charge transfer occurs from a low curvature region to a high curvature region of the deformed CNT bundle, which develops charge polarization only on the deformed structure. The long-range electrostatic interactions of polarized charges on the deformed CNT bundle with hydrogen molecules are observed to induce a high local-ordering of H 2 gas that results in hydrogen liquefaction. Our predicted heat of hydrogen liquefaction on the CNT bundle is 97.6 kcal kg -1 . On the other hand, hydrogen liquefaction is not observed in the CNT of a single type. This is because charge polarization is not developed on the single CNT as it is symmetrically deformed under the same pressure. Consequently, the hydrogen storage capacity on the CNT bundle is much higher due to liquefaction than that on the single CNT. Additionally, our results indicate that it would also be possible to liquefy H 2 gas on a more strongly polarized CNT bundle at temperatures higher than 80 K

Structure of LaH(PO3H)2.3H2O

International Nuclear Information System (INIS)

Loukili, M.; Durand, J.; Larbot, A.; Cot, L.; Rafiq, M.

1991-01-01

Lanthanum hydrogen bis(hydrogenphosphite) trihydrate, LaH(Po 3 H) 2 .3H 2 O, M r =353.8, monoclinic, P2 1 /c, a=9.687 (3), b=7.138 (2), c=13.518 A, β=104.48 (3) deg, V=905.0 (5) A 3 , Z=4, D m =2.56 (2), D x =2.598 Mg m -3 , λ(MoKα)=0.71073 A, μ(MoKα)=5.103 mm -1 , F(000)=672, T=300 K, R=0.032 for 1018 independent observed reflections. The structure contains two phosphite anions connected by a hydrogen bond. The La 3+ cation is eight coordinated by seven O atoms from phosphite anions and one O atom of a water molecule. (orig.)

Synthesis of Zn-MOF incorporating titanium-hydrides as active sites binding H{sub 2} molecules

Energy Technology Data Exchange (ETDEWEB)

Kim, Jongsik, E-mail: jkim40@nd.edu [Department of Chemical and Biomolecular Engineering, University of Notre Dame, 182, Fitzpatrick Hall, Notre Dame, IN 46556 (United States); Ok Kim, Dong; Wook Kim, Dong; Sagong, Kil [Hanwha Chemical Research & Development Center, 6, Shinseong-dong, Yuseong-gu, Daejeon 305-804 (Korea, Republic of)

2015-10-15

This paper describes the synthetic effort for a Zn-MOF imparting Ti-H as a preferential binding site potentially capturing H{sub 2} molecules via Kubas-type interaction. The formation mechanism of Ti-H innate to the final material was potentially demonstrated to follow a radical dissociation rather than a β-hydrogen elimination and a C-H reductive elimination. - Graphical abstract: This study details the synthesis and the formation mechanism of Zn-MOF adsorbent site-isolating TiH{sub 3} that can potentially capture H{sub 2} molecules via Kubas-binding mechanism. - Highlights: • OH-functionalized Zn-MOF was employed as a reactive template to site-isolate TiH{sub 3}. • This MOF was post-synthetically modified using a tetracyclohexyl titanium (IV). • This intermediate was hydrogenolyzed to change ligand from cyclohexyl to hydride. • Formation mechanism of TiH{sub 3} was investigated via two control GC–MS experiments. • Final Zn-MOF potentially site-isolating TiH{sub 3} species was used as a H{sub 2} adsorbent.

IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA to inhibit MHC II presentation.

Directory of Open Access Journals (Sweden)

Qiliang Cai

2013-10-01

Full Text Available Peptides presentation to T cells by MHC class II molecules is of importance in initiation of immune response to a pathogen. The level of MHC II expression directly influences T lymphocyte activation and is often targeted by various viruses. Kaposi's sarcoma-associated herpesvirus (KSHV encoded LANA is known to evade MHC class I peptide processing, however, the effect of LANA on MHC class II remains unclear. Here, we report that LANA down-regulates MHC II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA promoter pIII and pIV in a dose-dependent manner. Strikingly, although LANA knockdown efficiently disrupts the inhibition of CIITA transcripts from its pIII and pIV promoter region, the expression of HLA-DQβ but no other MHC II molecules was significantly restored. Moreover, we revealed that the presentation of HLA-DQβ enhanced by LANA knockdown did not help LANA-specific CD4+ T cell recognition of PEL cells, and the inhibition of CIITA by LANA is independent of IL-4 or IFN-γ signaling but dependent on the direct interaction of LANA with IRF-4 (an activator of both the pIII and pIV CIITA promoters. This interaction dramatically blocked the DNA-binding ability of IRF-4 on both pIII and pIV promoters. Thus, our data implies that LANA can evade MHC II presentation and suppress CIITA transcription to provide a unique strategy of KSHV escape from immune surveillance by cytotoxic T cells.

Efficient assembly of recombinant major histocompatibility complex class I molecules with preformed disulfide bonds

DEFF Research Database (Denmark)

Ostergaard Pedersen, L; Nissen, Mogens Holst; Hansen, N J

2001-01-01

The expression of major histocompatibility class I (MHC-I) crucially depends upon the binding of appropriate peptides. MHC-I from natural sources are therefore always preoccupied with peptides complicating their purification and analysis. Here, we present an efficient solution to this problem....... Recombinant MHC-I heavy chains were produced in Escherichia coli and subsequently purified under denaturing conditions. In contrast to common practice, the molecules were not reduced during the purification. The oxidized MHC-I heavy chain isoforms were highly active with respect to peptide binding....... This suggests that de novo folding of denatured MHC-I molecules proceed efficiently if directed by preformed disulfide bond(s). Importantly, these molecules express serological epitopes and stain specific T cells; and they bind peptides specifically. Several denatured MHC-I heavy chains were analyzed and shown...

MHC variability in heritage breeds of chickens.

Science.gov (United States)

Fulton, J E; Lund, A R; McCarron, A M; Pinegar, K N; Korver, D R; Classen, H L; Aggrey, S; Utterbach, C; Anthony, N B; Berres, M E

2016-02-01

The chicken Major Histocompatibility Complex (MHC) is very strongly associated with disease resistance and thus is a very important region of the chicken genome. Historically, MHC (B locus) has been identified by the use of serology with haplotype specific alloantisera. These antisera can be difficult to produce and frequently cross-react with multiple haplotypes and hence their application is generally limited to inbred and MHC-defined lines. As a consequence, very little information about MHC variability in heritage chicken breeds is available. DNA-based methods are now available for examining MHC variability in these previously uncharacterized populations. A high density SNP panel consisting of 101 SNP that span a 230,000 bp region of the chicken MHC was used to examine MHC variability in 17 heritage populations of chickens from five universities from Canada and the United States. The breeds included 6 heritage broiler lines, 3 Barred Plymouth Rock, 2 New Hampshire and one each of Rhode Island Red, Light Sussex, White Leghorn, Dark Brown Leghorn, and 2 synthetic lines. These heritage breeds contained from one to 11 haplotypes per line. A total of 52 unique MHC haplotypes were found with only 10 of them identical to serologically defined haplotypes. Furthermore, nine MHC recombinants with their respective parental haplotypes were identified. This survey confirms the value of these non-commercially utilized lines in maintaining genetic diversity. The identification of multiple MHC haplotypes and novel MHC recombinants indicates that diversity is being generated and maintained within these heritage populations. © 2016 Poultry Science Association Inc.

Facts on the fragmentation of antigens in presenting cells, on the association of antigen fragments with MHC molecules in cell-free systems, and speculation on the cell biology of antigen processing

DEFF Research Database (Denmark)

Werdelin, O; Mouritsen, S; Petersen, B L

1988-01-01

The processing of a protein antigen is a multi-step event taking place in antigen-presenting cells. Processing is a prerequisite for the recognition of most antigens by T lymphocytes. The antigen is ingested by endocytosis, transported to an acid cellular compartment and subjected to proteolytic...... fragmentation. Some of the antigen fragments bind to MHC class II molecules and are transported to the surface of the antigen-presenting cell where the actual presentation to T lymphocytes occurs. The nature of the processed antigen, how and where it is derived and subsequently becomes associated with MHC...... molecules are the questions discussed in this review. To us, the entire concept of processing has appeal not only because it explains some hitherto well-established, but poorly understood, phenomena such as the fact that T lymphocytes focus their attention entirely upon antigens on other cells. It has...

2-Methyl-3-(2-methylphenyl-7-nitroquinazolin-4(3H-one

Directory of Open Access Journals (Sweden)

Edward R. T. Tiekink

2012-03-01

Full Text Available In the title methaqualone analogue, C16H13N3O3, the 2-tolyl group is almost orthogonal [dihedral angle = 85.20 (5°] to the fused ring system (r.m.s. deviation of fitted non-H atoms = 0.029 Å. In the crystal, twofold symmetry generates two-molecule aggregates linked by C—H...O and π–π interactions [ring centroid–centroid distance = 3.4967 (6 Å].

A SIFT study of the reactions of H2ONO+ ions with several types of organic molecules

Science.gov (United States)

Smith, David; Wang, Tianshu; Spanel, Patrik

2003-11-01

A selected ion flow tube (SIFT) study has been carried out of the reactions of hydrated nitrosonium ions, NO+H2O, which theory has equated to protonated nitrous acid ions, H2ONO+. One objective of this study was to investigate if this ion exhibits the properties of both a cluster ion and a protonated acid in their reactions with a variety of organic molecules. The chosen reactant molecules comprise two each of the following types--amines, terpenes, aromatic hydrocarbons, esters, carboxylic acids, ketones, aldehydes and alcohols. The reactant H2ONO+ (NO+H2O) ions are formed in a discharge ion source and injected into helium carrier gas where they are partially vibrationally excited and partially dissociated to NO+ ions. Hence, the reactions of the H2ONO+ ions had to be studies simultaneously with NO+ ions, the reactions of the latter ions readily being studied by selectively injecting NO+ ions into the carrier gas. The results of this study indicate that the H2ONO+ ions undergo a wide variety of reaction processes that depend on the properties of the reactant molecules such as their ionisation energies and proton affinities. These processes include charge transfer with compounds, M, that have low ionisation energies (producing M+), proton transfer with compounds possessing large proton affinities (MH+), hydride ion transfer (M---H+), alkyl radical (M---R+), alkoxide radical transfer (M---OR+), ion-molecule association (NO+H2OM) and ligand switching (NO+M), producing the ions given in parentheses.

Gapped sequence alignment using artificial neural networks: application to the MHC class I system

DEFF Research Database (Denmark)

Andreatta, Massimo; Nielsen, Morten

2016-01-01

. On this relatively simple system, we developed a sequence alignment method based on artificial neural networks that allows insertions and deletions in the alignment. Results: We show that prediction methods based on alignments that include insertions and deletions have significantly higher performance than methods...... trained on peptides of single lengths. Also, we illustrate how the location of deletions can aid the interpretation of the modes of binding of the peptide-MHC, as in the case of long peptides bulging out of the MHC groove or protruding at either terminus. Finally, we demonstrate that the method can learn...... the length profile of different MHC molecules, and quantified the reduction of the experimental effort required to identify potential epitopes using our prediction algorithm. Availability and implementation: The NetMHC-4.0 method for the prediction of peptide-MHC class I binding affinity using gapped...

1,5-Dimethyl-2-phenyl-1H-pyrazol-3(2H-one–4,4′-(propane-2,2-diylbis[1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H-one] (1/1

Directory of Open Access Journals (Sweden)

Krzysztof Lyczko

2013-01-01

Full Text Available The asymmetric unit of the title compound, C11H12N2O·C25H28N4O2, contains two different molecules. The smaller is known as antipyrine [systematic name: 1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H-one] and the larger is built up from two antypirine molecules which are connected through a C atom of the pyrazolone ring to a central propanyl part [systematic name: 4,4′-(propane-2,2-diylbis[1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H-one]. Intramolecular C—H...O hydrogen bonds occur in the latter molecule. In the crystal, C—H...O hydrogen bonds link the molecules into a two-dimensional network parallel to (001.

Systems Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O at 25 deg C. Sistemy Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O pri 25 grad S

Energy Technology Data Exchange (ETDEWEB)

Skvortsov, V G; Sadetdinov, Sh V; Akimov, V M; Mitrasov, Yu N; Petrova, O V; Klopov, Yu N [Chuvashskij Gosudarstvennyj Pedagogicheskij Inst., Cheboksary (Russian Federation) Universitet Druzhby Narodov, Moscow (Russian Federation)

1994-02-01

Phase equilibriums in the Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O systems were investigated by methods of isothermal solubility, refractometry and PH-metry at 25 deg C for the first time. Lithium and sodium tetraborates was established to form phases of changed composition mM[sub 2]B[sub 4]O[sub 7][center dot]nN[sub 2]H[sub 3]C[sub 2]H[sub 4]OH[center dot]XH[sub 2]O, where M=Li, Na with hydrazine ethanol. K[sub 2]B[sub 4]O[sub 7][center dot]4H[sub 2]O precipitates in solid phase in the case of potassium salt. Formation of isomorphous mixtures was supported by X-ray diffraction and IR spectroscopy methods.

Crystal structure of 2,2′′-bis(2,7-dichloro-9-hydroxy-9H-fluoren-9-yl-1,1′:4′,1′′-terphenyl triethylamine trisolvate

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Henrik Klien

2015-12-01

Full Text Available In the title solvate, C44H26Cl4O2·3C6H15N, the asymmetric part of the unit cell comprises two halves of the diol molecules, 2,2′′-bis(2,7-dichloro-9-hydroxy-9H-fluoren-9-yl-1,1′:4′,1′′-terphenyl, and three molecules of triethylamine, i. e. the diol molecules are located on crystallographic symmetry centres. Two of the solvent molecules are disordered over two positions [occupancy ratios of 0.567 (3:0.433 (3 and 0.503 (3:0.497 (3]. In the diol molecules, the outer rings of the 1,1′:4′,1′′-terphenyl elements are twisted with reference to their central arene ring and the mean planes of the fluorenyl moieties are inclined with respect to the terphenyl ring to which they are connected, the latter making dihedral angles of 82.05 (8 and 82.28 (8°. The presence of two 9-fluoren-9-ol units attached at positions 2 and 2′′ of the terphenyl moiety induces a `folded' geometry which is stabilized by intramolecular C—H...O hydrogen bonds and π–π stacking interactions, the latter formed between the fluorenyl units and the central ring of the terphenyl unit [centroid–centroid distances = 3.559 (1 and 3.562 (1 Å]. The crystal is composed of 1:2 complex units, in which the solvent molecules are associated with the diol molecules via O—H...N hydrogen bonds, while the remaining solvent molecule is linked to the host by a C—H...N hydrogen bond. The given pattern of intermolecular interactions results in formation of chain structures extending along [010].

Study of the unimolecular decompositions of the (C3H6)+2 and (c-C3H6)+2 complexes

International Nuclear Information System (INIS)

Tzeng, W.; Ono, Y.; Linn, S.H.; Ng, C.Y.

1985-01-01

The major product channels identified in the unimolecular decompositions ofC 3 H + 6 xC 3 H 6 and c-C 3 H + 6 xc-C 3 H 6 in the total energy [neutral (C 3 H 6 ) 2 or (c-C 3 H 6 ) 2 heat of formation plus excitation energy] range of approx.230--450 kcal/mol are C 3 H + 7 +C 3 H 5 , C 4 H + 7 +C 2 H 5 , C 4 H + 8 +C 2 H 4 , and C 5 H + 9 +CH 3 . The measured appearance energy for C 4 H + 7 (9.54 +- 0.04 eV) from (C 3 H 6 ) 2 is equal to the thermochemical threshold for the formation of C 4 H + 7 +C 2 H 5 from (C 3 H 6 ) 2 , indicating that the exit potential energy barrier for the ion--molecule reaction C 3 H + 6 +C 3 H 6 →C 4 H + 7 +C 2 H 5 is negligible. There is evidence that the formations of C 4 H + 7 +C 2 H 4 +H from (C 3 H 6 ) + 2 and (c-C 3 H 6 ) + 2 also proceed with high probabilities when they are energetically allowed. The variations of the relative abundances for C 4 H + 7 ,C 4 H + 8 , and C 5 H + 9 from (C 3 H 6 ) + 2 and (c-C 3 H 6 ) + 2 as a function of ionizing photon energy are in qualitative agreement, suggesting that (C 3 H 6 ) + 2 and (c-C 3 H 6 ) + 2 rearrange to similar C 6 H + 12 isomers prior to fragmentation. The fact that C 6 H + 11 is found to be a primary ion from the unimolecular decomposition of (c-C 3 H 6 ) + 2 but not (C 3 H 6 ) + 2 supports the conclusion that the distribution of C 6 H + 12 collision complexes involved in the C 3 H + 6 +C 3 H 6 reactions is different from that in the cyclopropane ion--molecule reactions

Quantum infinite order sudden approximation for ion-molecule reactions: treatment of the He + H2+ system

International Nuclear Information System (INIS)

Baer, M.; Nakamura, H.; Kouri, D.J.

1986-01-01

In this work the ion-molecule reaction He + H 2 + (v/sub i/) → HeH + (v/sub f/) + H(v/sub i/ = 0-7, v/sub f/ = 0-2) was studied quantum mechanically in the energy range 1.3 eV ≤ E/sub tot/ ≤ 1.8 eV. The calculations were carried out employing the Reactive Infinite Order Sudden Approximation (RIOSA). The two features characteristic of this system in the above energy range, namely the strong enhancement of the reaction rate with the initial vibrational energy (at a fixed total energy) and the relatively weak dependence of the cross sections on translational energy, were found to be well reproduced in the numerical treatment. The results also revealed the existence of two mechanisms of the exchange process: one is the ordinary mechanism and the other is probably related to the spectator stripping model

Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism.

Science.gov (United States)

Jahromi, Mohamed M

2012-12-01

Evidence for genes associated with risk for Type 1 diabetes (T1D) in the extended region of the major histocompatibility complex (MHC) genes is accumulating. The aim of this study was to investigate the association pattern of the extended MHC region with T1D susceptibility to identify effects independent of well established DR/DQ genes. A total of 394 Europid families with T1D were genotyped for the single nucleotide polymorphism (SNP) in the olfactory receptor family 14, subfamily J, member 1 (OR14J1) gene, rs9257691, in the MHC telomeric region. The OR provides "an internal depiction of our external world" through the capture of odorant molecules in the main OR system by several large families of G-protein coupled receptors (GPCR). These receptors transduce and chemosignals into the central nervous system (CNS). This SNP was chosen to identify its association with T1D. Interestingly, OR14J1C allele was significantly associated with T1D that seems to go with DRB1*0401, Χ(2)=10.9, p=0.0003. However, by fixing both genes of DR*0401-DQB1*0302, high risk, the association of T1D with OR14J1C still existed, Χ(2)=7.4, p=0.005. The occurrence of association of the OR14J1C allele with T1D patients with DRB1*401/DQB1*0302 is an independent risk for T1D. As an accumulative report suggests the role of OR in the pathogenesis of diabetic microvascular and other diabetic complications, undoubtedly, this haplotype specific alteration of T1D risk is an independent risk for the disease and can address the promising MHC-linked gene other than DR/DQ. Moreover, there is nothing to hinder for that this might be a signal that identifies the role of OR gene in the pathogenesis of T1D in patients who are prone to diabetic complications. Copyright © 2012. Published by Elsevier B.V.

Ia-restricted B-B cell interaction. I. The MHC haplotype of bone marrow cells present during B cell ontogeny dictates the self-recognition specificity of B cells in the polyclonal B cell activation by a B cell differentiation factor, B151-TRF2

International Nuclear Information System (INIS)

Ono, S.; Takahama, Y.; Hamaoka, T.

1987-01-01

We have demonstrated that B cell recognition of Ia molecules is involved in polyclonal B cell differentiation by B151-TRF2. The present study was undertaken to examine the Ia recognition specificity of B151-TRF2-responsive B cells in fully major histocompatibility complex (MHC)-allogeneic P1----P2, semiallogeneic P1----(P1 x P2)F1, and double donor (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 radiation bone marrow chimeras. The B cells from both P1----P2 and P1----(P1 x P2)F1 chimeras could give rise to in vitro immunoglobulin M-producing cells upon stimulation with B151-TRF2 comparable in magnitude to that of normal P1 B cells, and their responses were inhibited by anti-I-AP1 but not by anti-I-AP2 monoclonal antibody even in the presence of mitomycin C-treated T cell-depleted P2 spleen cells as auxiliary cells. In contrast, the B151-TRF2 responses of P1 B cells isolated from both (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 double bone marrow chimeras became sensitive to the inhibition of not only anti-I-AP1 but also anti-I-AP2 monoclonal antibody only when the culture was conducted in the presence of P2 auxiliary cells, demonstrating that they adaptively differentiate to recognize as self-structures allogeneic as well as syngeneic Ia molecules. Moreover, the experiments utilizing B cells from H-2-congenic mice and B cell hybridoma clones as auxiliary cells revealed that B151-TRF2-responsive B cells recognize Ia molecules expressed on B cells. Taken together, these results demonstrate that B151-TRF2-responsive B cells recognize Ia molecules expressed by B cells as self-structures and that their self-recognition specificity is dictated by the MHC haplotype of bone marrow cells present during the B cell ontogeny but not by the MHC haplotype of a radiation-resistant host environment

CD1 and major histocompatibility complex II molecules follow a different course during dendritic cell maturation

NARCIS (Netherlands)

van der Wel, Nicole N.; Sugita, Masahiko; Fluitsma, Donna M.; Cao, Xaiochun; Schreibelt, Gerty; Brenner, Michael B.; Peters, Peter J.

2003-01-01

The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class IT compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1

The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-γ

International Nuclear Information System (INIS)

Zhang Benyue; Li Ping; Wang Exing; Brahmi, Zacharie; Dunn, Kenneth W.; Blum, Janice S.; Roman, Ann

2003-01-01

Major histocompatibility complex (MHC) class II antigens are expressed on human foreskin keratinocytes (HFKs) following exposure to interferon gamma. The expression of MHC class II proteins on the cell surface may allow keratinocytes to function as antigen-presenting cells and induce a subsequent immune response to virus infection. Invariant chain (Ii) is a chaperone protein which plays an important role in the maturation of MHC class II molecules. The sequential degradation of Ii within acidic endocytic compartments is a key process required for the successful loading of antigenic peptide onto MHC class II molecules. Since human papillomavirus (HPV) 16 E5 can inhibit the acidification of late endosomes in HFKs, the E5 protein may be able to affect proper peptide loading onto the MHC class II molecule. To test this hypothesis, HFKs were infected with either control virus or a recombinant virus expressing HPV16 E5 and the infected cells were subsequently treated with interferon-γ. ELISAs revealed a decrease of MHC class II expression on the surface of E5-expressing cells compared with control virus-infected cells after interferon treatment. Western blot analysis showed that, in cells treated with interferon gamma, E5 could prevent the breakdown of Ii and block the formation of peptide-loaded, SDS-stable mature MHC class II dimers, correlating with diminished surface MHC class II expression. These data suggest that HPV16 E5 may be able to decrease immune recognition of infected keratinocytes via disruption of MHC class II protein function

Immunotherapy of MHC class I-deficient tumours and epigenetic upregulation of MHC class I molecules on tumour cells

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Manning, Jasper; Indrová, Marie; Přibylová, Hana; Bieblová, Jana; Šímová, Jana; Bubeník, Jan

2007-01-01

Roč. 20, Suppl. 1 (2007), S29-S29 ISSN 1107-3756. [World Congress on Advances in Oncology /12./ and International Symposium on Molecular Medicine /10./. 11.10.2007-12.10.2007, Hernissos] R&D Projects: GA ČR GA301/04/0492; GA ČR GA301/07/1410 Institutional research plan: CEZ:AV0Z50520514 Keywords : Immunotherapy * MHC I-deficient tumours * epigenetics Subject RIV: EB - Genetics ; Molecular Biology

Dissociative electron attachment to vibrationally excited H2 molecules involving the 2Σg+ resonant Rydberg electronic state

International Nuclear Information System (INIS)

Celiberto, R.; Janev, R.K.; Wadehra, J.M.; Tennyson, J.

2012-01-01

Graphical abstract: Dissociative electron attachment cross sections as a function of the incident electron energy and for the initial vibration levels v i = 0–5, 10 of the H 2 molecule. Highlights: ► We calculated electron–hydrogen dissociative attachment cross sections and rates coefficients. ► Collision processes occurring through a resonant Rydberg state are considered. ► Cross sections and rates were obtained for vibrationally excited hydrogen molecules. ► The cross sections exhibit pronounced oscillatory structures. ► A comparison with the process involving the electron–hydrogen resonant ground state is discussed. - Abstract: Dissociative electron attachment cross sections (DEA) on vibrationally excited H 2 molecule taking place via the 2 Σ g + Rydberg-excited resonant state are studied using the local complex potential (LCP) model for resonant collisions. The cross sections are calculated for all initial vibrational levels (v i = 0–14) of the neutral molecule. In contrast to the previously noted dramatic increase in the DEA cross sections with increasing v i , when the process proceeds via the X 2 Σ u + shape resonance of H 2 , for the 2 Σ g + Rydberg resonance the cross sections increase only gradually up to v i = 3 and then decrease. Moreover, the cross sections for v i ⩾ 6 exhibit pronounced oscillatory structures. A discussion of the origin of the observed behavior of calculated cross sections is given. The DEA rate coefficients for all v i levels are also calculated in the 0.5–1000 eV temperature range.

Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II.

Science.gov (United States)

Hartlehnert, Maike; Derksen, Angelika; Hagenacker, Tim; Kindermann, David; Schäfers, Maria; Pawlak, Mathias; Kieseier, Bernd C; Meyer Zu Horste, Gerd

2017-10-02

The activation of T helper cells requires antigens to be exposed on the surface of antigen presenting cells (APCs) via MHC class II (MHC-II) molecules. Expression of MHC-II is generally limited to professional APCs, but other cell types can express MHC-II under inflammatory conditions. However, the importance of these conditional APCs is unknown. We and others have previously shown that Schwann cells are potentially conditional APCs, but the functional relevance of MHC-II expression by Schwann cells has not been studied in vivo. Here, we conditionally deleted the MHC-II β-chain from myelinating Schwann cells in mice and investigated how this influenced post-traumatic intraneural inflammation and neuropathic pain using the chronic constriction injury (CCI) model. We demonstrate that deletion of MHC-II in myelinating Schwann cells reduces thermal hyperalgesia and, to a lesser extent, also diminishes mechanical allodynia in CCI in female mice. This was accompanied by a reduction of intraneural CD4+ T cells and greater preservation of preferentially large-caliber axons. Activation of T helper cells by MHC-II on Schwann cells thus promotes post-traumatic axonal loss and neuropathic pain. Hence, we provide experimental evidence that Schwann cells gain antigen-presenting function in vivo and modulate local immune responses and diseases in the peripheral nerves.

Axotomy induces MHC class I antigen expression on rat nerve cells

DEFF Research Database (Denmark)

Maehlen, J; Schröder, H D; Klareskog, L

1988-01-01

Immunomorphological staining demonstrates that class I major histocompatibility complex (MHC)-coded antigen expression can be selectively induced on otherwise class I-negative rat nerve cells by peripheral axotomy. Induction of class I as well as class II antigen expression was simultaneously seen...... on non-neural cells in the immediate vicinity of the injured nerve cells. As nerve regeneration after axotomy includes growth of new nerve cell processes and formation of new nerve cell contacts, the present findings raise the question of a role for MHC-coded molecules in cell-cell interactions during...... nerve cell growth....

Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment.

Directory of Open Access Journals (Sweden)

Gouri Shankar Pandey

Full Text Available The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6 of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants. Using a computational binding predictor, we were able to expand our analysis to (a include all wild type peptides spanning each polymorphic position; and (b consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population. Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes

meso-4,4′-Difluoro-2,2′-{[(3aR,7aS-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene}diphenol

Directory of Open Access Journals (Sweden)

Augusto Rivera

2013-02-01

Full Text Available In the crystal structure of the title compound, C21H24F2N2O2, there are two intramolecular O—H...N hydrogen bonds involving the N atoms of the imidazolidine ring and the hydroxy groups. The crystal studied was a meso compound obtained by the reaction of the aminal (2S,7R,11S,16R-1,8,10,17-tetraazapentacyclo[8.8.1.18,17.02,7.011,16]cosane with 4-fluorophenol. The imidazolidine ring has a twisted conformation with a CH—CH—N—CH2 torsion angle of 44.99 (14° and, surprisingly, the lone pairs of the N atoms are disposed in a syn isomerism, making the title compound an exception to the typical `rabbit-ear effect' in 1,2-diamines. In the crystal, molecules are linked via C—H...F hydrogen bonds, forming chains along the c-axis direction. These chains are linked via another C—H...F hydrogen bond, forming a three-dimensional network.

(2,3,7,8,12,13,17,18-Octaethylporphyrinato-κ4Ncobalt(II–2-nitrobenzaldehyde (1/2

Directory of Open Access Journals (Sweden)

Anissa Mansour

2012-09-01

Full Text Available The asymmetric unit of the title compound, [Co(C36H44N4]·2C7H5NO3, is composed of one half of the complex, arranged about an inversion center, and a complete 2-nitrobenzaldehyde (NBA molecule. The structure consists of columns that contain interleaved molecules of NBA and [CoII(OEP] (OEP is 2,3,7,8,12,13,17,18-octaethylporphyrin, which are stacked along the a axis. The CoII atom is involved in a π interaction with the ring of the NBA molecule with a centroid–metal distance of 3.508 (6 Å. There is an intramolecular C—H...O hydrogen bond in the NBA molecule.

MHC class II B diversity in blue tits: a preliminary study.

Science.gov (United States)

Aguilar, Juan Rivero-de; Schut, Elske; Merino, Santiago; Martínez, Javier; Komdeur, Jan; Westerdahl, Helena

2013-07-01

In this study, we partly characterize major histocompatibility complex (MHC) class II B in the blue tit (Cyanistes caeruleus). A total of 22 individuals from three different European locations: Spain, The Netherlands, and Sweden were screened for MHC allelic diversity. The MHC genes were investigated using both PCR-based methods and unamplified genomic DNA with restriction fragment length polymorphism (RFLP) and southern blots. A total of 13 different exon 2 sequences were obtained independently from DNA and/or RNA, thus confirming gene transcription and likely functionality of the genes. Nine out of 13 alleles were found in more than one country, and two alleles appeared in all countries. Positive selection was detected in the region coding for the peptide binding region (PBR). A maximum of three alleles per individual was detected by sequencing and the RFLP pattern consisted of 4-7 fragments, indicating a minimum number of 2-4 loci per individual. A phylogenetic analysis, demonstrated that the blue tit sequences are divergent compared to sequences from other passerines resembling a different MHC lineage than those possessed by most passerines studied to date.

NLRC5/MHC class I transactivator is a target for immune evasion in cancer.

Science.gov (United States)

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.

"Plug-and-Play" potentials: Investigating quantum effects in (H2)2-Li+-benzene

Science.gov (United States)

D'Arcy, Jordan H.; Kolmann, Stephen J.; Jordan, Meredith J. T.

2015-08-01

Quantum and anharmonic effects are investigated in (H2)2-Li+-benzene, a model for hydrogen adsorption in metal-organic frameworks and carbon-based materials, using rigid-body diffusion Monte Carlo (RBDMC) simulations. The potential-energy surface (PES) is calculated as a modified Shepard interpolation of M05-2X/6-311+G(2df,p) electronic structure data. The RBDMC simulations yield zero-point energies (ZPE) and probability density histograms that describe the ground-state nuclear wavefunction. Binding a second H2 molecule to the H2-Li+-benzene complex increases the ZPE of the system by 5.6 kJ mol-1 to 17.6 kJ mol-1. This ZPE is 42% of the total electronic binding energy of (H2)2-Li+-benzene and cannot be neglected. Our best estimate of the 0 K binding enthalpy of the second H2 to H2-Li+-benzene is 7.7 kJ mol-1, compared to 12.4 kJ mol-1 for the first H2 molecule. Anharmonicity is found to be even more important when a second (and subsequent) H2 molecule is adsorbed; use of harmonic ZPEs results in significant error in the 0 K binding enthalpy. Probability density histograms reveal that the two H2 molecules are found at larger distance from the Li+ ion and are more confined in the θ coordinate than in H2-Li+-benzene. They also show that both H2 molecules are delocalized in the azimuthal coordinate, ϕ. That is, adding a second H2 molecule is insufficient to localize the wavefunction in ϕ. Two fragment-based (H2)2-Li+-benzene PESs are developed. These use a modified Shepard interpolation for the Li+-benzene and H2-Li+-benzene fragments, and either modified Shepard interpolation or a cubic spline to model the H2-H2 interaction. Because of the neglect of three-body H2, H2, Li+ terms, both fragment PESs lead to overbinding of the second H2 molecule by 1.5 kJ mol-1. Probability density histograms, however, indicate that the wavefunctions for the two H2 molecules are effectively identical on the "full" and fragment PESs. This suggests that the 1.5 kJ mol-1 error is

"Plug-and-Play" potentials: Investigating quantum effects in (H2)2-Li(+)-benzene.

Science.gov (United States)

D'Arcy, Jordan H; Kolmann, Stephen J; Jordan, Meredith J T

2015-08-21

Quantum and anharmonic effects are investigated in (H2)2-Li(+)-benzene, a model for hydrogen adsorption in metal-organic frameworks and carbon-based materials, using rigid-body diffusion Monte Carlo (RBDMC) simulations. The potential-energy surface (PES) is calculated as a modified Shepard interpolation of M05-2X/6-311+G(2df,p) electronic structure data. The RBDMC simulations yield zero-point energies (ZPE) and probability density histograms that describe the ground-state nuclear wavefunction. Binding a second H2 molecule to the H2-Li(+)-benzene complex increases the ZPE of the system by 5.6 kJ mol(-1) to 17.6 kJ mol(-1). This ZPE is 42% of the total electronic binding energy of (H2)2-Li(+)-benzene and cannot be neglected. Our best estimate of the 0 K binding enthalpy of the second H2 to H2-Li(+)-benzene is 7.7 kJ mol(-1), compared to 12.4 kJ mol(-1) for the first H2 molecule. Anharmonicity is found to be even more important when a second (and subsequent) H2 molecule is adsorbed; use of harmonic ZPEs results in significant error in the 0 K binding enthalpy. Probability density histograms reveal that the two H2 molecules are found at larger distance from the Li(+) ion and are more confined in the θ coordinate than in H2-Li(+)-benzene. They also show that both H2 molecules are delocalized in the azimuthal coordinate, ϕ. That is, adding a second H2 molecule is insufficient to localize the wavefunction in ϕ. Two fragment-based (H2)2-Li(+)-benzene PESs are developed. These use a modified Shepard interpolation for the Li(+)-benzene and H2-Li(+)-benzene fragments, and either modified Shepard interpolation or a cubic spline to model the H2-H2 interaction. Because of the neglect of three-body H2, H2, Li(+) terms, both fragment PESs lead to overbinding of the second H2 molecule by 1.5 kJ mol(-1). Probability density histograms, however, indicate that the wavefunctions for the two H2 molecules are effectively identical on the "full" and fragment PESs. This suggests that

Cryogenic buffer-gas loading and magnetic trapping of CrH and MnH molecules

Science.gov (United States)

Stoll, Michael; Bakker, Joost M.; Steimle, Timothy C.; Meijer, Gerard; Peters, Achim

2008-09-01

We report on the buffer-gas cooling and trapping of CrH and MnH molecules in a magnetic quadrupole trap with densities on the order of 106cm-3 at a temperature of 650mK . Storage times of up to 180ms have been observed, corresponding to a 20-fold lifetime enhancement with respect to the field-free diffusion through the He3 buffer-gas. Using Monte Carlo trajectory simulations, inelastic molecule- He3 collision cross sections of 1.6×10-18 and 3.1×10-17cm2 are extracted for CrH and MnH, respectively. Furthermore, elastic molecule- He3 collision cross sections of 1.4(±0.5)×10-14cm2 are determined for both species. We conclude that the confinement time of these molecules in a magnetic trapping field is limited by inelastic collisions with the helium atoms leading to Zeeman relaxation.

Geometry and bonding in the ground and lowest triplet state of D{sub 6h} symmetric crenellated edged C{sub 6[3m(m-1)+1]}H{sub 6(2m-1)} (m = 2,..., 6) graphene hydrocarbon molecules

Energy Technology Data Exchange (ETDEWEB)

Philpott, Michael R., E-mail: philpott@imr.edu [Center for Computational Materials Science, Institute of Materials Science, Tohoku University, 2-1-1 Katahira, Aoba-ku, 980-8577 Sendai (Japan); Kawazoe, Yoshiyuki [Center for Computational Materials Science, Institute of Materials Science, Tohoku University, 2-1-1 Katahira, Aoba-ku, 980-8577 Sendai (Japan)

2009-03-30

Ab initio plane wave all valence electron based DFT calculations were used to explore the dichotomy of perimeter vs. interior in the electronic and geometric structure of the D{sub 6h} singlet ground state and D{sub 2h} lowest triplet state of planar graphene hydrocarbon molecules with crenellated (arm chair) edges and the general formula C{sub 6[3m(m-1)+1]} H{sub 6(2m-1)} where m = 2,...,6. The largest molecule C{sub 546}H{sub 66} was 4.78 nm across and contained 2250 valence electrons. These molecules are nominally 'fully benzenoid hydrocarbons'. However with increasing size, the core of central atoms abandoned any fully benzenoid geometry they had in small systems and organized into single layer graphite (graphene) structure. The perimeter atoms of the crenellation adopted a conjugated geometry with unequal bonds and between core and perimeter there were some C{sub 6} rings retaining remnants of aromatic sextet-type properties. Compared to a zigzag edge the crenellated edge conferred stability in all the systems studied as measured by the singlet homo-lumo level gap BG{sub 0} and the singlet-lowest triplet energy gap {Delta}E{sub ST}. For the largest crenellated system (m = 6) BG{sub 0} and {Delta}E{sub ST} were approximately 0.7 eV, larger in value than for similarly sized hexagonal graphenes with zigzag edges. Triplet states were identified for all the molecules in the series and in the case of the m = 2 molecule hexabenzocoronene C{sub 42}H{sub 18}, two conformations with D{sub 2h} symmetry were identified and compared to features on the triplet state potential energy surface of benzene.

Synthesis and Characterisation of Tris(1-carboxyl-2-phenyl-1,2-ethyl eno dithiol enic-S,S') Tungsten Complex as Photo catalyst for Photolysis of H2O Molecules

International Nuclear Information System (INIS)

Fadhli Hadana Rahman; Rusli Daik; Mohammad Kassim; Khuzaimah; Wan Ramli Wan Daud

2008-01-01

Tris(1-carboxyl-2-phenyl-1,2-ethylenodithiolenic-S,S ' ) tungsten complex is one of the most promising photo catalyst to be used in photolysis of water to produce hydrogen. The first step of the synthesis involves a metathesis reaction of tetrapropylammonium bromide [((C 3 H 7 ) 4 N)Br] and ammonium tetrathiotungstate [(NH 4 ) 2 WS 4 ] to form a tetrapropylammonium tetrathiotungstate [((C 3 H 7 ) 4 N) 2 WS 4 ] (precursor). Then, the precursor was reacted with phenyl acetylenecarboxylic acid (C 9 H 6 O 2 ) to form tris(1-carboxyl-2-phenyl-1,2-ethylenodithiolenic-S,S ' ) tungsten complex (C 27 H 18 O 2 S 6 W). The infra-red, ultra violet/ visible (UV/ Vis) spectrum, nuclear magnetic resonance (NMR) and elemental micro-analysis of C, H, N and S agreed with the characteristic of the tris(1-carboxyl-2-phenyl-1,2-ethylenodithiolenic-S,S ' ) tungsten complex. The (W-S), (C-S) and (C=O) stretching frequencies were detected at 511, (1470 and 1035) and 1655 cm -1 , respectively. The 1 H NMR spectrum showed six protons in the complex. The 13 C NMR showed only 7 signals for carbon atom in the benzene ring, ethylene groups and carboxylic acid pendant group due to the symmetry of the molecules. The reaction yield was about 50 percent. Photolysis of acetone spiked H 2 O showed that the catalyst was able to produced 1.8 μmol/ h hydrogen. (author)

Production of H,D(2s, 2p) by electron impact (0 - 2000 eV) on simple hydrogen containing molecules, ch. 2, A2

International Nuclear Information System (INIS)

Moehlman, G.R.; Heer, F.J. de

1977-01-01

Absolute emission cross sections of Ly-α (H,D(2p → 1s)) radiation have been determined for 0 - 2000 eV electrons incident on H 2 , HD, HCl, H 2 O, NH 3 and CH 4 . By means of the application of electric quenching, the excitation cross sections of H,D(2s) could be obtained from the increase of the resulting Ly-α radiation for these molecules. Only in the case of electrons on H 2 , D 2 and HD was excitation of H,D(2s) found

Peripheral nerve injury causes transient expression of MHC class I antigens in rat motor neurons and skeletal muscles

DEFF Research Database (Denmark)

Maehlen, J; Nennesmo, I; Olsson, A B

1989-01-01

After a peripheral nerve lesion (rat facial and sciatic) an induction of major histocompatibility complex (MHC) antigens class I was detected immunohistochemically in skeletal muscle fibers and motor neurons. This MHC expression was transient after a nerve crush, when regeneration occurred......, but persisted after a nerve cut, when regeneration was prevented. Since the time course of MHC class I expression correlates to that of regeneration a role for this cell surface molecule in regeneration may be considered....

Experimental study of cluster formation in binary mixture of H2O and H2SO4 vapors in the presence of an ionizing radiation source

Science.gov (United States)

Singh, J. J.; Smith, A. C.; Yue, G. K.

1980-01-01

Molecular clusters formed in pure nitrogen containing H2O and H2SO4 vapors and exposed to a 3 mCi Ni63 beta source were studied in the mass range 50 to 780 amu using a quadrupole mass spectrometer. Measurements were made under several combinations of relative humidity and relative acidity ranging from 0.7 to 7.5 percent and 0.00047 to 0.06333 percent, respectively. The number of H2SO4 molecules in the clusters observed ranged from 1 to 7 whereas the number of H2O molecules ranged from 1 to 16. The experimental cluster spectra differ considerably from those calculated using the classical nucleation theory. First order calculations using modified surface tension values and including the effects of multipole moments of the nucleating molecules indicate that these effects may be enough to explain the difference between the measured and the calculated spectra.

Production of H, D (2s, 2p) by electron impact (0-2000 eV) on simple hydrogen containing molecules

International Nuclear Information System (INIS)

Moehlmann, G.R.; Shima, K.H.; Heer, F.J. de

1978-01-01

Absolute emission cross sections of Ly-α (H, D (2p → 1s)) radiation have been determined for 0-2000 eV electrons incident on H 2 , HD, D 2 , HCl, H 2 O, NH 3 and CH 4 . By means of the application of electric quenching the excitation cross sections of H, D (2s) could be obtained from the increase of the resulting Ly-α radiation for these molecules. It was found that only for H 2 , HD and D 2 fragments in the H (2s) state are formed. (Auth.)

MHC class IIB Exon 2 Polymorphism in the Grey Partridge (Perdix perdix) is shaped by selection, recombination and gene conversion

Czech Academy of Sciences Publication Activity Database

Promerová, Marta; Králová, Tereza; Bryjová, Anna; Albrecht, Tomáš; Bryja, Josef

2013-01-01

Roč. 8, č. 7 (2013), e69135 E-ISSN 1932-6203 R&D Projects: GA ČR GA206/08/1281 Institutional support: RVO:68081766 Keywords : major histocompatibility complex (MHC) * snipe Gallinago-media * Class-I genes * minimal-essential-MHC Subject RIV: EG - Zoology Impact factor: 3.534, year: 2013

Inelastic Scattering of Identical Molecules within Framework of the Mixed Quantum/Classical Theory: Application to Rotational Excitations in H2 + H2.

Science.gov (United States)

Semenov, Alexander; Babikov, Dmitri

2016-06-09

Theoretical foundation is laid out for description of permutation symmetry in the inelastic scattering processes that involve collisions of two identical molecules, within the framework of the mixed quantum/classical theory (MQCT). In this approach, the rotational (and vibrational) states of two molecules are treated quantum-mechanically, whereas their translational motion (responsible for scattering) is treated classically. This theory is applied to H2 + H2 system, and the state-to-state transition cross sections are compared versus those obtained from the full-quantum calculations and experimental results from the literature. Good agreement is found in all cases. It is also found that results of MQCT, where the Coriolis coupling is included classically, are somewhat closer to exact full-quantum results than results of the other approximate quantum methods, where those coupling terms are neglected. These new developments allow applications of MQCT to a broad variety of molecular systems and processes.

Copper(II) perrhenate Cu(C{sub 3}H{sub 7}OH){sub 2}(ReO{sub 4}){sub 2}: Synthesis from isopropanol and CuReO{sub 4}, structure and properties

Energy Technology Data Exchange (ETDEWEB)

Mikhailova, D., E-mail: d.mikhailova@ifw-dresden.de [Karlsruhe Institute of Technology (KIT), Institute for Applied Materials (IAM), Hermann-von-Helmholtz-Platz 1, D-76434 Eggenstein-Leopoldshafen (Germany); Institute for Complex Materials, IFW Dresden, Helmholtzstrasse 20, D-01069 Dresden (Germany); Max Planck Institute for Chemical Physics of Solids, Nöthnitzer Str. 40, D-01187 Dresden (Germany); Engel, J.M. [Materials Science, Technische Universität Darmstadt, Alarich-Weiss-Str. 2, D-64287 Darmstadt (Germany); Schmidt, M. [Max Planck Institute for Chemical Physics of Solids, Nöthnitzer Str. 40, D-01187 Dresden (Germany); Tsirlin, A.A. [National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn (Estonia); Ehrenberg, H. [Karlsruhe Institute of Technology (KIT), Institute for Applied Materials (IAM), Hermann-von-Helmholtz-Platz 1, D-76434 Eggenstein-Leopoldshafen (Germany); Materials Science, Technische Universität Darmstadt, Alarich-Weiss-Str. 2, D-64287 Darmstadt (Germany)

2015-12-15

The crystal structure of Cu{sup +}Re{sup 7+}O{sub 4} is capable of a quasi-reversible incorporation of C{sub 3}H{sub 7}OH molecules. A room-temperature reaction between CuReO{sub 4} and C{sub 3}H{sub 7}OH under oxidizing conditions leads to the formation of a novel metal-organic hybrid compound Cu{sup 2+}(C{sub 3}H{sub 7}OH){sub 2}(ReO{sub 4}){sub 2}. Upon heating under reducing conditions, this compound transforms back into CuReO{sub 4}, albeit with ReO{sub 2} and metallic Cu as by-products. The crystal structure of Cu(C{sub 3}H{sub 7}OH){sub 2}(ReO{sub 4}){sub 2} solved from single-crystal X-ray diffraction (Pbca, a=10.005(3) Å, b=7.833(2) Å, and c=19.180(5) Å) reveals layers of corner-sharing CuO{sub 6}-octahedra and ReO{sub 4}-tetrahedra, whereas isopropyl groups are attached to both sides of these layers, thus providing additional connections within the layers through hydrogen bonds. Cu(C{sub 3}H{sub 7}OH){sub 2}(ReO{sub 4}){sub 2} is paramagnetic down to 4 K because the spatial arrangement of the Cu{sup 2+} half-filled orbitals prevents magnetic superexchange. The paramagnetic effective moment of 2.0(1) μ{sub B} is slightly above the spin-only value and typical for Cu{sup 2+} ions. - Highlights: • Novel Cu(C{sub 3}H{sub 7}OH){sub 2}(ReO{sub 4}){sub 2} compound has a sequence of inorganic and organic layers. • Hydrogen bonds provide an additional bonding Isopropanol molecules serve as a reducing agent during decomposition. • No direct Cu-O-Re-O-Cu connections via d{sub x2-y2} orbital of Cu{sup 2+} explain paramagnetism. • Hydrogen bonds provide an additional bonding. • Isopropanol molecules serve as a reducing agent during decomposition.

2S protein Ara h 7.0201 has unique epitopes compared to other Ara h 7 isoforms and is comparable to 2S proteins Ara h 2 and 6 in basophil degranulation capacity.

Science.gov (United States)

Hayen, S M; Ehlers, A M; den Hartog Jager, C F; Garssen, J; Knol, E F; Knulst, A C; Suer, W; Willemsen, L E M; Otten, H G

2018-07-01

Screening for specific IgE against 2S albumin proteins Ara h 2 and 6 has good positive predictive value in diagnosing peanut allergy. From the third 2S member Ara h 7, 3 isoforms have been identified. Their allergenicity has not been elucidated. This study investigated the allergenicity of Ara h 7 isoforms compared to Ara h 2 and 6. Sensitization of 15 DBPCFC-confirmed peanut-allergic patients to recombinant Ara h 2.0201, Ara h 6.01 and isoforms of recombinant Ara h 7 was determined by IgE immunoblotting strips. A basophil activation test (BAT) was performed in 9 patients to determine IgE-cross-linking capacities of the allergens. Sensitivity to the allergens was tested in 5 patients who were sensitized to at least 1 Ara h 7 isoform, by a concentration range in the BAT. 3D prediction models and sequence alignments were used to visualize differences between isoforms and to predict allergenic epitope regions. Sensitization to Ara h 7.0201 was most frequent (80%) and showed to be equally potent as Ara h 2.0201 and 6.01 in inducing basophil degranulation. Sensitization to Ara h 7.0201 together with Ara h 2.0201 and/or 6.01 was observed, indicating the presence of unique epitopes compared to the other 2 isoforms. Differences between the 3 Ara h 7 isoforms were observed in C-terminal cysteine residues, pepsin and trypsin cleavage sites and 3 single amino acid substitutions. The majority of peanut-allergic patients are sensitized to isoform Ara h 7.0201, which is functionally as active as Ara h 2.0201 and 6.01. Unique epitopes are most likely located in the C-terminus or an allergenic loop region which is a known allergenic epitope region for Ara h 2.0201 and 6.01. Due to its unique epitopes and allergenicity, it is an interesting candidate to improve the diagnostic accuracy for peanut allergy. © 2018 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.

Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.

Directory of Open Access Journals (Sweden)

Mark T Orr

2005-09-01

Full Text Available Herpes simplex virus (HSV has a number of genes devoted to immune evasion. One such gene, ICP47, binds to the transporter associated with antigen presentation (TAP 1/2 thereby preventing transport of viral peptides into the endoplasmic reticulum, loading of peptides onto nascent major histocompatibility complex (MHC class I molecules, and presentation of peptides to CD8 T cells. However, ICP47 binds poorly to murine TAP1/2 and so inhibits antigen presentation by MHC class I in mice much less efficiently than in humans, limiting the utility of murine models to address the importance of MHC class I inhibition in HSV immunopathogenesis. To address this limitation, we generated recombinant HSVs that efficiently inhibit antigen presentation by murine MHC class I. These recombinant viruses prevented cytotoxic T lymphocyte killing of infected cells in vitro, replicated to higher titers in the central nervous system, and induced paralysis more frequently than control HSV. This increase in virulence was due to inhibition of antigen presentation to CD8 T cells, since these differences were not evident in MHC class I-deficient mice or in mice in which CD8 T cells were depleted. Inhibition of MHC class I by the recombinant viruses did not impair the induction of the HSV-specific CD8 T-cell response, indicating that cross-presentation is the principal mechanism by which HSV-specific CD8 T cells are induced. This inhibition in turn facilitates greater viral entry, replication, and/or survival in the central nervous system, leading to an increased incidence of paralysis.

Ethyl (E-2-(2,7-dimethyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-4-ylideneacetate

Directory of Open Access Journals (Sweden)

Oulemda Bassou

2017-02-01

Full Text Available In the title compound, C14H14O5, the two heterocyclic rings are coplanar (r.m.s. deviation = 0.008 Å, with the largest deviation from the mean plane being 0.012 (1 Å. The mean plane through the acetate group is inclined slightly with respect to the oxopyrano[4,3-b]pyran-4-yl system, as indicated by the dihedral angle of 1.70 (7° between them. Two intramolecular hydrogen bonds, completing S(6 ring motifs, are observed in the molecule. In the crystal, molecules are linked by weak C—H...O hydrogen bonds involving the same acceptor atom, forming chains propagating along the c-axis direction and enclosing R21(6 ring motifs. The chains are linked via offset π–π interactions [intercentroid distance = 3.622 (1 Å], involving inversion-related oxopyrano[4,3-b]pyran-4-yl ring systems, forming slabs parallel to the bc plane.

Methyl 5,7-dihydroxy-2,2,9-trimethyl-6,11-dioxo-6,11-dihydro-2H-anthra[2,3-b]pyran-8-carboxylate

Directory of Open Access Journals (Sweden)

Annelise Lobstein

2008-12-01

Full Text Available The title compound, C22H18O7, also known as laurentiquinone B, is a new anthraquinone which was isolated from Vismia laurentii, a Cameroonian medicinal plant. The asymmetric unit contains two independent molecules. Each of them contains four fused rings, three of which are coplanar and typical of anthracene, while the heterocyclic rings adopt envelope conformations. Intramolecular O—H...O hydrogen bonds result in the formation of two planar rings, which are also almost coplanar with the adjacent rings. In the crystal structure, intermolecular O—H...O and C—H...O hydrogen bonds link the molecules and a π–π contact is also present [centroid-centroid distance = 3.967 (3 Å].

2,2′-Bis{8-[(benzylaminomethylidene]-1,6-dihydroxy-5-isopropyl-3-methylnaphthalen-7(8H-one}

Directory of Open Access Journals (Sweden)

Shukhrat M. Hakberdiev

2013-11-01

Full Text Available The asymmetric unit of the title compound, C44H44N2O6, contains two independent molecules with similar conformations. The dihydronaphthalene ring systems are approximately planar [maximum deviations = 0.036 (2, 0.128 (2, 0.0.24 (2 and 0.075 (2 Å]. The dihedral angle between two dihydronaphthalene ring systems is 83.37 (4° in one molecule and 88.99 (4° in the other. The carbonyl O atom is linked with the adjacent hydroxy and imino groups via intramolecular O—H...O and N—H...O hydrogen bonds. In the crystal, molecules are linked through O—H...O hydrogen bonds into layers parallel to (001, and adjacent layers are further stacked by π–π interactions between dihydronaphthalene and phenyl rings into a three-dimensional supramolecular architecture. In the crystal, one of the isopropyl groups is disordered over two positions with an occupancy ratio of 0.684 (8:0.316 (8.

3-(4-Fluorophenyl-1-[1′-(4-fluorophenyl-2-oxo-5′,6′,7′,7a′-tetrahydro-1H-indole-3(2H-spiro-3′(2′H-1H′-pyrrolizin-2′-yl]prop-2-en-1-one

Directory of Open Access Journals (Sweden)

S. Sriman Narayanan

2008-09-01

Full Text Available In the title compound, C29H24F2N2O2, one of the pyrrolidine rings of the pyrrolizine system is disordered over two sites, with occupancy factors 0.734:0.266 (12. Both components of the disordered pyrrolidine ring adopt envelope conformations, whereas the other pyrrolidine ring adopts a twist conformation. The molecules are linked into centrosymmetric dimers by N—H...O hydrogen bonds and the dimers are connected via C—H...π interactions. The crystal structure is also stabilized by intermolecular C—H...F hydrogen bonds.

Importance of collisional rates for anomalous absorption in H2CO molecule

International Nuclear Information System (INIS)

Sharma, Monika; Sharma, M.K.; Chandra, Suresh

2012-01-01

Formaldehyde (H 2 CO) is the first organic molecule identified in a number of galactic and extragalactic radio sources through its transition 1 10 –1 11 at 4.830 GHz in absorption. Later on, this transition was found in anomalous absorption. In some cosmic objects, this transition however was found in emission and even as a maser radiation. Since the transition 1 10 –1 11 of ortho-H 2 CO is considered as a unique probe of high density gas at low temperature, the study of H 2 CO has always been of great importance for astrophysicists as well as for spectroscopists. In view of the availability of better input data required for such investigation, it is worth while to investigate again about the radiations from ortho-H 2 CO. In the present study, we have investigated anomalous absorption of 1 10 –1 11 , 2 11 –2 12 and 3 12 –3 13 transitions of ortho-H 2 CO. The present results are more reliable as compared to those obtained earlier. -- Highlights: ► Accurate rotational levels and A-coefficients for H 2 CO are calculated. ► Transitions 1 10 –1 11 , 2 11 –2 12 and 3 12 –3 13 show anomalous absorption. ► Anomalous absorption is found to increase with kinetic temperature. ► Anomalous absorption may be found for n H 2 ≈10 4 cm −3 . ► Colliding partner para-H 2 may be approximated as He atom.

Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1).

Science.gov (United States)

Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Fernández, Pablo; Pozner, Roberto G; Lang, Roland; Balboa, Luciana; Giambartolomei, Guillermo H; Barrionuevo, Paula

2017-03-01

Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4 + T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection. © Society for Leukocyte Biology.

MHC protocols

National Research Council Canada - National Science Library

Powis, Stephen H; Vaughan, Robert W

2003-01-01

... because it contains genes encoding components of the complement pathway. The entire human MHC has recently been sequenced (1) and each subregion is now known to contain many other genes, a number of which have immunological functions. The study of polymorphism within the MHC is well established, because the region contains the highly polymorphic HLA genes. HLA polym...

Limitations of Ab Initio Predictions of Peptide Binding to MHC Class II Molecules

DEFF Research Database (Denmark)

Zhang, Hao; Lund, Ole; Nielsen, Morten

2010-01-01

potentials derived from the analysis of known protein structures; energetic evaluation of different peptide snapshots in a molecular dynamics simulation; and direct analysis of contacts made in known 3D structures of peptide:MHC complexes. These methods are ab initio in that they require structural data...

Different features of the MHC class I heterodimer have evolved at different rates. Chicken B-F and beta 2-microglobulin sequences reveal invariant surface residues

DEFF Research Database (Denmark)

Kaufman, J; Andersen, R; Avila, D

1992-01-01

molecules and the MHC-encoded nonclassical molecules more than CD1 or the class I-like FcR. In contrast, the chicken alpha 3 domain is equally homologous to all alpha 3 domains, to beta 2m and to class II beta 2 domains. For each pair of extracellular domains (alpha 1 vs alpha 2, alpha 3 vs beta 2m...... of small exons in the cytoplasmic region. The cDNA sequences were compared to turkey beta 2m, the apparent allele B-F12 alpha and other vertebrate homologs, using the 2.6 A structure of the human HLA-A2 molecule as a model. Both chicken alpha 1 and alpha 2 domains resemble mammalian classical class I...... the ends of the peptide, two residues that bind CD8, and three residues that are phosphorylated. The positions of the allelic residues are conserved. There are other patches of invariant residues on alpha 1, alpha 2, and beta 2m; these might bind TCR or other molecules involved in class I function...

De novo transcriptome assembly facilitates characterisation of fast-evolving gene families, MHC class I in the bank vole (Myodes glareolus).

Science.gov (United States)

Migalska, M; Sebastian, A; Konczal, M; Kotlík, P; Radwan, J

2017-04-01

The major histocompatibility complex (MHC) plays a central role in the adaptive immune response and is the most polymorphic gene family in vertebrates. Although high-throughput sequencing has increasingly been used for genotyping families of co-amplifying MHC genes, its potential to facilitate early steps in the characterisation of MHC variation in nonmodel organism has not been fully explored. In this study we evaluated the usefulness of de novo transcriptome assembly in characterisation of MHC sequence diversity. We found that although de novo transcriptome assembly of MHC I genes does not reconstruct sequences of individual alleles, it does allow the identification of conserved regions for PCR primer design. Using the newly designed primers, we characterised MHC I sequences in the bank vole. Phylogenetic analysis of the partial MHC I coding sequence (2-4 exons) of the bank vole revealed a lack of orthology to MHC I of other Cricetidae, consistent with the high gene turnover of this region. The diversity of expressed alleles was characterised using ultra-deep sequencing of the third exon that codes for the peptide-binding region of the MHC molecule. High allelic diversity was demonstrated, with 72 alleles found in 29 individuals. Interindividual variation in the number of expressed loci was found, with the number of alleles per individual ranging from 5 to 14. Strong signatures of positive selection were found for 8 amino acid sites, most of which are inferred to bind antigens in human MHC, indicating conservation of structure despite rapid sequence evolution.

Tolerance to MHC class II disparate allografts through genetic modification of bone marrow

Science.gov (United States)

Jindra, Peter T.; Tripathi, Sudipta; Tian, Chaorui; Iacomini, John; Bagley, Jessamyn

2012-01-01

Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-Ab (I-Ab) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction. PMID:22833118

Solid-State Synthesis and Structure of the Enigmatic Ammonium Octaborate: (NH4)2[B7O9(OH)5]·3/4B(OH)3·5/4H2O.

Science.gov (United States)

Neiner, Doinita; Sevryugina, Yulia V; Schubert, David M

2016-09-06

The compound known since the 19th century as ammonium octaborate was structurally characterized revealing the ammonium salt of the ribbon isomer of the heptaborate anion, [B7O9(OH)5](2-), with boric acid and water molecules. Of composition (NH4)2B7.75O12.63·4.88H2O, it approximates the classical ammonium octaborate composition (NH4)2B8O13·6H2O and has the structural formula {(NH4)2[B7O9(OH)5]}4·3B(OH)3·5H2O. It spontaneously forms at room temperature in solid-state mixtures of ammonium tetraborate and ammonium pentaborate. It crystallizes in the monoclinic space group P21/c with a = 11.4137(2) Å, b = 11.8877(2) Å, c = 23.4459(3) Å, β = 90.092(1)°, V = 3181.19(8) Å(3), and Z = 2 and contains well-ordered ammonium cations and [B7O9(OH)5](2-) anions and disordered B(OH)3 and H2O molecules linked by extensive H bonding. Expeditious solid-state formation of the heptaborate anion under ambient conditions has important implications for development of practical syntheses of industrially useful borates.

4,4′-Dichloro-2,2′-[(3aR,7aR/3aS,7aS-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diylbis(methylene]diphenol

Directory of Open Access Journals (Sweden)

Michal Dušek

2010-10-01

Full Text Available Molecules of the the title compound, C21H24Cl2N2O2, are located on a twofold rotation axis, which passes through the C atom linking the two N atoms. Two intramolecular O—H...N hydrogen bonds were observed. In the crystal, non-classical intermolecular C—H...O hydrogen bonds link the molecules into chains along the a axis. The crystal studied was a racemic twin.

Molecular characterization of classical and nonclassical MHC class I genes from the golden pheasant (Chrysolophus pictus).

Science.gov (United States)

Zeng, Q-Q; Zhong, G-H; He, K; Sun, D-D; Wan, Q-H

2016-02-01

Classical major histocompatibility complex (MHC) class I allelic polymorphism is essential for competent antigen presentation. To improve the genotyping efforts in the golden pheasant, it is necessary to differentiate more accurately between classical and nonclassical class I molecules. In our study, all MHC class I genes were isolated from one golden pheasant based on two overlapping PCR amplifications. In total, six full-length class I nucleotide sequences (A-F) were identified, and four were novel. Two (A and C) belonged to the IA1 gene, two (B and D) were alleles derived from the IA2 gene through transgene amplification, and two (E and F) comprised a third novel locus, IA3 that was excluded from the core region of the golden pheasant MHC-B. IA1 and IA2 exhibited the broad expression profiles characteristic of classical loci, while IA3 showed no expression in multiple tissues and was therefore defined as a nonclassical gene. Phylogenetic analysis indicated that the three IA genes in the golden pheasant share a much closer evolutionary relationship than the corresponding sequences in other galliform species. This observation was consistent with high sequence similarity among them, which likely arises from the homogenizing effect of recombination. Our careful distinction between the classical and nonclassical MHC class I genes in the golden pheasant lays the foundation for developing locus-specific genotyping and establishing a good molecular marker system of classical MHC I loci. © 2015 John Wiley & Sons Ltd.

Orf virus interferes with MHC class I surface expression by targeting vesicular transport and Golgi

Directory of Open Access Journals (Sweden)

Rohde Jörg

2012-07-01

Full Text Available Abstract Background The Orf virus (ORFV, a zoonotic Parapoxvirus, causes pustular skin lesions in small ruminants (goat and sheep. Intriguingly, ORFV can repeatedly infect its host, despite the induction of a specific immunity. These immune modulating and immune evading properties are still unexplained. Results Here, we describe that ORFV infection of permissive cells impairs the intracellular transport of MHC class I molecules (MHC I as a result of structural disruption and fragmentation of the Golgi apparatus. Depending on the duration of infection, we observed a pronounced co-localization of MHC I and COP-I vesicular structures as well as a reduction of MHC I surface expression of up to 50%. These subversion processes are associated with early ORFV gene expression and are accompanied by disturbed carbohydrate trimming of post-ER MHC I. The MHC I population remaining on the cell surface shows an extended half-life, an effect that might be partially controlled also by late ORFV genes. Conclusions The presented data demonstrate that ORFV down-regulates MHC I surface expression in infected cells by targeting the late vesicular export machinery and the structure and function of the Golgi apparatus, which might aid to escape cellular immune recognition.

Cellular expression or binding of desLys58-beta2 microglobulin is not dependent on the presence of the tri-molecular MHC class I complex

DEFF Research Database (Denmark)

Wang, M; Corlin, D B; Heegaard, N H H

2008-01-01

-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....

Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II recepter HLA-DR1

Energy Technology Data Exchange (ETDEWEB)

Mullen, M.; Haan, K.M.; Longnecker, R.; Jardetzky, T.

2010-03-08

Epstein-Barr virus (EBV) causes infectious mononucleosis, establishes long-term latent infections, and is associated with a variety of human tumors. The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. EBV gp42 belongs to the C-type lectin superfamily, with homology to NK receptors of the immune system. We report the crystal structure of gp42 bound to the human MHC class II molecule HLA-DR1. The gp42 binds HLA-DR1 using a surface site that is distinct from the canonical lectin and NK receptor ligand binding sites. At the canonical ligand binding site, gp42 forms a large hydrophobic groove, which could interact with other ligands necessary for EBV entry, providing a mechanism for coupling MHC recognition and membrane fusion.

Structure of trihydrated rare-earth acid diphosphates LnHP2O7·3H2O (Ln=La, Er)

International Nuclear Information System (INIS)

Ben Moussa, S.; Ventemillas, S.; Cabeza, A.; Gutierrez-Puebla, E.; Sanz, J.

2004-01-01

In trihydrated lanthanum acid-diphosphates LnHP 2 O 7 ·3H 2 O, prepared from acid LnCl 3 and Na 4 P 2 O 7 solutions (pH=1), two crystal forms were obtained. Layered structures of two representative members of this family have been determined by single-crystal X-ray diffraction (XRD) technique. In the case of orthorhombic LaHP 2 O 7 ·3H 2 O (type I), lanthanum cations are ninefold coordinated and diphosphate groups adopt a staggered (alternated) configuration. In the case of triclinic ErHP 2 O 7 ·3H 2 O (type II), erbium cations are eightfold coordinated and diphosphate groups adopt an eclipsed configuration. In agreement with Infrared (IR) spectroscopic data, a bended configuration for diphosphate groups has been deduced. In both structures, one-dimensional chains of edge-sharing rare-earth polyhedra are linked together by diphosphate groups to form the phosphate layers. In both diphosphates, PO 4 and HPO 4 environments have been identified by 31 P MAS-NMR technique. In the two compounds, OH groups of HPO 4 tetrahedra point out of diphosphate planes interacting with adjacent layers. In La-diphosphate, the interaction between HPO 4 groups and water molecules of adjacent layers is favored; however, in Er-diphosphate, the interaction between phosphate acid groups of contiguous layers is produced. Based on structural information deduced, differences detected in IR and NMR spectra of two disphosphates are discussed

An investigation onto the molecular structure of 5-chloro-3-(2-(4-ethylpiperazine-1-il)-2-oxoethyl)benzo[d]thiazole-2(3H)-on drug molecule before and after atmospheric pressure plasma treatment

Science.gov (United States)

Tanışlı, Murat; Taşal, Erol; Şahin, Neslihan; Dikmen, Gökhan

2018-05-01

The spectra of molecular structure for the 5-chloro-3-(2-(4-ethylpiperazine-1-il)-2-oxoethyl)benzo[d]thiazole-2(3H)-on drug molecule (abbreviated as 5KEB) before and after the atmospheric pressure plasma treatments (APPTs) of neon (Ne) and argon (Ar) were investigated. The Fourier transform infrared (FT-IR), ultraviolet visible (UV-Vis) spectra and NMR measurements of the 5KEB drug molecule dissolved in toluene and ethanol solvents were recorded and examined for liquid phases. Then FT-IR, UV-Vis spectra and NMR measurements were analysed. It is seen that some bonds of 5KEB molecule were decomposed. There were also unobserved vibrational modes. After the Ne plasma at the atmospheric pressure applied to 5KEB drug molecule dissolved in toluene, the bonds as 9Ssbnd 8C; 9Ssbnd 8C = 10 O, 8Csbnd 7N, 7Nsbnd 8C = 10O were vanished, and then the new bonds of the 7N = 8C, 7N = 8C = 10 O, 9Ssbnd 5Csbnd 4Csbnd 7N = 8C = 10O were observed. New photoproducts may be defined as the stretching peaks, stretching vibrational modes for 5KEB drug molecule in liquid phase prepared with ethanol and toluene solvents after APPT. Also, after Ar plasma at atmospheric pressure applied here, the 9Ssbnd 8C bond of the 5KEB drug molecule dissolved in toluene was broken. The isomerization process in UV-Vis was defined by π-π* and n-π* electronic transitions. According to NMR results, protons of pyridine ring, protons of CH2 group bonded to carbonyl group and protons of CH3 group more affected than other protons from Ar and Ne APPTs and these protons were eliminated by Ar and Ne APPTs.

Formation of H- ions via vibrational excited molecules produced from recombinative wall desorption of H atoms in a low-pressure H/sub 2/ positive column

NARCIS (Netherlands)

Amorim, J.; Loureiro, J.; Schram, D.C.

2001-01-01

Recombinative wall desorption of hydrogen atoms in a low-pressure hydrogen positive column leading to formation of H/sub 2/ (X/sup 1/ Sigma /sub g//sup +/, v) molecules in optimum levels for H/sup -/ production by dissociative attachment is investigated. We employed a kinetic model that solves the

Synthesis, Molecular Structure and Characterization of Allylic Derivatives of 6-Amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]-triazin-8(7H-one

Directory of Open Access Journals (Sweden)

Gene-Hsiang Lee

2006-06-01

Full Text Available 1-Allyl- (2 and 7-allyl-6-amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one (3 were obtained via the 18-crown-6-ether catalyzed room temperature reactionof 6-amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one (1 with potassiumcarbonate and allyl bromide in dry acetone. The structures of these two derivatives wereverified by 2D-NMR measurements, including gHSQC and gHMBC measurements. Theminor compound 2 may possess aromatic character. A single crystal X-ray diffractionexperiment indicated that the major compound 3 crystallizes from dimethyl sulfoxide in themonoclinic space group P21/n and its molecular structure includes an attached dimethylsulfoxide molecule, resulting in the molecular formula C10H16N6O2S. Molecular structuresof 3 are linked by extensive intermolecular N-H···N hydrogen bonding [graph set C 1 (7]. 1Each molecule is attached to the dimethyl sulfoxide oxygen via N-H···O intermolecularhydrogen bonding. The structure is further stabilized by π-π stacking interactions.

Lipofection indirectly increases expression of endogenous major histocompatibility complex class I molecules on tumor cells.

Science.gov (United States)

Fox, B A; Drury, M; Hu, H M; Cao, Z; Huntzicker, E G; Qie, W; Urba, W J

1998-01-01

Direct intratumoral injection of a lipid/DNA complex encoding an allogeneic major histocompatibility complex (MHC) class I molecule leads to regression of both an immunogenic murine tumor and also melanoma lesions in some patients. We have sought to understand the mechanism(s) for this augmentation of antitumor activity. While optimizing parameters for in vitro gene transfer into the D5 subclone of B16BL6, it was noted that lipofected tumors not only expressed the new alloantigen but also exhibited increased expression of endogenous MHC class I, both H-2 Kb and H-2 Db. This increase in expression was not restricted to the small percentage of cells that expressed the transfected gene, but appeared to affect the majority of cells in culture. Class I expression was not increased by lipopolysaccharide, DNA alone, lipid, or lipid/lipopolysaccharide mixtures. Enhanced class I expression required a DNA/lipid complex and was greatest when parameters optimized for gene transfer of the alloantigen were used. All DNA plasmids tested had this effect, including one plasmid whose DNA was not transcribed because it lacked an expression cassette. Because of the critical role that MHC class I antigens play in immune recognition, we propose that lipid complex-mediated gene transfer may provide immunological advantages beyond those that are attributable to expression of the specific gene transferred.

Specific IgE to peanut 2S albumin Ara h 7 has a discriminative ability comparable to Ara h 2 and 6.

Science.gov (United States)

Blankestijn, M A; Otten, H G; Suer, W; Weimann, A; Knol, E F; Knulst, A C

2018-01-01

Little is known on the clinical relevance of peanut 2S albumin Ara h 7. To investigate the discriminative ability of Ara h 7 in peanut allergy and assess the role of cross-reactivity between Ara h 2, 6 and Ara h 7 isoforms. Sensitization to recombinant peanut storage proteins Ara h 1, 2, 3, 6, and 7 was assessed using a line blot in sera from 40 peanut-tolerant and 40 peanut-allergic patients, based on food challenge outcome. A dose-dependent ELISA inhibition experiment was performed with recombinant Ara h 2, 6 and Ara h 7 isoforms. For Ara h 7.0201, an area under the ROC curve was found of 0.83, comparable to Ara h 2 (AUC 0.81) and Ara h 6 (AUC 0.85). Ara h 7 intensity values strongly correlated with those from Ara h 2 and 6 (r s = 0.81). Of all patients sensitized to 2S albumins Ara h 2, 6, or 7, the majority was co-sensitized to all three (n = 24, 68%), although mono-sensitization to either 2S albumin was also observed in selected patients (Ara h 2: n = 6, 17%; Ara h 6: n = 2, 6%; Ara h 7: n = 2, 6%). Binding to Ara h 7.0101 could be strongly inhibited by Ara h 7.0201, but not the other way around. Specific IgE against Ara h 7.0201 has a predictive ability for peanut allergy similar to Ara h 2 and 6 and possesses unique IgE epitopes as well as epitopes shared between the other Ara h 7 isoform and Ara h 2 and 6. While co-sensitization to all three 2S albumins is most common, mono-sensitization to either Ara h 2, 6, or 7 occurs in selected patients, leading to a risk of misdiagnosis when testing for a single 2S albumin. © 2017 John Wiley & Sons Ltd.

Characterization of a Nonclassical Class I MHC Gene in a Reptile, the Galápagos Marine Iguana (Amblyrhynchus cristatus)

Science.gov (United States)

Glaberman, Scott; Du Pasquier, Louis; Caccone, Adalgisa

2008-01-01

Squamates are a diverse order of vertebrates, representing more than 7,000 species. Yet, descriptions of full-length major histocompatibility complex (MHC) genes in this group are nearly absent from the literature, while the number of MHC studies continues to rise in other vertebrate taxa. The lack of basic information about MHC organization in squamates inhibits investigation into the relationship between MHC polymorphism and disease, and leaves a large taxonomic gap in our understanding of amniote MHC evolution. Here, we use both cDNA and genomic sequence data to characterize a class I MHC gene (Amcr-UA) from the Galápagos marine iguana, a member of the squamate subfamily Iguaninae. Amcr-UA appears to be functional since it is expressed in the blood and contains many of the conserved peptide-binding residues that are found in classical class I genes of other vertebrates. In addition, comparison of Amcr-UA to homologous sequences from other iguanine species shows that the antigen-binding portion of this gene is under purifying selection, rather than balancing selection, and therefore may have a conserved function. A striking feature of Amcr-UA is that both the cDNA and genomic sequences lack the transmembrane and cytoplasmic domains that are necessary to anchor the class I receptor molecule into the cell membrane, suggesting that the product of this gene is secreted and consequently not involved in classical class I antigen-presentation. The truncated and conserved character of Amcr-UA lead us to define it as a nonclassical gene that is related to the few available squamate class I sequences. However, phylogenetic analysis placed Amcr-UA in a basal position relative to other published classical MHC genes from squamates, suggesting that this gene diverged near the beginning of squamate diversification. PMID:18682845

Characterization of a nonclassical class I MHC gene in a reptile, the Galápagos marine iguana (Amblyrhynchus cristatus.

Directory of Open Access Journals (Sweden)

Scott Glaberman

Full Text Available Squamates are a diverse order of vertebrates, representing more than 7,000 species. Yet, descriptions of full-length major histocompatibility complex (MHC genes in this group are nearly absent from the literature, while the number of MHC studies continues to rise in other vertebrate taxa. The lack of basic information about MHC organization in squamates inhibits investigation into the relationship between MHC polymorphism and disease, and leaves a large taxonomic gap in our understanding of amniote MHC evolution. Here, we use both cDNA and genomic sequence data to characterize a class I MHC gene (Amcr-UA from the Galápagos marine iguana, a member of the squamate subfamily Iguaninae. Amcr-UA appears to be functional since it is expressed in the blood and contains many of the conserved peptide-binding residues that are found in classical class I genes of other vertebrates. In addition, comparison of Amcr-UA to homologous sequences from other iguanine species shows that the antigen-binding portion of this gene is under purifying selection, rather than balancing selection, and therefore may have a conserved function. A striking feature of Amcr-UA is that both the cDNA and genomic sequences lack the transmembrane and cytoplasmic domains that are necessary to anchor the class I receptor molecule into the cell membrane, suggesting that the product of this gene is secreted and consequently not involved in classical class I antigen-presentation. The truncated and conserved character of Amcr-UA lead us to define it as a nonclassical gene that is related to the few available squamate class I sequences. However, phylogenetic analysis placed Amcr-UA in a basal position relative to other published classical MHC genes from squamates, suggesting that this gene diverged near the beginning of squamate diversification.

Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.

Science.gov (United States)

Hacker, Ulrich T; Schildhauer, Ines; Barroso, Margarita Céspedes; Kofler, David M; Gerner, Franz M; Mysliwietz, Josef; Buening, Hildegard; Hallek, Michael; King, Susan B S

2006-05-01

The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.

An open-framework three-dimensional indium oxalate: [In(OH)(C2O4)(H2O)]3.H2O

International Nuclear Information System (INIS)

Yang Sihai; Li Guobao; Tian Shujian; Liao Fuhui; Lin Jianhua

2005-01-01

By hydrothermal reaction of In 2 O 3 with H 2 C 2 O 4 .2H 2 O in the presence of H 3 BO 3 at 155 deg. C, an open-framework three-dimensional indium oxalate of formula [In(OH)(C 2 O 4 )(H 2 O)] 3 .H 2 O (1) has been obtained. The compound crystallizes in the trigonal system, space group R3c with a=18.668(3)A, c=7.953(2)A, V=2400.3(7)A 3 , Z=6, R 1 =0.0352 at 298K. The small pores in 1 are filled with water molecules. It loses its filled water at about 180 deg. C without the change of structure, then the bounded water at 260 deg. C, and completely decompounds at 324 deg. C. The residue is confirmed to be In 2 O 3

Proteasome, transporter associated with antigen processing, and class I genes in the nurse shark Ginglymostoma cirratum: evidence for a stable class I region and MHC haplotype lineages.

Science.gov (United States)

Ohta, Yuko; McKinney, E Churchill; Criscitiello, Michael F; Flajnik, Martin F

2002-01-15

Cartilaginous fish (e.g., sharks) are derived from the oldest vertebrate ancestor having an adaptive immune system, and thus are key models for examining MHC evolution. Previously, family studies in two shark species showed that classical class I (UAA) and class II genes are genetically linked. In this study, we show that proteasome genes LMP2 and LMP7, shark-specific LMP7-like, and the TAP1/2 genes are linked to class I/II. Functional LMP7 and LMP7-like genes, as well as multiple LMP2 genes or gene fragments, are found only in some sharks, suggesting that different sets of peptides might be generated depending upon inherited MHC haplotypes. Cosmid clones bearing the MHC-linked classical class I genes were isolated and shown to contain proteasome gene fragments. A non-MHC-linked LMP7 gene also was identified on another cosmid, but only two exons of this gene were detected, closely linked to a class I pseudogene (UAA-NC2); this region probably resulted from a recent duplication and translocation from the functional MHC. Tight linkage of proteasome and class I genes, in comparison with gene organizations of other vertebrates, suggests a primordial MHC organization. Another nonclassical class I gene (UAA-NC1) was detected that is linked neither to MHC nor to UAA-NC2; its high level of sequence similarity to UAA suggests that UAA-NC1 also was recently derived from UAA and translocated from MHC. These data further support the principle of a primordial class I region with few class I genes. Finally, multiple paternities in one family were demonstrated, with potential segregation distortions.

Synthesis and crystal structure of trans-[Ni(pyzdcH)M 2 (H 2 O) 2 ...

African Journals Online (AJOL)

The determined structure of the title compound C24H20Ni2N8O20 consists of the mononuclear trans-[Ni(pyzdc)2(H2O)2], (pyzdc = pyrazine-2,3- dicarboxylate). The Ni(II) atom is hexa-coordinated by two (pyzdcH)- groups and two water molecules. The coordinated water molecules are in trans-diaxial positions and the ...

Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy

Science.gov (United States)

Chakrabarti, Saikat; Roy, Syamal

2016-01-01

Background Previously we reported that Kala-azar patients show progressive decrease in serum cholesterol as a function of splenic parasite burden. Splenic macrophages (MΦ) of Leishmania donovani (LD) infected mice show decrease in membrane cholesterol, while LD infected macrophages (I-MΦ) show defective T cell stimulating ability that could be corrected by liposomal delivery of cholesterol. T helper cells recognize peptide antigen in the context of class II MHC molecule. It is known that the conformation of a large number of membrane proteins is dependent on membrane cholesterol. In this investigation we tried to understand the influence of decreased membrane cholesterol in I-MΦ on the conformation of MHC-II protein and peptide-MHC-II stability, and its bearing on the antigen specific T-cell activation. Methodology/Principal Findings MΦ of CBA/j mice were infected with Leishmania donovani (I-MΦ). Two different anti-Aκ mAbs were used to monitor the status of MHC-II protein under parasitized condition. One of them (11.5–2) was conformation specific, whereas the other one (10.2.16) was not. Under parasitized condition, the binding of 11.5–2 decreased significantly with respect to the normal counterpart, whereas that of 10.2.16 remained unaltered. The binding of 11.5–2 was restored to normal upon liposomal delivery of cholesterol in I-MΦ. By molecular dynamics (MD) simulation studies we found that there was considerable conformational fluctuation in the transmembrane domain of the MHC-II protein in the presence of membrane cholesterol than in its absence, which possibly influenced the distal peptide binding groove. This was evident from the faster dissociation of the cognate peptide from peptide-MHC complex under parasitized condition, which could be corrected by liposomal delivery of cholesterol in I-MΦ. Conclusion The decrease in membrane cholesterol in I-MΦ may lead to altered conformation of MHC II, and this may contribute to a faster dissociation of

Adsorption and dissociation of oxygen molecules on Si(111)-(7×7) surface

International Nuclear Information System (INIS)

Niu, Chun-Yao; Wang, Jian-Tao

2013-01-01

The adsorption and dissociation of O 2 molecules on Si(111)-(7×7) surface have been studied by first-principles calculations. Our results show that all the O 2 molecular species adsorbed on Si(111)-(7×7) surface are unstable and dissociate into atomic species with a small energy barrier about 0.1 eV. The single O 2 molecule adsorption tends to form an ins×2 or a new metastable ins×2* structure on the Si adatom sites and the further coming O 2 molecules adsorb on those structures to produce an ad-ins×3 structure. The ad-ins×3 structure is indeed highly stable and kinetically limited for diving into the subsurface layer to form the ins×3-tri structure by a large barrier of 1.3 eV. Unlike the previous views, we find that all the ad-ins, ins×2, and ad-ins×3 structures show bright images, while the ins×2*, ins×3, and ins×3-tri structures show dark images. The proposed oxidation pathways and simulated scanning tunneling microscope images account well for the experimental results and resolve the long-standing confusion and issue about the adsorption and reaction of O 2 molecules on Si(111) surface

Diaquabis[2,6-bis(4H-1,2,4-triazol-4-ylpyridine-κN2]bis(selenocyanato-κNcobalt(II

Directory of Open Access Journals (Sweden)

Yuan-Yuan Liu

2012-08-01

Full Text Available In the title compound, [Co(NCSe2(C9H7N72(H2O2], the Co2+ cation is coordinated by two selenocyanate anions, two 2,6-bis(4H-1,2,4-triazol-4-ylpyridine ligands and two water molecules within a slightly distorted N4O2 octahedron. The asymmetric unit consists of one Co2+ cation, which is located on a center of inversion, as well as one selenocyanate anion, one 2,6-bis(4H-1,2,4-triazol-4-ylpyridine ligand and one water molecule in general positions. Intermolecular O—H...N hydrogen bonds join the complex molecules into layers parallel to the bc plane. The layers are linked by C—H...N and C—H...Se hydrogen bonds into a three-dimensional supramolecular architecture.

Effects of autoionizing states on two-photon double ionization of the H2 molecule

International Nuclear Information System (INIS)

Guan, Xiaoxu; Bartschat, Klaus; Schneider, Barry I; Koesterke, Lars

2014-01-01

Treating the effects of autoionizing intermediate states on two-photon double ionization (DI) of the H 2 molecule using time-dependent laser pulses is a significant computational challenge. Relatively long exposure times are critical to understanding the dynamics. Using the fixed-nuclei approximation, we demonstrate how the doubly excited states enhance the angle-integrated generalized cross sections in H 2 , and how they affect the angular distribution pattern of the ejected electrons. As the energy approaches the threshold for sequential DI, there is a sharp rise in the cross section due to virtual sequential ionization

Central-field intermolecular potentials from the differential elastic scattering of H2(D2) by other molecules

International Nuclear Information System (INIS)

Kuppermann, Aron; Gordon, R.J.; Coggiola, M.J.

1974-01-01

Differential elastic scattering cross sections for the systems H 2 +O 2 , SF 6 , NH 3 , CO, and CH 4 and for D 2 +O 2 , SF 6 , and NH 3 have been obtained from crossed beam studies. In all cases, rapid quantum oscillations have been resolved which permit the determination of intermolecular potentiel parameters if a central-field assumption is adopted. These potentials were found to be independent of both the isotopic form of the hydrogen molecule, and the relative collision energy. As a result of this, and the ability of these spherical potentials to quantitatively describe the measured scattering, it is concluded that anisotropy effects do not seem important in these H 2 (D 2 ) systems

Crystal structure of 4-(4b,8a-dihydro-9H-pyrido[3,4-b]indol-1-yl-7-methyl-2H-chromen-2-one

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S. Samundeeswari

2017-01-01

Full Text Available The title compound, C21H14N2O2, was prepared by Pictet–Spengler cyclization of tryptamine and 4-formyl coumarin. In the molecule, the dihedral angle between the mean planes of the coumarin and β-carboline ring systems is 63.8 (2°. In the crystal, molecules are linked via N—H...N hydrogen bonds, forming chains along the b-axis direction. Within the chains, there are a number of offset π–π interactions present [shortest intercentroid distance = 3.457 (2 Å].

[Pr2(pdc3(Hpdc(H2O4]n·n(H3hp·8n(H2O, a One-Dimensional Coordination Polymer Containing PrO6N3 Tri-Capped Trigonal Prisms and PrO8N Mono-Capped Square Anti-Prisms (H2pdc = Pyridine 2,6-Dicarboxylic Acid, C7H5NO4; 3hp = 3-Hydroxy Pyridine, C5H5NO

Directory of Open Access Journals (Sweden)

Shahzad Sharif

2012-08-01

Full Text Available The synthesis, structure and some properties of the one-dimensional coordination polymer, [Pr2(pdc3(Hpdc]n·n(H3hp·8n(H2O, (H2pdc = pyridine 2,6-dicarboxylic acid, C7H5NO4; 3hp = 3-hydroxypyridine, C5H5NO are described. One of the Pr3+ ions is coordinated by two O,N,O-tridentate pdc2− ligands and one tridentate Hpdc− anion to generate a fairly regular PrO6N3 tri-capped trigonal prism, with the N atoms acting as the caps. The second Pr3+ ion is coordinated by one tridentate pdc2− dianion, four water molecules and two monodentate bridging pdc2− ligands to result in a PrO8N coordination polyhedron that approximates to a mono-capped square-anti-prism. The ligands bridge the metal-atom nodes into a chain, which extends in the [100] direction. The H3hp+ cation and uncoordinated water molecules occupy the inter-chain regions and an N–HLO and numerous O–HLO hydrogen bonds consolidate the structure. The H3hp+ species appears to intercalate between pendant pdc rings to consolidate the polymeric structure. Crystal data: 1 (C33H43N5O29Pr2, Mr = 1255.54, triclinic,  (No. 2, Z = 2, a = 13.2567(1 Å, b = 13.6304(2 Å, c = 13.6409(2 Å, α = 89.695(1°, β = 63.049(1°, γ = 86.105(1°, V = 2191.16(5 Å3, R(F = 0.033, wR(F2 = 0.084.

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression.

Science.gov (United States)

Bell, Charlotte R; MacHugh, Niall D; Connelley, Timothy K; Degnan, Kathryn; Morrison, W Ivan

2015-07-09

Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP-alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I-defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells

Benchmarking semiempirical and DFT methods for the interaction of thiophene and diethyl sulfide molecules with a Ti(OH)4(H2O) cluster.

Science.gov (United States)

Vorontsov, Alexander V; Smirniotis, Panagiotis G

2017-08-01

Semiempirical methods pm6 and pm7 as well as density functional theory functionals exchange LSDA, exchange-correlation PW91 and PBE, hybrid B3LYP1 and PBE0 were compared for energy and geometry of thiophene, diethyl sulfide (DES) molecules and their binding to a frozen Ti(OH) 4 (H 2 O) complex having one coordinatively unsaturated Ti 5C site representing small fragment of TiO 2 anatase (001) surface. PBE0/6-31G(d) with DFT-D3 dispersion correction was the best method for description of thiophene and DES molecules geometries as comparison with experimental data demonstrated. Semiempirical methods pm6 and pm7 resulted in only three of four possible binding configurations of thiophene with the Ti(OH) 4 (H 2 O) complex while pm7 described correctly the enthalpy and all configurations of DES binding with the Ti(OH) 4 (H 2 O) complex. SBKJC pseudopotential and LSDA with and without dispersion correction produced flawed results for many configurations. PBE0 and PBE with and without dispersion correction and PW91 with 6-31G(d) basis set systematically produced dependable results for thiophene and DES binding to the Ti(OH) 4 (H 2 O) complex. PBE0-D3/6-31G(d), B3LYP1-D3/6-31G(d), and PBE-D3/6-31G(d) gave best match of binding energy for thiophene while PBE0/6-31G(d) gave best match of DES binding energy as comparison with CCSD(T) energy demonstrated. On the basis of the superior results obtained with PBE0/6-31G(d), it is the recommended method for modeling of adsorption over TiO 2 surfaces. Such a conclusion is in agreement with recent literature.

Effects of the molecule-electrode interface on the low-bias conductance of Cu-H2-Cu single-molecule junctions.

Science.gov (United States)

Jiang, Zhuoling; Wang, Hao; Shen, Ziyong; Sanvito, Stefano; Hou, Shimin

2016-07-28

The atomic structure and electronic transport properties of a single hydrogen molecule connected to both symmetric and asymmetric Cu electrodes are investigated by using the non-equilibrium Green's function formalism combined with the density functional theory. Our calculations show that in symmetric Cu-H2-Cu junctions, the low-bias conductance drops rapidly upon stretching, while asymmetric ones present a low-bias conductance spanning the 0.2-0.3 G0 interval for a wide range of electrode separations. This is in good agreement with experiments on Cu atomic contacts in a hydrogen environment. Furthermore, the distribution of the calculated vibrational energies of the two hydrogen atoms in the asymmetric Cu-H2-Cu junction is also consistent with experiments. These findings provide clear evidence for the formation of asymmetric Cu-H2-Cu molecular junctions in breaking Cu atomic contacts in the presence of hydrogen and are also helpful for the design of molecular devices with Cu electrodes.

Prevention of MHC-alloimmunization by UV-B irradiation in a murine model: effects of UV dose and number of transfused cells

International Nuclear Information System (INIS)

Grijzenhout, M.A.; Claas, F.H.J.

1994-01-01

The optimal dose of UV-B radiation for prevention of in vivo alloimmunization (AI) against major histocompatibility complex (MHC) antigens was investigated in a murine transfusion model. Two groups with five C57BL/6 mice (H-2 b ) each were transfused at weekly intervals with 1 x 10 5 or 1 x 10 6 DBA/2 (H-2 d ) leucocytes. Both suspensions induced anti-H-2 d antibodies in all mice after the second transfusion. The minimal UV-B dose required for abolition of alloreactivity in the mixed leucocyte reaction (MLR) was 0.6 J/cm 2 . This dose completely prevented the onset of MHC-AI in all five mice transfused with six suspensions containing 1 x 10 5 leucocytes. In contrast, suspensions with 1 x 10 6 leucocytes and exposed to 0.6 J/cm 2 induced immunization in 4/5 mice. Further increase of the dose to 1.8 or 5.4 J/cm 2 did not prevent the onset of MHC-AI. We conclude that the number of leucocytes per transfusion determines the efficacy of UV irradiation for the prevention of MHC-AI. For UV irradiation of human platelet concentrates (PCs) we propose to reduce the number of leucocytes by centrifugation prior to UV exposure. UV-B irradiation of PCs with high numbers of leucocytes may not be effective for prevention of alloimmunization. (Author)

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

DEFF Research Database (Denmark)

Nielsen, Morten; Lundegaard, Claus; Lund, Ole

2007-01-01

the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance...... of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC) and three mouse H2-IA alleles. RESULTS: The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation...... between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR), we demonstrate a consistent gain in predictive performance...

Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules

KAUST Repository

Chawla, Mohit; Credendino, Raffaele; Oliva, Romina; Cavallo, Luigi

2015-01-01

Non-natural (synthetic) nucleobases, including 7-ethynyl- and 7-triazolyl-8-aza-7-deazaadenosine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenosine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenosine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanosine when paired to cytosine. To stress further the H-bonding pairing in the modified adenosine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules

KAUST Repository

Chawla, Mohit

2015-09-21

Non-natural (synthetic) nucleobases, including 7-ethynyl- and 7-triazolyl-8-aza-7-deazaadenosine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenosine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenosine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanosine when paired to cytosine. To stress further the H-bonding pairing in the modified adenosine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

Extreme MHC class I diversity in the sedge warbler (Acrocephalus schoenobaenus); selection patterns and allelic divergence suggest that different genes have different functions.

Science.gov (United States)

Biedrzycka, Aleksandra; O'Connor, Emily; Sebastian, Alvaro; Migalska, Magdalena; Radwan, Jacek; Zając, Tadeusz; Bielański, Wojciech; Solarz, Wojciech; Ćmiel, Adam; Westerdahl, Helena

2017-07-05

Recent work suggests that gene duplications may play an important role in the evolution of immunity genes. Passerine birds, and in particular Sylvioidea warblers, have highly duplicated major histocompatibility complex (MHC) genes, which are key in immunity, compared to other vertebrates. However, reasons for this high MHC gene copy number are yet unclear. High-throughput sequencing (HTS) allows MHC genotyping even in individuals with extremely duplicated genes. This HTS data can reveal evidence of selection, which may help to unravel the putative functions of different gene copies, i.e. neofunctionalization. We performed exhaustive genotyping of MHC class I in a Sylvioidea warbler, the sedge warbler, Acrocephalus schoenobaenus, using the Illumina MiSeq technique on individuals from a wild study population. The MHC diversity in 863 genotyped individuals by far exceeds that of any other bird species described to date. A single individual could carry up to 65 different alleles, a large proportion of which are expressed (transcribed). The MHC alleles were of three different lengths differing in evidence of selection, diversity and divergence within our study population. Alleles without any deletions and alleles containing a 6 bp deletion showed characteristics of classical MHC genes, with evidence of multiple sites subject to positive selection and high sequence divergence. In contrast, alleles containing a 3 bp deletion had no sites subject to positive selection and had low divergence. Our results suggest that sedge warbler MHC alleles that either have no deletion, or contain a 6 bp deletion, encode classical antigen presenting MHC molecules. In contrast, MHC alleles containing a 3 bp deletion may encode molecules with a different function. This study demonstrates that highly duplicated MHC genes can be characterised with HTS and that selection patterns can be useful for revealing neofunctionalization. Importantly, our results highlight the need to consider the

Nqrs Data for C6H7F7N2OSb2 (Subst. No. 0880)

Science.gov (United States)

Chihara, H.; Nakamura, N.

This document is part of Subvolume A `Substances Containing Ag … C10H15' of Volume 48 `Nuclear Quadrupole Resonance Spectroscopy Data' of Landolt-Börnstein - Group III `Condensed Matter'. It contains an extract of Section `3.2 Data tables' of the Chapter `3 Nuclear quadrupole resonance data' providing the NQRS data for C6H7F7N2OSb2 (Subst. No. 0880)

Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II-containing compartments

NARCIS (Netherlands)

Wubbolts, R.; Fernandez-Borja, M.; Jordens, I.; Reits, E.; Dusseljee, S.; Echeverri, C.; Vallee, R. B.; Neefjes, J.

1999-01-01

MHC class II molecules exert their function at the cell surface by presenting to T cells antigenic fragments that are generated in the endosomal pathway. The class II molecules are targetted to early lysosomal structures, termed MIIC, where they interact with antigenic fragments and are subsequently

Crystal structures of ZnCl2·2.5H2O, ZnCl2·3H2O and ZnCl2·4.5H2O

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Erik Hennings

2014-12-01

Full Text Available The formation of different complexes in aqueous solutions is an important step in understanding the behavior of zinc chloride in water. The structure of concentrated ZnCl2 solutions is governed by coordination competition of Cl− and H2O around Zn2+. According to the solid–liquid phase diagram, the title compounds were crystallized below room temperature. The structure of ZnCl2·2.5H2O contains Zn2+ both in a tetrahedral coordination with Cl− and in an octahedral environment defined by five water molecules and one Cl− shared with the [ZnCl4]2− unit. Thus, these two different types of Zn2+ cations form isolated units with composition [Zn2Cl4(H2O5] (pentaaqua-μ-chlorido-trichloridodizinc. The trihydrate {hexaaquazinc tetrachloridozinc, [Zn(H2O6][ZnCl4]}, consists of three different Zn2+ cations, one of which is tetrahedrally coordinated by four Cl− anions. The two other Zn2+ cations are each located on an inversion centre and are octahedrally surrounded by water molecules. The [ZnCl4] tetrahedra and [Zn(H2O6] octahedra are arranged in alternating rows parallel to [001]. The structure of the 4.5-hydrate {hexaaquazinc tetrachloridozinc trihydrate, [Zn(H2O6][ZnCl4]·3H2O}, consists of isolated octahedral [Zn(H2O6] and tetrahedral [ZnCl4] units, as well as additional lattice water molecules. O—H...O hydrogen bonds between the water molecules as donor and ZnCl4 tetrahedra and water molecules as acceptor groups leads to the formation of a three-dimensional network in each of the three structures.

Cryogenic buffer-gas loading and magnetic trapping of CrH and MnH molecules

OpenAIRE

Stoll, M.; Bakker, J.; Steimle, T.; Meijer, G.; Peters, A.

2008-01-01

We report on the buffer-gas cooling and trapping of CrH and MnH molecules in a magnetic quadrupole trap with densities on the order of 106 cm−3 at a temperature of 650 mK. Storage times of up to 180 ms have been observed, corresponding to a 20-fold lifetime enhancement with respect to the field-free diffusion through the 3He buffer-gas. Using Monte Carlo trajectory simulations, inelastic molecule-3He collision cross sections of 1.6×10−18 and 3.1×10−17 cm2 are extracted for CrH and MnH, respec...

Long Carbon Chains in the Warm Carbon-chain-chemistry Source L1527: First Detection of C7H in Molecular Clouds

Science.gov (United States)

Araki, Mitsunori; Takano, Shuro; Sakai, Nami; Yamamoto, Satoshi; Oyama, Takahiro; Kuze, Nobuhiko; Tsukiyama, Koichi

2017-09-01

Long carbon-chain molecules were searched for toward the low-mass star-forming region L1527, which is a prototypical source of warm carbon-chain chemistry (WCCC), using the 100 m Green Bank Telescope. Long carbon-chain molecules, C7H (2Π1/2), C6H (2Π3/2 and 2Π1/2), CH3C4H, and C6H2 (cumulene carbene, CCCCCCH2), and cyclic species of C3H and C3H2O were detected. In particular, C7H was detected for the first time in molecular clouds. The column density of C7H is determined to be 6 × 1010 cm-2. The column densities of the carbon-chain molecules including CH3C4H and C6H in L1527 relative to those in the starless dark cloud Taurus Molecular Cloud-1 Cyanopolyyne Peak (TMC-1 CP) tend to be systematically lower for long carbon-chain lengths. However, the column densities of C7H and C6H2 do not follow this trend and are found to be relatively abundant in L1527. This result implies that these long carbon-chain molecules are remnants of the cold starless phase. The results—that both the remnants and WCCC products are observed toward L1527—are consistent with the suggestion that the protostar can also be born in the parent core at a relatively early stage in the chemical evolution.

[KDy(Hptc3(H3ptc]n·2n(Hbipy·5n(H2O, a Layered Coordination Polymer Containing DyO6N3 Tri-Capped Trigonal Prisms (H3ptc = Pyridine 2,4,6-Tricarboxylic Acid, C8H5NO6; Bipy = 2,2'-Bipyridine, C10H8N2

Directory of Open Access Journals (Sweden)

Shoaib Anwar

2012-08-01

Full Text Available The synthesis, structure and properties of the bimetallic layered coordination polymer, [KDy(C8H3NO63(C8H5NO6]n·2n(C10H9N2·5n(H2O = [KDy(Hptc3(H3ptc]n·2n(Hbipy·5n(H2O, are described. The Dy3+ ion is coordinated by three O,N,O-tridentate doubly-deprotonated pyridine tri-carboxylate (Hptc ligands to generate a fairly regular DyO6N3 tri-capped trigonal prism, with the N atoms acting as the caps. The potassium ion is coordinated by an O,N,O-tridentate H3ptc molecule as well as monodentate and bidentate Hptc ligands to result in an irregular KNO9 coordination geometry. The ligands bridge the metal-atom nodes into a bimetallic, layered, coordination polymer, which extends as corrugated layers in the (010 plane, with the mono-protonated bipyridine cations and water molecules occupying the inter-layer regions: Unlike related structures, there are no dysprosium–water bonds. Many O–HLO and N–HLO hydrogen bonds consolidate the structure. Characterization and bioactivity data are described. Crystal data: C52H42DyKN8O29, Mr = 1444.54, triclinic,  (No. 2, Z = 2, a = 9.188(2 Å, b = 15.7332(17 Å, c = 19.1664(19 Å, α = 92.797(6°, β = 92.319(7°, γ = 91.273(9°, V = 2764.3(7 Å3, R(F = 0.029, wR(F2 = 0.084.

MHC class II tetramers made from isolated recombinant α and β chains refolded with affinity-tagged peptides

DEFF Research Database (Denmark)

Braendstrup, Peter; Justesen, Sune Frederik Lamdahl; Osterbye, Thomas

2013-01-01

Targeting CD4+ T cells through their unique antigen-specific, MHC class II-restricted T cell receptor makes MHC class II tetramers an attractive strategy to identify, validate and manipulate these cells at the single cell level. Currently, generating class II tetramers is a specialized undertaking...... effectively limiting their use and emphasizing the need for improved methods of production. Using class II chains expressed individually in E. coli as versatile recombinant reagents, we have previously generated peptide-MHC class II monomers, but failed to generate functional class II tetramers. Adding...... a monomer purification principle based upon affinity-tagged peptides, we here provide a robust method to produce class II tetramers and demonstrate staining of antigen-specific CD4+ T cells. We also provide evidence that both MHC class II and T cell receptor molecules largely accept affinity-tagged peptides...

Crystal structures of NiSO4·9H2O and NiSO4·8H2O: magnetic properties, stability with respect to morenosite (NiSO4·7H2O), the solid-solution series (Mg x Ni1-x )SO4·9H2O

Science.gov (United States)

Fortes, A. D.; Knight, K. S.; Gibbs, A. S.; Wood, I. G.

2018-02-01

Since being discovered initially in mixed-cation systems, a method of forming end-member NiSO4·9H2O and NiSO4·8H2O has been found. We have obtained powder diffraction data from protonated analogues (with X-rays) and deuterated analogues (using neutrons) of these compounds over a range of temperatures, allowing us to determine their crystal structures—including all H-atoms—and to characterise the transitions on warming from 220 to 278 K; glass → 9-hydrate → 8-hydrate + ice → 7-hydrate + ice → partial melt (7-hydrate + liquid). NiSO4·8D2O is triclinic, space-group P\\bar {1} , Z = 2, with unit cell parameters at 150 K, a = 6.12463(8) Å, b = 6.8401(1) Å, c = 12.5339(2) Å, α = 92.846(1)°, β = 97.822(1)°, γ = 96.627(1)° and V = 515.58(1) Å3. The structure consists of two symmetry-inequivalent Ni(D2O)6 octahedra on sites of \\bar {1} symmetry. These are directly joined by a water-water H-bond to form chains of octahedra parallel with the c-axis at x = 0. Two interstitial water molecules serve both to bridge the Ni(D2O)6 octahedral chains in the b-c plane and also to connect with the SO4 2- tetrahedral oxyanion. These tetrahedra are linked by the two interstitial water molecules in a reticular motif to form sheets perpendicular to c. NiSO4·9D2O is monoclinic, space-group P21/c, Z = 4, with unit-cell parameters at 150 K, a = 6.69739(6) Å, b = 11.8628(1) Å, c = 14.5667(1) Å, β = 94.9739(8)° and V = 1152.96(1) Å3. The structure is isotypic with the Mg analogue described elsewhere (Fortes et al., Acta Cryst B 73:47‒64, 2017b). It shares the motif of H-bonded octahedral chains with NiSO4·8D2O, although in the enneahydrate these run parallel with the b-axis at x = 0. Three interstitial water molecules bridge the Ni(D2O)6 octahedra to the SO4 2- tetrahedral oxyanion. The tetrahedra sit at x ≈ 0.5 and are linked by two of the three interstitial water molecules in a pentagonal motif to form ribbons parallel with b. A solid-solution series

MHC polymorphism and disease resistance in Atlantic salmon (Salmo salar); facing pathogens with single expressed major histocompatibility class I and class II loci

NARCIS (Netherlands)

Grimholt, U.; Larsen, S.; Nordmo, R.; Midtlyng, P.; Kjoeglum, S.; Storset, A.; Saebo, S.; Stet, R.J.M.

2003-01-01

Few studies have yet addressed the functional aspects of MHC molecules in fish. To lay the foundation for this, we evaluated the association between disease resistance and MHC class I and class II polymorphism in Atlantic salmon. Standardized disease challenge trials were performed on a semi-wild

Scaling of C{sub 60} ionization and fragmentation with the energy deposited in collisions with H{sup +}, H{sub 2}{sup +}, H{sub 3}{sup +} and He{sup +} ions (2-130 keV)

Energy Technology Data Exchange (ETDEWEB)

Bordenave-Montesquieu, D. [LCAR, IRSAMC, UMR 5589 CNRS, Universite Paul Sabatier, Toulouse (France)]. E-mail: dbm@yosemite.ups-tlse.fr; Moretto-Capelle, P.; Bordenave-Montesquieu, A.; Rentenier, A. [LCAR, IRSAMC, UMR 5589 CNRS, Universite Paul Sabatier, Toulouse (France)

2001-03-14

Fragmentation, ionization and C{sub 2} fragment evaporation of the C{sub 60} molecule induced by collisions with H{sup +}, H{sub 2}{sup +}, H{sub 3}{sup +} and He{sup +} monocharged ions have been measured in coincidence with the electron emission in the 2-130 keV projectile energy range. The time-of-flight mass spectra were found to vary strongly with the collision energy or velocity and the projectile. On the other hand, they scale rather nicely with the energy deposited in the molecule. Relative weights of the total multi-fragmentation into small C{sub n}{sup +} fragments (n=1-14), individual multi-fragmentation (n=1,7 and 11), double ionization of the intact molecule and evaporation of C{sub 2} molecules associated with the doubly charged fullerene ion, are used to illustrate our finding quantitatively. (author). Letter-to-the-editor.

Configuration and stability of 1, 1-diamino-2, 2-dinitrothylene (FOX-7) embedded in graphene

Energy Technology Data Exchange (ETDEWEB)

Wang, Yan Qun [College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou (China); Wang, Gui Xiang [School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing (China)

2016-10-15

The configuration and stability of 1,1-diamino-2,2-dinitroethylene (FOX-7) embedded in graphene were studied using density functional theory with all-electron double numerical polarized basis sets. The results suggested that graphene had a greater impact on the planarity of FOX-7 molecules than did H-bonding. Under the synergistic effect of graphene and H-bonding, the geometry of H-bonded FOX-7 embedded in graphene was flatter than that of FOX-7 without H-bonds, which facilitated π–π stacking, as well as the stability of FOX-7 in graphene. The conjugated structure of FOX-7 contributed to its stability between layers of graphene. When the conjugated structure in FOX-7 was completely disrupted, the stabilization energy decreased by 48.6%. This theoretical work is useful for gaining new insights into the microscopic interaction of energetic molecules with graphene, and it will provide theoretical guidance for the encapsulation and storage of energetic materials.

Configuration and stability of 1, 1-diamino-2, 2-dinitrothylene (FOX-7) embedded in graphene

International Nuclear Information System (INIS)

Wang, Yan Qun; Wang, Gui Xiang

2016-01-01

The configuration and stability of 1,1-diamino-2,2-dinitroethylene (FOX-7) embedded in graphene were studied using density functional theory with all-electron double numerical polarized basis sets. The results suggested that graphene had a greater impact on the planarity of FOX-7 molecules than did H-bonding. Under the synergistic effect of graphene and H-bonding, the geometry of H-bonded FOX-7 embedded in graphene was flatter than that of FOX-7 without H-bonds, which facilitated π–π stacking, as well as the stability of FOX-7 in graphene. The conjugated structure of FOX-7 contributed to its stability between layers of graphene. When the conjugated structure in FOX-7 was completely disrupted, the stabilization energy decreased by 48.6%. This theoretical work is useful for gaining new insights into the microscopic interaction of energetic molecules with graphene, and it will provide theoretical guidance for the encapsulation and storage of energetic materials

Specific blockade by CD54 and MHC II of CD40-mediated signaling for B cell proliferation and survival

DEFF Research Database (Denmark)

Doyle, I S; Hollmann, C A; Crispe, I N

2001-01-01

Regulation of B lymphocyte proliferation is critical to maintenance of self-tolerance, and intercellular interactions are likely to signal such regulation. Here, we show that coligation of either the adhesion molecule ICAM-1/CD54 or MHC II with CD40 inhibited cell cycle progression and promoted...... these effects. Addition of BCR or IL-4 signals did not overcome the effect of ICAM-1 or MHC II on CD40-induced proliferation. FasL expression was not detected in B cell populations. These results show that MHC II and ICAM-1 specifically modulate CD40-mediated signaling, so inhibiting proliferation...

Molecular and crystal structure of nido-9-C5H5N-11-I-7,8-C2B9H10: supramolecular architecture via hydrogen bonding X-H...I (X = B, C)

International Nuclear Information System (INIS)

Polyanskaya, T.M.

2006-01-01

A monocrystal X-ray diffraction study of a new iodine-containing cluster compound 9-(pyridine)-11-iodo-decahydro-7,8-dicarba-nido-undecaborane [9-C 5 H 5 N-11-I-7,8-C 2 B 9 H 10 ] has been performed. Crystal data: C 7 H 15 B 9 NI, M = 337.39, monoclinic, space group P2 1 /c, unit cell parameters: a=9.348(1) A, b=11.159(1) A, c=13.442(2) A, β=98.13(1) deg, V=1388.1(5) A 3 , Z=4, d calc = 1.614 g/cm 3 , T = 295 K, F(000)=648, μ=2.276 mm -1 . The structure was solved by a direct method and refined in the full-matrix anisotropic approximation (isotropic for hydrogen atoms) to final agreement factors R 1 = 0.0254, wR 2 = 0.0454 for 2437 I hkl >2σ I from 3590 measured I hkl (an Enraf-Nonius CAD-4 diffractometer, λMoK α , graphite monochromator, θ/2θ-scanning). The molecules are joined into a supramolecular assembly by hydrogen bonds X-H...I (X = B, C) [ru