Sample records for complex class i-related

  1. Emerging Major Histocompatibility Complex Class I-Related Functions of NLRC5.

    PubMed

    Chelbi, S T; Dang, A T; Guarda, G

    2017-01-01

    Recent evidence demonstrates a key role for the nucleotide-binding oligomerization domain-like receptor (NLR) family member NLRC5 (NLR family, CARD domain containing protein 5) in the transcriptional regulation of major histocompatibility complex (MHC) class I and related genes. Detailed information on NLRC5 target genes in various cell types and conditions is emerging. Thanks to its analogy to CIITA (class II major MHC transactivator), a NLR family member known for over 20 years to be the master regulator of MHC class II gene transcription, also the molecular mechanisms underlying NLRC5 function are being rapidly unraveled. MHC class I molecules are crucial in regulating innate and adaptive cytotoxic responses. Whereas CD8 + T cells detect antigens presented on MHC class I molecules by infected or transformed cells, natural killer (NK) lymphocytes eliminate target cells with downregulated MHC class I expression. Data uncovering the relevance of NLRC5 in homeostasis and activity of these two lymphocyte subsets have been recently reported. Given the importance of CD8 + T and NK cells in controlling infection and cancer, it is not surprising that NLRC5 is also starting to emerge as a central player in these diseases. This chapter summarizes and discusses novel insights into the molecular mechanisms underlying NLRC5 activity and its relevance to pathological conditions. A thorough understanding of both aspects is essential to evaluate the clinical significance and therapeutic potential of NLRC5. © 2017 Elsevier Inc. All rights reserved.

  2. A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization

    PubMed Central

    Goldstein, Leonard D.; Howarth, Mark; Cardelli, Luca; Emmott, Stephen; Elliott, Tim; Werner, Joern M.

    2011-01-01

    Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human

  3. Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum

    PubMed Central

    Lee, Sungwook; Park, Boyoun; Kang, Kwonyoon

    2009-01-01

    In contrast to the fairly well-characterized mechanism of assembly of MHC class I-peptide complexes, the disassembly mechanism by which peptide-loaded MHC class I molecules are released from the peptide-loading complex and exit the endoplasmic reticulum (ER) is poorly understood. Optimal peptide binding by MHC class I molecules is assumed to be sufficient for triggering exit of peptide-filled MHC class I molecules from the ER. We now show that protein disulfide isomerase (PDI) controls MHC class I disassembly by regulating dissociation of the tapasin-ERp57 disulfide conjugate. PDI acts as a peptide-dependent molecular switch; in the peptide-bound state, it binds to tapasin and ERp57 and induces dissociation of the tapasin-ERp57 conjugate. In the peptide-free state, PDI is incompetent to bind to tapasin or ERp57 and fails to dissociate the tapasin-ERp57 conjugates, resulting in ER retention of MHC class I molecules. Thus, our results indicate that even after optimal peptide loading, MHC class I disassembly does not occur by default but, rather, is a regulated process involving PDI-mediated interactions within the peptide-loading complex. PMID:19477919

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

    PubMed Central

    2012-01-01

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

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

    PubMed

    Kuduk, Katarzyna; Babik, Wiesław; Bojarska, Katarzyna; Sliwińska, Ewa B; Kindberg, Jonas; Taberlet, Pierre; Swenson, Jon E; Radwan, Jacek

    2012-10-02

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

  6. Regulation of calreticulin–major histocompatibility complex (MHC) class I interactions by ATP

    PubMed Central

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

    2015-01-01

    The MHC class I peptide loading complex (PLC) facilitates the assembly of MHC class I molecules with peptides, but factors that regulate the stability and dynamics of the assembly complex are largely uncharacterized. Based on initial findings that ATP, in addition to MHC class I-specific peptide, is able to induce MHC class I dissociation from the PLC, we investigated the interaction of ATP with the chaperone calreticulin, an endoplasmic reticulum (ER) luminal, calcium-binding component of the PLC that is known to bind ATP. We combined computational and experimental measurements to identify residues within the globular domain of calreticulin, in proximity to the high-affinity calcium-binding site, that are important for high-affinity ATP binding and for ATPase activity. High-affinity calcium binding by calreticulin is required for optimal nucleotide binding, but both ATP and ADP destabilize enthalpy-driven high-affinity calcium binding to calreticulin. ATP also selectively destabilizes the interaction of calreticulin with cellular substrates, including MHC class I molecules. Calreticulin mutants that affect ATP or high-affinity calcium binding display prolonged associations with monoglucosylated forms of cellular MHC class I, delaying MHC class I dissociation from the PLC and their transit through the secretory pathway. These studies reveal central roles for ATP and calcium binding as regulators of calreticulin–substrate interactions and as key determinants of PLC dynamics. PMID:26420867

  7. Pseudorabies virus-induced suppression of major histocompatibility complex class I antigen expression.

    PubMed Central

    Mellencamp, M W; O'Brien, P C; Stevenson, J R

    1991-01-01

    The ability of pseudorabies virus (PrV) to down-modulate expression of major histocompatibility complex class I antigens in murine and porcine cells was investigated. When quantified by flow cytometry, surface expression of class I Kk and Dk antigens on PrV-infected cells decreased by 60% or more. Down-modulation was associated with a decrease in total cellular class I antigens, indicating regulation at the transcriptional or posttranscriptional level. PrV did not suppress expression of transferrin receptor, suggesting a selective regulatory mechanism. Images PMID:1851884

  8. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation

    PubMed Central

    Wieczorek, Marek; Abualrous, Esam T.; Sticht, Jana; Álvaro-Benito, Miguel; Stolzenberg, Sebastian; Noé, Frank; Freund, Christian

    2017-01-01

    Antigen presentation by major histocompatibility complex (MHC) proteins is essential for adaptive immunity. Prior to presentation, peptides need to be generated from proteins that are either produced by the cell’s own translational machinery or that are funneled into the endo-lysosomal vesicular system. The prolonged interaction between a T cell receptor and specific pMHC complexes, after an extensive search process in secondary lymphatic organs, eventually triggers T cells to proliferate and to mount a specific cellular immune response. Once processed, the peptide repertoire presented by MHC proteins largely depends on structural features of the binding groove of each particular MHC allelic variant. Additionally, two peptide editors—tapasin for class I and HLA-DM for class II—contribute to the shaping of the presented peptidome by favoring the binding of high-affinity antigens. Although there is a vast amount of biochemical and structural information, the mechanism of the catalyzed peptide exchange for MHC class I and class II proteins still remains controversial, and it is not well understood why certain MHC allelic variants are more susceptible to peptide editing than others. Recent studies predict a high impact of protein intermediate states on MHC allele-specific peptide presentation, which implies a profound influence of MHC dynamics on the phenomenon of immunodominance and the development of autoimmune diseases. Here, we review the recent literature that describe MHC class I and II dynamics from a theoretical and experimental point of view and we highlight the similarities between MHC class I and class II dynamics despite the distinct functions they fulfill in adaptive immunity. PMID:28367149

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

    PubMed

    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.

  10. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors.

    PubMed

    Stewart, C Andrew; Laugier-Anfossi, Fanny; Vély, Frédéric; Saulquin, Xavier; Riedmuller, Jenifer; Tisserant, Agnès; Gauthier, Laurent; Romagné, François; Ferracci, Géraldine; Arosa, Fernando A; Moretta, Alessandro; Sun, Peter D; Ugolini, Sophie; Vivier, Eric

    2005-09-13

    Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. Infection of cells with Epstein-Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide-MHC class I complexes on Epstein-Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by a broad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger NK effector responses when faced with cognate ligand, consistent with fine control during NK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders.

  11. Recognition of peptide–MHC class I complexes by activating killer immunoglobulin-like receptors

    PubMed Central

    Stewart, C. Andrew; Laugier-Anfossi, Fanny; Vély, Frédéric; Saulquin, Xavier; Riedmuller, Jenifer; Tisserant, Agnès; Gauthier, Laurent; Romagné, François; Ferracci, Géraldine; Arosa, Fernando A.; Moretta, Alessandro; Sun, Peter D.; Ugolini, Sophie; Vivier, Eric

    2005-01-01

    Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. Infection of cells with Epstein–Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide–MHC class I complexes on Epstein–Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by a broad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger NK effector responses when faced with cognate ligand, consistent with fine control during NK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders. PMID:16141329

  12. Peptide selection by class I molecules of the major histocompatibility complex.

    PubMed

    Elliott, T; Smith, M; Driscoll, P; McMichael, A

    1993-12-01

    Class I molecules of the major histocompatibility complex (MHC) bind peptides derived from cytoplasmic proteins. Comparison of over 100 such peptides reveals the importance of the carboxy-terminal residue in selective binding. Recent evidence implicates the proteases and transporters of the processing pathway in providing peptides with the correct residues at the carboxyl terminus.

  13. Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.

    PubMed

    Kulski, Jerzy K; Shiina, Takashi; Anzai, Tatsuya; Kohara, Sakae; Inoko, Hidetoshi

    2002-12-01

    The major histocompatibility complex (MHC) genomic region is composed of a group of linked genes involved functionally with the adaptive and innate immune systems. The class I and class II genes are intrinsic features of the MHC and have been found in all the jawed vertebrates studied so far. The MHC genomic regions of the human and the chicken (B locus) have been fully sequenced and mapped, and the mouse MHC sequence is almost finished. Information on the MHC genomic structures (size, complexity, genic and intergenic composition and organization, gene order and number) of other vertebrates is largely limited or nonexistent. Therefore, we are mapping, sequencing and analyzing the MHC genomic regions of different human haplotypes and at least eight nonhuman species. Here, we review our progress with these sequences and compare the human MHC structure with that of the nonhuman primates (chimpanzee and rhesus macaque), other mammals (pigs, mice and rats) and nonmammalian vertebrates such as birds (chicken and quail), bony fish (medaka, pufferfish and zebrafish) and cartilaginous fish (nurse shark). This comparison reveals a complex MHC structure for mammals and a relatively simpler design for nonmammalian animals with a hypothetical prototypic structure for the shark. In the mammalian MHC, there are two to five different class I duplication blocks embedded within a framework of conserved nonclass I and/or nonclass II genes. With a few exceptions, the class I framework genes are absent from the MHC of birds, bony fish and sharks. Comparative genomics of the MHC reveal a highly plastic region with major structural differences between the mammalian and nonmammalian vertebrates. Additional genomic data are needed on animals of the reptilia, crocodilia and marsupial classes to find the origins of the class I framework genes and examples of structures that may be intermediate between the simple and complex MHC organizations of birds and mammals, respectively.

  14. Dynamics of major histocompatibility complex class I association with the human peptide-loading complex.

    PubMed

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

    2012-09-07

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

  15. MHC class I diversity in chimpanzees and bonobos.

    PubMed

    Maibach, Vincent; Hans, Jörg B; Hvilsom, Christina; Marques-Bonet, Tomas; Vigilant, Linda

    2017-10-01

    Major histocompatibility complex (MHC) class I genes are critically involved in the defense against intracellular pathogens. MHC diversity comparisons among samples of closely related taxa may reveal traces of past or ongoing selective processes. The bonobo and chimpanzee are the closest living evolutionary relatives of humans and last shared a common ancestor some 1 mya. However, little is known concerning MHC class I diversity in bonobos or in central chimpanzees, the most numerous and genetically diverse chimpanzee subspecies. Here, we used a long-read sequencing technology (PacBio) to sequence the classical MHC class I genes A, B, C, and A-like in 20 and 30 wild-born bonobos and chimpanzees, respectively, with a main focus on central chimpanzees to assess and compare diversity in those two species. We describe in total 21 and 42 novel coding region sequences for the two species, respectively. In addition, we found evidence for a reduced MHC class I diversity in bonobos as compared to central chimpanzees as well as to western chimpanzees and humans. The reduced bonobo MHC class I diversity may be the result of a selective process in their evolutionary past since their split from chimpanzees.

  16. Crystallization and x-ray diffraction analysis of a putative bacterial class I labdane-related diterpene synthase [Crysallization and preliminary x-ray diffraction analysis of a bacterial class I labdane-related diterpene synthase

    DOE PAGES

    Serrano-Posada, Hugo; Centeno-Leija, Sara; Rojas-Trejo, Sonia; ...

    2015-08-25

    Here, labdane-related diterpenoids are natural products with potential pharmaceutical applications that are rarely found in bacteria. Here, a putative class I labdane-related diterpene synthase (LrdC) identified by genome mining in a streptomycete was successfully crystallized using the microbatch method. Crystals of the LrdC enzyme were obtained in a holo form with its natural cofactor Mg 2+ (LrdC-Mg 2+) and in complex with inorganic pyrophosphate (PP i) (LrdC-Mg 2+–PP i). Crystals of native LrdC-Mg 2+ diffracted to 2.50 Å resolution and belonged to the trigonal space group P3 221, with unit-cell parameters a = b = 107.1, c = 89.2 Å.more » Crystals of the LrdC-Mg 2+–PP i complex grown in the same conditions as the native enzyme with PEG 8000 diffracted to 2.36 Å resolution and also belonged to the trigonal space group P3 221. Crystals of the LrdC-Mg 2+–PP i complex grown in a second crystallization condition with PEG 3350 diffracted to 2.57 Å resolution and belonged to the monoclinic space group P2 1, with unit-cell parameters a = 49.9, b = 104.1, c = 66.5 Å, β = 111.4°. The structure was determined by the single-wavelength anomalous dispersion (SAD) technique using the osmium signal from a potassium hexachloroosmate (IV) derivative.« less

  17. Transcriptional and posttranscriptional regulation of class I major histocompatibility complex genes following transformation with human adenoviruses.

    PubMed Central

    Shemesh, J; Rotem-Yehudar, R; Ehrlich, R

    1991-01-01

    Transformation of rodent cells by human adenoviruses is a well-established model system for studying the expression, regulation, and function of class I antigens. In this report, we demonstrate that the highly oncogenic adenovirus type 12 operates at the transcriptional and posttranscriptional levels in regulating the activity of major histocompatibility complex class I genes and products in transformed cells. Adenovirus type 12 suppresses the cell surface expression of class I antigens in most cell lines. Nevertheless, in a number of cell lines suppression is the result of reduction in the amount of stable specific mRNA, while in another group of cell lines suppression involves interference with processing of a posttranscriptional product. The two mechanisms operate both for the endogenous H-2 genes and for a miniature swine class I transgene that is expressed in the cells. Images PMID:1895404

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

    PubMed Central

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

    2015-01-01

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

  19. Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.

    PubMed

    Vanneste, Y; Thome, A N; Vandersmissen, E; Charlet, C; Franchimont, D; Martens, H; Lhiaubet, A M; Schimpff, R M; Rostène, W; Geenen, V

    1997-06-01

    This study shows the expression at the cell surface of human thymic epithelial cells (TEC) of a neurotensin (NT)-like immunoreactivity. NT radio-immunoassay (RIA) revealed that cultured human TEC contain +/-5 ng immunoreactive (ir) NT/10(6) cells, of which 5% is associated with plasma cell membranes. HPLC analysis of NT-ir present in human TEC showed a major peak of NT-ir corresponding to NT1-13. NT-ir was not detected in the supernatant of human TEC cultures. Using an affinity column prepared with a anti-MHC class I monoclonal antibody, NT-ir-related peptides were retained on the column and eluted together with MHC class I-related proteins. According to the elution time on HPLC of these peptides, they correspond to intact NT1-13, as well as to smaller fragments of NT1-13.

  20. Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules.

    PubMed

    Chapman, Daniel C; Stocki, Pawel; Williams, David B

    2015-01-01

    Human cytomegalovirus uses a variety of mechanisms to evade immune recognition through major histocompatibility complex class I molecules. One mechanism mediated by the immunoevasin protein US2 causes rapid disposal of newly synthesized class I molecules by the endoplasmic reticulum-associated degradation pathway. Although several components of this degradation pathway have been identified, there are still questions concerning how US2 targets class I molecules for degradation. In this study we identify cyclophilin C, a peptidyl prolyl isomerase of the endoplasmic reticulum, as a component of US2-mediated immune evasion. Cyclophilin C could be co-isolated with US2 and with the class I molecule HLA-A2. Furthermore, it was required at a particular expression level since depletion or overexpression of cyclophilin C impaired the degradation of class I molecules. To better characterize the involvement of cyclophilin C in class I degradation, we used LC-MS/MS to detect US2-interacting proteins that were influenced by cyclophilin C expression levels. We identified malectin, PDIA6, and TMEM33 as proteins that increased in association with US2 upon cyclophilin C knockdown. In subsequent validation all were shown to play a functional role in US2 degradation of class I molecules. This was specific to US2 rather than general ER-associated degradation since depletion of these proteins did not impede the degradation of a misfolded substrate, the null Hong Kong variant of α1-antitrypsin.

  1. Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Chapman, Daniel C.; Stocki, Pawel; Williams, David B.

    2015-01-01

    Human cytomegalovirus uses a variety of mechanisms to evade immune recognition through major histocompatibility complex class I molecules. One mechanism mediated by the immunoevasin protein US2 causes rapid disposal of newly synthesized class I molecules by the endoplasmic reticulum-associated degradation pathway. Although several components of this degradation pathway have been identified, there are still questions concerning how US2 targets class I molecules for degradation. In this study we identify cyclophilin C, a peptidyl prolyl isomerase of the endoplasmic reticulum, as a component of US2-mediated immune evasion. Cyclophilin C could be co-isolated with US2 and with the class I molecule HLA-A2. Furthermore, it was required at a particular expression level since depletion or overexpression of cyclophilin C impaired the degradation of class I molecules. To better characterize the involvement of cyclophilin C in class I degradation, we used LC-MS/MS to detect US2-interacting proteins that were influenced by cyclophilin C expression levels. We identified malectin, PDIA6, and TMEM33 as proteins that increased in association with US2 upon cyclophilin C knockdown. In subsequent validation all were shown to play a functional role in US2 degradation of class I molecules. This was specific to US2 rather than general ER-associated degradation since depletion of these proteins did not impede the degradation of a misfolded substrate, the null Hong Kong variant of α1-antitrypsin. PMID:26691022

  2. Structural and Functional Dissection of Human Cytomegalovirus US3 in Binding Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Lee, Sungwook; Yoon, Juhan; Park, Boyoun; Jun, Youngsoo; Jin, Mirim; Sung, Ha Chin; Kim, Ik-Hwan; Kang, Seongman; Choi, Eui-Ju; Ahn, Byung Yoon; Ahn, Kwangseog

    2000-01-01

    The human cytomegalovirus US3, an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, forms a complex with major histocompatibility complex (MHC) class I molecules and retains them in the ER, thereby preventing cytolysis by cytotoxic T lymphocytes. To identify which parts of US3 confine the protein to the ER and which parts are responsible for the association with MHC class I molecules, we constructed truncated mutant and chimeric forms in which US3 domains were exchanged with corresponding domains of CD4 and analyzed them for their intracellular localization and the ability to associate with MHC class I molecules. All of the truncated mutant and chimeric proteins containing the luminal domain of US3 were retained in the ER, while replacement of the US3 luminal domain with that of CD4 led to cell surface expression of the chimera. Thus, the luminal domain of US3 was sufficient for ER retention. Immunolocalization of the US3 glycoprotein after nocodazole treatment and the observation that the carbohydrate moiety of the US3 glycoprotein was not modified by Golgi enzymes indicated that the ER localization of US3 involved true retention, without recycling through the Golgi. Unlike the ER retention signal, the ability to associate with MHC class I molecules required the transmembrane domain in addition to the luminal domain of US3. Direct interaction between US3 and MHC class I molecules could be demonstrated after in vitro translation by coimmunoprecipitation. Together, the present data indicate that the properties that allow US3 to be localized in the ER and bind MHC class I molecules are located in different parts of the molecule. PMID:11070025

  3. Antigenic peptides containing large PEG loops designed to extend out of the HLA-A2 binding site form stable complexes with class I major histocompatibility complex molecules.

    PubMed Central

    Bouvier, M; Wiley, D C

    1996-01-01

    Recognition of peptides bound to class I major histocompatibility complex (MHC) molecules by specific receptors on T cells regulates the development and activity of the cellular immune system. We have designed and synthesized de novo cyclic peptides that incorporate PEG in the ring structure for binding to class I MHC molecules. The large PEG loops are positioned to extend out of the peptide binding site, thus creating steric effects aimed at preventing the recognition of class I MHC complexes by T-cell receptors. Peptides were synthesized and cyclized on polymer support using high molecular weight symmetrical PEG dicarboxylic acids to link the side chains of lysine residues substituted at positions 4 and 8 in the sequence of the HLA-A2-restricted human T-lymphotrophic virus type I Tax peptide. Cyclic peptides promoted the in vitro folding and assembly of HLA-A2 complexes. Thermal denaturation studies using circular dichroism spectroscopy showed that these complexes are as stable as complexes formed with antigenic peptides. Images Fig. 2 Fig. 4 PMID:8643447

  4. Placental Extravillous Cytotrophoblasts Persistently Express Class I Major Histocompatibility Complex Molecules after Human Cytomegalovirus Infection

    PubMed Central

    Terauchi, Masakazu; Koi, Hideki; Hayano, Chikako; Toyama-Sorimachi, Noriko; Karasuyama, Hajime; Yamanashi, Yuji; Aso, Takeshi; Shirakata, Masaki

    2003-01-01

    Human cytomegalovirus (HCMV) downregulates the class I major histocompatibility complexes (MHCs), HLA-A and -B, in infected fibroblasts to escape from antigen-specific cytotoxic T lymphocytes. The HCMV genes responsible for the downregulation of MHCs are US2, US3, US6, and US11, which encode type I membrane proteins working at the endoplasmic reticulum (ER). However, it is largely unknown whether HCMV downregulates the class I MHC molecules in placental extravillous cytotrophoblasts (EVT), which express HLA-C, -E, and -G to protect a semiallogenic fetus from maternal natural killer (NK) cells at the fetomaternal interface. Here, we report that differentiated EVT prepared from human first-trimester chorionic villi persistently express class I MHC molecules upon HCMV infection. When these US proteins were expressed in uninfected EVT, they were localized at the ER in the entire cytoplasm. However, subsequent HCMV infection resulted in dissociation of these US proteins from the ER, which relocated toward the cell membrane. In fibroblasts, these US proteins were localized at the ER before and after HCMV infection. These results suggest that the US gene products are not integrated into ER of HCMV-infected EVT and fail to downregulate class I MHC molecules. PMID:12857887

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

    PubMed Central

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

    2012-01-01

    Mate choice for major histocompatibility complex (MHC) compatibility has been found in several taxa, although rarely in birds. MHC is a crucial component in adaptive immunity and by choosing an MHC-dissimilar partner, heterozygosity and potentially broad pathogen resistance is maximized in the offspring. The MHC genotype influences odour cues and preferences in mammals and fish and hence olfactory-based mate choice can occur. We tested whether blue petrels, Halobaena caerulea, choose partners based on MHC compatibility. This bird is long-lived, monogamous and can discriminate between individual odours using olfaction, which makes it exceptionally well suited for this analysis. We screened MHC class I and II B alleles in blue petrels using 454-pyrosequencing and quantified the phylogenetic, functional and allele-sharing similarity between individuals. Partners were functionally more dissimilar at the MHC class II B loci than expected from random mating (p = 0.033), whereas there was no such difference at the MHC class I loci. Phylogenetic and non-sequence-based MHC allele-sharing measures detected no MHC dissimilarity between partners for either MHC class I or II B. Our study provides evidence of mate choice for MHC compatibility in a bird with a high dependency on odour cues, suggesting that MHC odour-mediated mate choice occurs in birds. PMID:22951737

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

    PubMed

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

    2012-11-07

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

  7. Immunomodulation of glioma cells after gene therapy: induction of major histocompatibility complex class I but not class II antigen in vitro.

    PubMed

    Parsa, A T; Chi, J H; Hurley, P T; Jeyapalan, S A; Bruce, J N

    2001-09-01

    Acquired immunity has been demonstrated in Fischer rats bearing syngeneic 9L tumors after herpes simplex virus (HSV) thymidine kinase (TK) gene transfection and ganciclovir treatment. The nature of this immunity in rats and its relevance to the HSV TK/ganciclovir protocol for human subjects remain to be determined. In this study, levels of major histocompatibility complex (MHC) Class I and II antigen expression were measured before and after HSV TK transfection, in an effort to document immunomodulatory changes caused by gene therapy. Tumor cells from the 9L gliosarcoma cell line, three primary human glioma cultures, and the human glioma cell line U87 MG were transduced with HSV TK vector-containing supernatant from fibroblast-producing cells (titer of 5 x 10(6) colony-forming units/ml) and selected in G418 medium for neomycin resistance. Clones were pooled or individually selected for cell-killing assays with ganciclovir, to confirm TK expression (10(3) cells/well in a 96-well dish). Northern analyses using MHC Class I and Class II complementary deoxyribonucleic acid probes were performed on blots containing total ribonucleic acid from wild-type tumor cells and HSV TK transfectants. A beta-actin complementary deoxyribonucleic acid probe served as an internal control. Cell surface expression was confirmed with flow cytometry. The induction of MHC Class I was tested for cycloheximide and genistein sensitivity. All cell cultures exhibited increases in MHC Class I but not MHC Class II expression, as determined by Northern analysis densitometry and flow cytometry. Cycloheximide treatment did not diminish the up-regulation of MHC Class I after retroviral transfection, implicating a signal transduction pathway that does not require ongoing protein synthesis. Genistein pretreatment of cell cultures did diminish the up-regulation of MHC Class I, implicating a tyrosine kinase in the signaling cascade. Induction of MHC Class I in rat and human glioma cells after HSV TK

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  10. Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control

    PubMed Central

    van Hateren, Andy; Bailey, Alistair; Elliott, Tim

    2017-01-01

    We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation. PMID:28299193

  11. Genes in one megabase of the HLA class I region

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wei, H.; Fan, Wu-Fang; Xu, Hongxia

    1993-11-15

    To define the gene content of the HLA class I region, cDNA selection was applied to three overlapping yeast artificial chromosomes (YACs) that spanned 1 megabase (Mb) of this region of the human major histocompatibility complex. These YACs extended from the region centromeric to HLA-E to the region telomeric to HLA-F. In additions to the recognized class I genes and pseudogenes and the anonymous non-class-I genes described recently by the authors and others, 20 additional anonymous cDNA clones were identified from this 1-Mb region. They also identified a long repetitive DNA element in the region between HLA-B and HLA-E. Homologuesmore » of this outside of the HLA complex. The portion of the HLA class I region represented by these YACs shows an average gene density as high as the class II and class III regions. Thus, the high gene density portion of the HLA complex is extended to more than 3 Mb.« less

  12. Contrasting evolutionary histories of MHC class I and class II loci in grouse—effects of selection and gene conversion

    PubMed Central

    Minias, P; Bateson, Z W; Whittingham, L A; Johnson, J A; Oyler-McCance, S; Dunn, P O

    2016-01-01

    Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens. PMID:26860199

  13. Deciphering complex patterns of class-I HLA-peptide cross-reactivity via hierarchical grouping.

    PubMed

    Mukherjee, Sumanta; Warwicker, Jim; Chandra, Nagasuma

    2015-07-01

    T-cell responses in humans are initiated by the binding of a peptide antigen to a human leukocyte antigen (HLA) molecule. The peptide-HLA complex then recruits an appropriate T cell, leading to cell-mediated immunity. More than 2000 HLA class-I alleles are known in humans, and they vary only in their peptide-binding grooves. The polymorphism they exhibit enables them to bind a wide range of peptide antigens from diverse sources. HLA molecules and peptides present a complex molecular recognition pattern, as many peptides bind to a given allele and a given peptide can be recognized by many alleles. A powerful grouping scheme that not only provides an insightful classification, but is also capable of dissecting the physicochemical basis of recognition specificity is necessary to address this complexity. We present a hierarchical classification of 2010 class-I alleles by using a systematic divisive clustering method. All-pair distances of alleles were obtained by comparing binding pockets in the structural models. By varying the similarity thresholds, a multilevel classification was obtained, with 7 supergroups, each further subclassifying to yield 72 groups. An independent clustering performed based only on similarities in their epitope pools correlated highly with pocket-based clustering. Physicochemical feature combinations that best explain the basis of clustering are identified. Mutual information calculated for the set of peptide ligands enables identification of binding site residues contributing to peptide specificity. The grouping of HLA molecules achieved here will be useful for rational vaccine design, understanding disease susceptibilities and predicting risk of organ transplants.

  14. Molecular modeling of class I and II alleles of the major histocompatibility complex in Salmo salar.

    PubMed

    Cárdenas, Constanza; Bidon-Chanal, Axel; Conejeros, Pablo; Arenas, Gloria; Marshall, Sergio; Luque, F Javier

    2010-12-01

    Knowledge of the 3D structure of the binding groove of major histocompatibility (MHC) molecules, which play a central role in the immune response, is crucial to shed light into the details of peptide recognition and polymorphism. This work reports molecular modeling studies aimed at providing 3D models for two class I and two class II MHC alleles from Salmo salar (Sasa), as the lack of experimental structures of fish MHC molecules represents a serious limitation to understand the specific preferences for peptide binding. The reliability of the structural models built up using bioinformatic tools was explored by means of molecular dynamics simulations of their complexes with representative peptides, and the energetics of the MHC-peptide interaction was determined by combining molecular mechanics interaction energies and implicit continuum solvation calculations. The structural models revealed the occurrence of notable differences in the nature of residues at specific positions in the binding groove not only between human and Sasa MHC proteins, but also between different Sasa alleles. Those differences lead to distinct trends in the structural features that mediate the binding of peptides to both class I and II MHC molecules, which are qualitatively reflected in the relative binding affinities. Overall, the structural models presented here are a valuable starting point to explore the interactions between MHC receptors and pathogen-specific interactions and to design vaccines against viral pathogens.

  15. Class-first analysis in a continuum: an approach to the complexities of schools, society, and insurgent science

    NASA Astrophysics Data System (ADS)

    Valdiviezo, Laura Alicia

    2010-06-01

    This essay addresses Katherine Richardson Bruna's paper: Mexican Immigrant Transnational Social Capital and Class Transformation: Examining the Role of Peer Mediation in Insurgent Science, through five main points . First, I offer a comparison between the traditional analysis of classism in Latin America and Richardson Bruna's call for a class-first analysis in the North American social sciences where there has been a tendency to obviate the specific examination of class relations and class issues. Secondly, I discuss that a class-first analysis solely cannot suffice to depict the complex dimensions in the relations of schools and society. Thus, I suggest a continuum in the class-first analysis. Third, I argue that social constructions surrounding issues of language, ethnicity, and gender necessarily intersect with issues of class and that, in fact, those other constructions offer compatible epistemologies that aid in representing the complexity of social and institutional practices in the capitalist society. Richardson Bruna's analysis of Augusto's interactions with his teacher and peers in the science class provides a fourth point of discussion in this essay. As a final point in my response I discuss Richardson Bruna's idea of making accessible class-first analysis knowledge to educators and especially to science teachers.

  16. Contrasting evolutionary histories of MHC class I and class II loci in grouse—Effects of selection and gene conversion

    USGS Publications Warehouse

    Minias, Piotr; Bateson, Zachary W.; Whittingham, Linda A.; Johnson, Jeff A.; Oyler-McCance, Sara J.; Dunn, Peter O.

    2016-01-01

    Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens.

  17. Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant.

    PubMed

    Serreze, D V; Leiter, E H; Christianson, G J; Greiner, D; Roopenian, D C

    1994-03-01

    Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Leelayuwat, C.; Degli-Esposti, M.A.; Abraham, L.J.

    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 DNAmore » 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.« less

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

    PubMed Central

    2012-01-01

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

  20. Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens

    PubMed Central

    Xing, Dongxia; Li, Sufang; Robinson, Simon N.; Yang, Hong; Steiner, David; Komanduri, Krishna V.; Shpall, Elizabeth J.

    2009-01-01

    In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these “Th-1 DCs” exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance generation of CD8+ T lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation of more effective vaccination strategies. PMID:19171878

  1. Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules.

    PubMed

    Glasner, Ariella; Oiknine-Djian, Esther; Weisblum, Yiska; Diab, Mohammad; Panet, Amos; Wolf, Dana G; Mandelboim, Ofer

    2017-11-15

    NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus

  2. Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Glasner, Ariella; Oiknine-Djian, Esther; Weisblum, Yiska; Diab, Mohammad; Panet, Amos; Wolf, Dana G.

    2017-01-01

    ABSTRACT NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika

  3. Functional role of the MrpA- and MrpD-homologous protein subunits in enzyme complexes evolutionary related to respiratory chain complex I.

    PubMed

    Moparthi, Vamsi K; Kumar, Brijesh; Al-Eryani, Yusra; Sperling, Eva; Górecki, Kamil; Drakenberg, Torbjörn; Hägerhäll, Cecilia

    2014-01-01

    NADH:quinone oxidoreductase or complex I is a large membrane bound enzyme complex that has evolved from the combination of smaller functional building blocks. Intermediate size enzyme complexes exist in nature that comprise some, but not all of the protein subunits in full size 14-subunit complex I. The membrane spanning complex I subunits NuoL, NuoM and NuoN are homologous to each other and to two proteins from one particular class of Na(+)/H(+) antiporters, denoted MrpA and MrpD. In complex I, these ion transporter protein subunits are prime candidates for harboring important parts of the proton pumping machinery. Using a model system, consisting of Bacillus subtilis MrpA and MrpD deletion strains and a low copy expression plasmid, it was recently demonstrated that NuoN can rescue the strain deleted for MrpD but not that deleted for MrpA, whereas the opposite tendency was seen for NuoL. This demonstrated that the MrpA-type and MrpD-type proteins have unique functional specializations. In this work, the corresponding antiporter-like protein subunits from the smaller enzymes evolutionarily related to complex I were tested in the same model system. The subunits from 11-subunit complex I from Bacillus cereus behaved essentially as those from full size complex I, corroborating that this enzyme should be regarded as a bona fide complex I. The hydrogenase-3 and hydrogenase-4 antiporter-like proteins on the other hand, could substitute equally well for MrpA or MrpD at pH7.4, suggesting that these enzymes have intermediate forms of the antiporter-like proteins, which seemingly lack the functional specificity. © 2013. Published by Elsevier B.V. All rights reserved.

  4. Characterization of major histocompatibility complex class I, and class II DRB loci of captive and wild Indian leopards (Panthera pardus fusca).

    PubMed

    Parmar, Drashti R; Mitra, Siuli; Bhadouriya, Snehalata; Rao, Tirupathi; Kunteepuram, Vaishnavi; Gaur, Ajay

    2017-12-01

    The major histocompatibility complex (MHC), in vertebrate animals, is a multi-genic protein complex that encodes various receptors. During a disease, MHC interacts with the antigen and triggers a cascade of adaptive immune responses to overcome a disease outbreak. The MHC is very important region from immunological point of view, but it is poorly characterized among Indian leopards. During this investigation, we examined genetic diversity for MHC class I (MHC-I) and MHC class II-DRB (MHC-II) among wild and captive Indian leopards. This study estimated a pool of 9 and 17 alleles for MHC-I and MHC-II, respectively. The wild group of individuals showed higher nucleotide diversity and amino acid polymorphism compared to the captive group. A phylogenetic comparison with other felids revealed a clustering in MHC-I and interspersed presence in MHC-II sequences. A test for selection also revealed a deviation from neutrality at MHC-II DRB loci and higher non-synonymous substitution rate (dN) among the individuals from wild group. Further, the wild individuals showed higher dN for both MHC I and II genes compared to the group that was bred under captive conditions. These findings suggest the role of micro-evolutionary forces, such as pathogen-mediated selection, to cause MHC variations among the two groups of Indian leopards, because the two groups have been bred in two different environments for a substantial period of time. Since, MHC diversity is often linked with the quality of immunological health; the results obtained from this study fill the gap of knowledge on disease predisposition among wild and captive Indian leopards.

  5. Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding.

    PubMed

    Tenzer, S; Peters, B; Bulik, S; Schoor, O; Lemmel, C; Schatz, M M; Kloetzel, P-M; Rammensee, H-G; Schild, H; Holzhütter, H-G

    2005-05-01

    Epitopes presented by major histocompatibility complex (MHC) class I molecules are selected by a multi-step process. Here we present the first computational prediction of this process based on in vitro experiments characterizing proteasomal cleavage, transport by the transporter associated with antigen processing (TAP) and MHC class I binding. Our novel prediction method for proteasomal cleavages outperforms existing methods when tested on in vitro cleavage data. The analysis of our predictions for a new dataset consisting of 390 endogenously processed MHC class I ligands from cells with known proteasome composition shows that the immunological advantage of switching from constitutive to immunoproteasomes is mainly to suppress the creation of peptides in the cytosol that TAP cannot transport. Furthermore, we show that proteasomes are unlikely to generate MHC class I ligands with a C-terminal lysine residue, suggesting processing of these ligands by a different protease that may be tripeptidyl-peptidase II (TPPII).

  6. Expression and clinical value of the soluble major histocompatibility complex class I-related chain A molecule in the serum of patients with renal tumors.

    PubMed

    Zhao, Y-K; Jia, C-M; Yuan, G-J; Liu, W; Qiu, Y; Zhu, Q-G

    2015-06-29

    We investigated the expression and clinical value of the soluble major histocompatibility complex class I-related chain A (sMICA) molecule in the serum of patients with renal tumors. Sixty patients diagnosed with renal tumors were enrolled in the experimental group, whereas 20 healthy volunteers served as the control group. The sMICA levels were measured via enzyme-linked immunosorbent assay, and the results were analyzed in combination with data from pathol-ogy examination. The experimental group had a statistically significant higher sMICA level (P < 0.05) than the control group. The sMICA level was higher in patients with malignant tumors than in those with be-nign tumors. We also observed a positive relationship among different tumor-node-metastasis (TNM) pathological stages with more advanced diseases exhibiting higher sMICA levels. As a tumor-associated antigen, MICA has a close relationship with renal tumorigenesis and immune es-cape. Our results indicated that sMICA levels were related to tumor pathol-ogy, TNM stage, and metastasis. Therefore, sMICA might be a potential marker for tumor characteristics, prognosis, and recurrence prediction.

  7. Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

    PubMed Central

    Bilousova, Tina; Dang, Hoa; Xu, Willem; Gustafson, Sarah; Jin, Yingli; Wickramasinghe, Lalinda; Won, Tony; Bobarnac, Gabriela; Middleton, Blake; Tian, Jide; Kaufman, Daniel L.

    2012-01-01

    We studied cultured hippocampal neurons from embryonic wildtype, major histocompatibility complex class I (MHCI) heavy chain-deficient (KbDb−/−) and NSE-Db (which have elevated neuronal MHCI expression) C57BL/6 mice. KbDb−/− neurons displayed slower neuritogenesis and establishment of polarity, while NSE-Db neurons had faster neurite outgrowth, more primary neurites, and tended to have accelerated polarization. Additional studies with ϐ2M−/− neurons, exogenous ϐ2M, and a self-MHCI monomer suggest that free heavy chain cis interactions with other surface molecules can promote neuritogenesis while tripartite MHCI interactions with classical MHCI receptors can inhibit axon outgrowth. Together with the results of others, MHCI appears to differentially modulate neuritogenesis and synaptogenesis. PMID:22503373

  8. Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

    PubMed Central

    Ben-Arieh, Sayeh Vahdati; Zimerman, Baruch; Smorodinsky, Nechama I.; Yaacubovicz, Margalit; Schechter, Chana; Bacik, Igor; Gibbs, Jim; Bennink, Jack R.; Yewdell, Jon W.; Coligan, John E.; Firat, Hüseyin; Lemonnier, François; Ehrlich, Rachel

    2001-01-01

    HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/β2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses. PMID:11581431

  9. Co-evolution with chicken class I genes.

    PubMed

    Kaufman, Jim

    2015-09-01

    The concept of co-evolution (or co-adaptation) has a long history, but application at molecular levels (e.g., 'supergenes' in genetics) is more recent, with a consensus definition still developing. One interesting example is the chicken major histocompatibility complex (MHC). In contrast to typical mammals that have many class I and class I-like genes, only two classical class I genes, two CD1 genes and some non-classical Rfp-Y genes are known in chicken, and all are found on the microchromosome that bears the MHC. Rarity of recombination between the closely linked and polymorphic genes encoding classical class I and TAPs allows co-evolution, leading to a single dominantly expressed class I molecule in each MHC haplotype, with strong functional consequences in terms of resistance to infectious pathogens. Chicken tapasin is highly polymorphic, but co-evolution with TAP and class I genes remains unclear. T-cell receptors, natural killer (NK) cell receptors, and CD8 co-receptor genes are found on non-MHC chromosomes, with some evidence for co-evolution of surface residues and number of genes along the avian and mammalian lineages. Over even longer periods, co-evolution has been invoked to explain how the adaptive immune system of jawed vertebrates arose from closely linked receptor, ligand, and antigen-processing genes in the primordial MHC. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. The leader peptide of mutacin 1140 has distinct structural components compared to related class I lantibiotics

    PubMed Central

    Escano, Jerome; Stauffer, Byron; Brennan, Jacob; Bullock, Monica; Smith, Leif

    2014-01-01

    Lantibiotics are ribosomally synthesized peptide antibiotics composed of an N-terminal leader peptide that promotes the core peptide's interaction with the post translational modification (PTM) enzymes. Following PTMs, mutacin 1140 is transported out of the cell and the leader peptide is cleaved to yield the antibacterial peptide. Mutacin 1140 leader peptide is structurally unique compared to other class I lantibiotic leader peptides. Herein, we further our understanding of the structural differences of mutacin 1140 leader peptide with regard to other class I leader peptides. We have determined that the length of the leader peptide is important for the biosynthesis of mutacin 1140. We have also determined that mutacin 1140 leader peptide contains a novel four amino acid motif compared to related lantibiotics. PTM enzyme recognition of the leader peptide appears to be evolutionarily distinct from related class I lantibiotics. Our study on mutacin 1140 leader peptide provides a basis for future studies aimed at understanding its interaction with the PTM enzymes. PMID:25400246

  11. Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors

    PubMed Central

    Mevers, Emily; Higgins, Kathleen W.; Fomina, Yevgenia; Zhang, Jianming; Mandinova, Anna; Newman, David; Shaw, Stanley Y.; Clardy, Jon; Mootha, Vamsi K.

    2016-01-01

    Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as “complex I bypass.” In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of ~40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-α-lapachone and dehydroiso-α-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology. PMID:27622560

  12. Analysis of MHC class I folding: novel insights into intermediate forms

    PubMed Central

    Simone, Laura C.; Tuli, Amit; Simone, Peter D.; Wang, Xiaojian; Solheim, Joyce C.

    2012-01-01

    Folding around a peptide ligand is integral to the antigen presentation function of major histocompatibility complex (MHC) class I molecules. Several lines of evidence indicate that the broadly cross-reactive 34-1-2 antibody is sensitive to folding of the MHC class I peptide-binding groove. Here, we show that peptide-loading complex proteins associated with the murine MHC class I molecule Kd are found primarily in association with the 34-1-2+ form. This led us to hypothesize that the 34-1-2 antibody may recognize intermediately, as well as fully, folded MHC class I molecules. In order to further characterize the form(s) of MHC class I molecules recognized by 34-1-2, we took advantage of its cross-reactivity with Ld. Recognition of the open and folded forms of Ld by the 64-3-7 and 30-5-7 antibodies, respectively, has been extensively characterized, providing us with parameters against which to compare 34-1-2 reactivity. We found that the 34-1-2+ Ld molecules displayed characteristics indicative of incomplete folding, including increased tapasin association, endoplasmic reticulum retention, and instability at the cell surface. Moreover, we demonstrate that an Ld-specific peptide induced folding of the 34-1-2+ Ld intermediate. Altogether, these results yield novel insights into the nature of MHC class I molecules recognized by the 34-1-2 antibody. PMID:22329842

  13. Analysis of MHC class I genes across horse MHC haplotypes

    PubMed Central

    Tallmadge, Rebecca L.; Campbell, Julie A.; Miller, Donald C.; Antczak, Douglas F.

    2010-01-01

    The genomic sequences of 15 horse Major Histocompatibility Complex (MHC) class I genes and a collection of MHC class I homozygous horses of five different haplotypes were used to investigate the genomic structure and polymorphism of the equine MHC. A combination of conserved and locus-specific primers was used to amplify horse MHC class I genes with classical and non-classical characteristics. Multiple clones from each haplotype identified three to five classical sequences per homozygous animal, and two to three non-classical sequences. Phylogenetic analysis was applied to these sequences and groups were identified which appear to be allelic series, but some sequences were left ungrouped. Sequences determined from MHC class I heterozygous horses and previously described MHC class I sequences were then added, representing a total of ten horse MHC haplotypes. These results were consistent with those obtained from the MHC homozygous horses alone, and 30 classical sequences were assigned to four previously confirmed loci and three new provisional loci. The non-classical genes had few alleles and the classical genes had higher levels of allelic polymorphism. Alleles for two classical loci with the expected pattern of polymorphism were found in the majority of haplotypes tested, but alleles at two other commonly detected loci had more variation outside of the hypervariable region than within. Our data indicate that the equine Major Histocompatibility Complex is characterized by variation in the complement of class I genes expressed in different haplotypes in addition to the expected allelic polymorphism within loci. PMID:20099063

  14. Herpes B Virus, Macacine Herpesvirus 1, Breaks Simplex Virus Tradition via Major Histocompatibility Complex Class I Expression in Cells from Human and Macaque Hosts

    PubMed Central

    Vasireddi, Mugdha

    2012-01-01

    B virus of the family Herpesviridae is endemic to rhesus macaques but results in 80% fatality in untreated humans who are zoonotically infected. Downregulation of major histocompatibility complex (MHC) class I in order to evade CD8+ T-cell activation is characteristic of most herpesviruses. Here we examined the cell surface presence and total protein expression of MHC class I molecules in B virus-infected human foreskin fibroblast cells and macaque kidney epithelial cells in culture, which are representative of foreign and natural host initial target cells of B virus. Our results show <20% downregulation of surface MHC class I molecules in either type of host cells infected with B virus, which is statistically insignificantly different from that observed in uninfected cells. We also examined the surface expression of MHC class Ib molecules, HLA-E and HLA-G, involved in NK cell inhibition. Our results showed significant upregulation of HLA-E and HLA-G in host cells infected with B virus relative to the amounts observed in other herpesvirus-infected cells. These results suggest that B virus-infected cell surfaces maintain normal levels of MHC class Ia molecules, a finding unique among simplex viruses. This is a unique divergence in immune evasion for B virus, which, unlike human simplex viruses, does not inhibit the transport of peptides for loading onto MHC class Ia molecules because B virus ICP47 lacks a transporter-associated protein binding domain. The fact that MHC class Ib molecules were significantly upregulated has additional implications for host-pathogen interactions. PMID:22973043

  15. ERp57 interacts with conserved cysteine residues in the MHC class I peptide-binding groove.

    PubMed

    Antoniou, Antony N; Santos, Susana G; Campbell, Elaine C; Lynch, Sarah; Arosa, Fernando A; Powis, Simon J

    2007-05-15

    The oxidoreductase ERp57 is a component of the major histocompatibility complex (MHC) class I peptide-loading complex. ERp57 can interact directly with MHC class I molecules, however, little is known about which of the cysteine residues within the MHC class I molecule are relevant to this interaction. MHC class I molecules possess conserved disulfide bonds between cysteines 101-164, and 203-259 in the peptide-binding and alpha3 domain, respectively. By studying a series of mutants of these conserved residues, we demonstrate that ERp57 predominantly associates with cysteine residues in the peptide-binding domain, thus indicating ERp57 has direct access to the peptide-binding groove of MHC class I molecules during assembly.

  16. Major histocompatibility complex class I chain related gene-A microsatellite polymorphism shows secondary association with type 1 diabetes and celiac disease in North Indians.

    PubMed

    Kumar, N; Sharma, G; Kaur, G; Tandon, N; Bhatnagar, S; Mehra, N

    2012-10-01

    Microsatellite polymorphism in exon 5 of major histocompatibility complex class I chain related gene-A (MIC-A) has been implicated in the etiology of autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD). In this study on North Indian population, the MIC-A5.1 allele, carrying a premature termination codon in transmembrane region, was observed with increased frequency in T1D (29.6%, odds ratio OR = 2.1, P = 0.00017) and CD patients (40.3%, OR = 3.37, P = 1.67E-05) than in controls (16.7%). When the MIC-A5.1 association was adjusted for linkage with human leukocyte antigen (HLA)-DR3, the statistical significance of the association was abolished. This implies that the observed association of MIC-A5.1 is due to its linkage disequilibrium (D' = 0.94) with HLA-B8-DR3-DQ2 haplotype and is secondary to the overall association with DR3 positive MHC haplotypes. © 2012 John Wiley & Sons A/S.

  17. The leader peptide of mutacin 1140 has distinct structural components compared to related class I lantibiotics.

    PubMed

    Escano, Jerome; Stauffer, Byron; Brennan, Jacob; Bullock, Monica; Smith, Leif

    2014-12-01

    Lantibiotics are ribosomally synthesized peptide antibiotics composed of an N-terminal leader peptide that promotes the core peptide's interaction with the post translational modification (PTM) enzymes. Following PTMs, mutacin 1140 is transported out of the cell and the leader peptide is cleaved to yield the antibacterial peptide. Mutacin 1140 leader peptide is structurally unique compared to other class I lantibiotic leader peptides. Herein, we further our understanding of the structural differences of mutacin 1140 leader peptide with regard to other class I leader peptides. We have determined that the length of the leader peptide is important for the biosynthesis of mutacin 1140. We have also determined that mutacin 1140 leader peptide contains a novel four amino acid motif compared to related lantibiotics. PTM enzyme recognition of the leader peptide appears to be evolutionarily distinct from related class I lantibiotics. Our study on mutacin 1140 leader peptide provides a basis for future studies aimed at understanding its interaction with the PTM enzymes. © 2014 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  18. Crystallization and X-ray diffraction analysis of a putative bacterial class I labdane-related diterpene synthase.

    PubMed

    Serrano-Posada, Hugo; Centeno-Leija, Sara; Rojas-Trejo, Sonia; Stojanoff, Vivian; Rodríguez-Sanoja, Romina; Rudiño-Piñera, Enrique; Sánchez, Sergio

    2015-09-01

    Labdane-related diterpenoids are natural products with potential pharmaceutical applications that are rarely found in bacteria. Here, a putative class I labdane-related diterpene synthase (LrdC) identified by genome mining in a streptomycete was successfully crystallized using the microbatch method. Crystals of the LrdC enzyme were obtained in a holo form with its natural cofactor Mg(2+) (LrdC-Mg(2+)) and in complex with inorganic pyrophosphate (PPi) (LrdC-Mg(2+)-PPi). Crystals of native LrdC-Mg(2+) diffracted to 2.50 Å resolution and belonged to the trigonal space group P3221, with unit-cell parameters a = b = 107.1, c = 89.2 Å. Crystals of the LrdC-Mg(2+)-PPi complex grown in the same conditions as the native enzyme with PEG 8000 diffracted to 2.36 Å resolution and also belonged to the trigonal space group P3221. Crystals of the LrdC-Mg(2+)-PPi complex grown in a second crystallization condition with PEG 3350 diffracted to 2.57 Å resolution and belonged to the monoclinic space group P21, with unit-cell parameters a = 49.9, b = 104.1, c = 66.5 Å, β = 111.4°. The structure was determined by the single-wavelength anomalous dispersion (SAD) technique using the osmium signal from a potassium hexachloroosmate (IV) derivative.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gogate, N.; Yamabe, Toshio; Verma, L.

    1996-04-01

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

  20. Characterisation of major histocompatibility complex class I transcripts in an Australian dragon lizard.

    PubMed

    Hacking, Jessica; Bertozzi, Terry; Moussalli, Adnan; Bradford, Tessa; Gardner, Michael

    2018-07-01

    Characterisation of squamate major histocompatibility complex (MHC) genes has lagged behind other taxonomic groups. MHC genes encode cell-surface glycoproteins that present self- and pathogen-derived peptides to T cells and play a critical role in pathogen recognition. Here we characterise MHC class I transcripts for an agamid lizard (Ctenophorus decresii) and investigate the evolution of MHC class I in Iguanian lizards. An iterative assembly strategy was used to identify six full-length C. decresii MHC class I transcripts, which were validated as likely to encode classical class I MHC molecules. Evidence for exon shuffling recombination was uncovered for C. decresii transcripts and Bayesian phylogenetic analysis of Iguanian MHC class I sequences revealed a pattern expected under a birth-and-death mode of evolution. This work provides a stepping stone towards further research on the agamid MHC class I region. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. The carboxypeptidase angiotensin converting enzyme (ACE) shapes the MHC class I peptide repertoire

    PubMed Central

    Shen, Xiao Z.; Billet, Sandrine; Lin, Chentao; Okwan-Duodu, Derick; Chen, Xu; Lukacher, Aron E.; Bernstein, Kenneth E.

    2011-01-01

    The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell mediated adaptive immune responses. Aminopeptidases are implicated in the editing of peptides for MHC class I loading, but C-terminal editing is thought due to proteasome cleavage. By comparing genetically deficient, wild-type and over-expressing mice, we now identify the dipeptidase angiotensin-converting enzyme (ACE) as playing a physiologic role in peptide processing for MHC class I. ACE edits the C-termini of proteasome-produced class I peptides. The lack of ACE exposes novel antigens but also abrogates some self-antigens. ACE has major effects on surface MHC class I expression in a haplotype-dependent manner. We propose a revised model of MHC class I peptide processing by introducing carboxypeptidase activity. PMID:21964607

  2. Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection

    PubMed Central

    Gameiro, Steven F.; Zhang, Ali; Ghasemi, Farhad; Barrett, John W.; Mymryk, Joe S.

    2017-01-01

    Oncoproteins from high-risk human papillomaviruses (HPV) downregulate the transcription of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus in tissue culture model systems. This could allow infected or transformed cells to evade the adaptive immune response. Using data from over 800 human cervical and head & neck tumors from The Cancer Genome Atlas (TCGA), we determined the impact of HPV status on the mRNA expression of all six MHC-I heavy chain genes, and the β2 microglobulin light chain. Unexpectedly, these genes were all expressed at high levels in HPV positive (HPV+) cancers compared with normal control tissues. Indeed, many of these genes were expressed at significantly enhanced levels in HPV+ tumors. Similarly, the transcript levels of several other components of the MHC-I peptide-loading complex were also high in HPV+ cancers. The coordinated expression of high mRNA levels of the MHC-I antigen presentation apparatus could be a consequence of the higher intratumoral levels of interferon γ in HPV+ carcinomas, which correlate with signatures of increased infiltration by T- and NK-cells. These data, which were obtained from both cervical and oral tumors in large human cohorts, indicates that HPV oncoproteins do not efficiently suppress the transcription of the antigen presentation apparatus in human tumors. PMID:28891951

  3. Amyloid Precursor-like Protein 2 Association with HLA Class I Molecules

    PubMed Central

    Tuli, Amit; Sharma, Mahak; Wang, Xiaojian; Simone, Laura C.; Capek, Haley L.; Cate, Steven; Hildebrand, William H.; Naslavsky, Naava; Caplan, Steve; Solheim, Joyce C.

    2009-01-01

    Amyloid precursor-like protein 2 (APLP2) is a ubiquitously expressed protein. The previously demonstrated functions for APLP2 include binding to the mouse major histocompatibility complex (MHC) class I molecule H-2Kd and down regulating its cell surface expression. In this study, we have investigated the interaction of APLP2 with the human leukocyte antigen (HLA) class I molecule in human tumor cell lines. APLP2 was readily detected in pancreatic, breast, and prostate tumor lines, although it was found only in very low amounts in lymphoma cell lines. In a pancreatic tumor cell line, HLA class I was extensively co-localized with APLP2 in vesicular compartments following endocytosis of HLA class I molecules. In pancreatic, breast, and prostate tumor lines, APLP2 was bound to the HLA class I molecule. APLP2 was found to bind to HLA-A24, and more strongly to HLA-A2. Increased expression of APLP2 resulted in reduced surface expression of HLA-A2 and HLA-A24. Overall, these studies demonstrate that APLP2 binds to the HLA class I molecule, co-localizes with it in intracellular vesicles, and reduces the level of HLA class I molecule cell surface expression. PMID:19184004

  4. Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair

    PubMed Central

    Wu, Zhongqi-Phyllis; Washburn, Lorraine; Bilousova, Tina V.; Boudzinskaia, Maia; Escande-Beillard, Nathalie; Querubin, Jyes; Dang, Hoa; Xie, Cui-Wei; Tian, Jide; Kaufman, Daniel L.

    2012-01-01

    Mice deficient in classical major histocompatibility complex class I (MHCI) have aberrations in neurodevelopment. The consequences of up-regulated neuronal MHCI expression have not been examined. We found that transgenic C57Bl/6 mice that are engineered to express higher levels of self-Db on their CNS neurons have alterations in their hippocampal morphology and retinogeniculate projections, as well as impaired neurorepair responses. Thus, enhanced neuronal classical MHCI expression can lead to aberrations in neural circuitry and neurorepair. These findings complement a growing body of knowledge concerning the neurobiological activities of MHCI and may have potential clinical relevance. PMID:20950866

  5. Engineering chimeric human and mouse major histocompatibility complex (MHC) class I tetramers for the production of T-cell receptor (TCR) mimic antibodies

    PubMed Central

    Bentley, Carol; Yates, Jenna; Salimi, Maryam; Greig, Jenny; Wiblin, Sarah; Hassanali, Tasneem; Banham, Alison H.

    2017-01-01

    Therapeutic monoclonal antibodies targeting cell surface or secreted antigens are among the most effective classes of novel immunotherapies. However, the majority of human proteins and established cancer biomarkers are intracellular. Peptides derived from these intracellular proteins are presented on the cell surface by major histocompatibility complex class I (MHC-I) and can be targeted by a novel class of T-cell receptor mimic (TCRm) antibodies that recognise similar epitopes to T-cell receptors. Humoural immune responses to MHC-I tetramers rarely generate TCRm antibodies and many antibodies recognise the α3 domain of MHC-I and β2 microglobulin (β2m) that are not directly involved in presenting the target peptide. Here we describe the production of functional chimeric human-murine HLA-A2-H2Dd tetramers and modifications that increase their bacterial expression and refolding efficiency. These chimeric tetramers were successfully used to generate TCRm antibodies against two epitopes derived from wild type tumour suppressor p53 (RMPEAAPPV and GLAPPQHLIRV) that have been used in vaccination studies. Immunisation with chimeric tetramers yielded no antibodies recognising the human α3 domain and β2m and generated TCRm antibodies capable of specifically recognising the target peptide/MHC-I complex in fully human tetramers and on the cell surface of peptide pulsed T2 cells. Chimeric tetramers represent novel immunogens for TCRm antibody production and may also improve the yield of tetramers for groups using these reagents to monitor CD8 T-cell immune responses in HLA-A2 transgenic mouse models of immunotherapy. PMID:28448627

  6. Characterization of binding specificities of Bovine Leucocyte class I molecules: Impacts for rational epitope discovery

    USDA-ARS?s Scientific Manuscript database

    The binding of peptides to classical major histocompatibility complex (MHC) class-I proteins is the single most selective step in antigen presentation. However, the peptide binding specificity of cattle MHC (bovine leucocyte antigen, BoLA) class I (BoLA-I) molecules remains poorly characterized. Her...

  7. A Novel Way to Relate Ontology Classes

    PubMed Central

    Choksi, Ami T.; Jinwala, Devesh C.

    2015-01-01

    The existing ontologies in the semantic web typically have anonymous union and intersection classes. The anonymous classes are limited in scope and may not be part of the whole inference process. The tools, namely, the pellet, the jena, and the protégé, interpret collection classes as (a) equivalent/subclasses of union class and (b) superclasses of intersection class. As a result, there is a possibility that the tools will produce error prone inference results for relations, namely, sub-, union, intersection, equivalent relations, and those dependent on these relations, namely, complement. To verify whether a class is complement of other involves utilization of sub- and equivalent relations. Motivated by the same, we (i) refine the test data set of the conference ontology by adding named, union, and intersection classes and (ii) propose a match algorithm to (a) calculate corrected subclasses list, (b) correctly relate intersection and union classes with their collection classes, and (c) match union, intersection, sub-, complement, and equivalent classes in a proper sequence, to avoid error prone match results. We compare the results of our algorithms with those of a candidate reasoner, namely, the pellet reasoner. To the best of our knowledge, ours is a unique attempt in establishing a novel way to relate ontology classes. PMID:25984560

  8. Complex MHC class I gene transcription profiles and their functional impact in orangutans

    PubMed Central

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

    2015-01-01

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

  9. Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

    NASA Technical Reports Server (NTRS)

    Armstrong, J. W.; Simske, S. J.; Beharka, A. A.; Balch, S.; Luttges, M. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

  10. Class I Underground Injection Control Program: Study of the Risks Associated with Class I Underground Injection Wells

    EPA Pesticide Factsheets

    The document provides describes the current Class I UIC program, the history of Class I injection, and studies of human health risks associated with Class I injection wells, which were conducted for past regulatory efforts and policy documentation.

  11. Active site nanospace of aminoacyl tRNA synthetase: difference between the class I and class II synthetases.

    PubMed

    Dutta, Saheb; Choudhury, Kaberi; Banik, Sindrila Dutta; Nandi, Nilashis

    2014-03-01

    The present work is aimed at understanding the origin of the difference in the molecular organization of the active site nanospaces of the class I and class II aminoacyl tRNA synthetases (aaRSs) which are tunnel-like structures. The active site encloses the cognate amino acid (AA) and the adenosine triphosphate (ATP) to carry out aminoacylation reaction. Comparison of the structures of the active site of the class I and class II (aaRSs) shows that the nanodimensional tunnels are curved in opposite directions in the two classes. We investigated the origin of this difference using quantum mechanical computation of electrostatic potential (ESP) of substrates, surrounding residues and ions, using Atoms in Molecule (AIM) Theory and charge population analysis. We show that the difference is principally due to the variation in the spatial charge distribution of ATP in the two classes which correspond to extended and bent conformations of ATP. The present computation shows that the most feasible pathway for nucleophilic attack to alphaP is oppositely directed for class I and class II aaRSs. The available crystal structures show that the cognate AA is indeed located along the channel favorable for nucleophilic attack as predicted by the ESP analysis. It is also shown that the direction of the channel changes its orientation when the orientation of ATP is changed from extended to a bent like structure. We further used the AIM theory to confirm the direction of the approach of AA in each case and the results corroborate the results from the ESP analysis. The opposite curvatures of the active site nanospaces in class I and class II aaRSs are related with the influence of the charge distributions of the extended and bent conformations of ATP, respectively. The results of the computation of electrostatic potential by successive addition of active site residues show that their roles on the reaction are similar in both classes despite the difference in the organization of the

  12. Discovery of novel MHC-class I alleles and haplotypes in Filipino cynomolgus macaques (Macaca fascicularis) by pyrosequencing and Sanger sequencing: Mafa-class I polymorphism.

    PubMed

    Shiina, Takashi; Yamada, Yukiho; Aarnink, Alice; Suzuki, Shingo; Masuya, Anri; Ito, Sayaka; Ido, Daisuke; Yamanaka, Hisashi; Iwatani, Chizuru; Tsuchiya, Hideaki; Ishigaki, Hirohito; Itoh, Yasushi; Ogasawara, Kazumasa; Kulski, Jerzy K; Blancher, Antoine

    2015-10-01

    Although the low polymorphism of the major histocompatibility complex (MHC) transplantation genes in the Filipino cynomolgus macaque (Macaca fascicularis) is expected to have important implications in the selection and breeding of animals for medical research, detailed polymorphism information is still lacking for many of the duplicated class I genes. To better elucidate the degree and types of MHC polymorphisms and haplotypes in the Filipino macaque population, we genotyped 127 unrelated animals by the Sanger sequencing method and high-resolution pyrosequencing and identified 112 different alleles, 28 at cynomolgus macaque MHC (Mafa)-A, 54 at Mafa-B, 12 at Mafa-I, 11 at Mafa-E, and seven at Mafa-F alleles, of which 56 were newly described. Of them, the newly discovered Mafa-A8*01:01 lineage allele had low nucleotide similarities (<86%) with primate MHC class I genes, and it was also conserved in the Vietnamese and Indonesian populations. In addition, haplotype estimations revealed 17 Mafa-A, 23 Mafa-B, and 12 Mafa-E haplotypes integrated with 84 Mafa-class I haplotypes and Mafa-F alleles. Of these, the two Mafa-class I haplotypes, F/A/E/B-Hp1 and F/A/E/B-Hp2, had the highest haplotype frequencies at 10.6 and 10.2%, respectively. This suggests that large scale genetic screening of the Filipino macaque population would identify these and other high-frequency Mafa-class I haplotypes that could be used as MHC control animals for the benefit of biomedical research.

  13. Altered Expression of TAP-1 and Major Histocompatibility Complex Class I in Laryngeal Papillomatosis: Correlation of TAP-1 with Disease

    PubMed Central

    Vambutas, Andrea; Bonagura, Vincent R.; Steinberg, Bettie M.

    2000-01-01

    Recurrent respiratory papillomatosis (RRP) is an insidious disease caused by human papillomavirus (HPV) infection. It is characterized by a variable clinical course that can include frequent disease recurrence, significant morbidity, and occasional mortality. The mechanisms responsible for the variability in the clinical course and the persistence of latent HPV infection remain unknown. Effective T-cell-mediated clearance of HPV-infected cells may be defective in patients with RRP, leading to recurrent disease and failure to suppress latent HPV reactivation. This study describes the down-regulation of the transporter associated with antigen presentation (TAP-1) and the major histocompatibility complex (MHC) class I protein expression in laryngeal papilloma tissue biopsies and cell culture of primary explants. There was a statistically significant correlation between reduction of TAP-1 expression in biopsy tissues and rapid recurrence of disease. Patients with RRP had less frequent recurrence if their papillomas expressed TAP-1 at levels close to that of normal tissue, compared with those with very low expression of TAP-1, who had frequent recurrence (32 versus 5 weeks to the next surgical intervention). These findings suggest that HPV may evade immune recognition by down-regulating class I MHC cell surface expression via decreased TAP-1 levels. Expression of TAP-1 could be used for prognostic evaluation of disease severity. Gamma interferon was able to restore class I MHC expression at the surfaces of laryngeal papilloma cells in culture. This up-regulation of class I MHC antigen at the cell surface potentially allows the infected cell to become a target for the immune system again. This finding provides some promise for nonsurgical treatment of laryngeal papillomas. PMID:10618282

  14. Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach.

    PubMed

    Nielsen, Morten; Lundegaard, Claus; Worning, Peder; Hvid, Christina Sylvester; Lamberth, Kasper; Buus, Søren; Brunak, Søren; Lund, Ole

    2004-06-12

    Prediction of which peptides will bind a specific major histocompatibility complex (MHC) constitutes an important step in identifying potential T-cell epitopes suitable as vaccine candidates. MHC class II binding peptides have a broad length distribution complicating such predictions. Thus, identifying the correct alignment is a crucial part of identifying the core of an MHC class II binding motif. In this context, we wish to describe a novel Gibbs motif sampler method ideally suited for recognizing such weak sequence motifs. The method is based on the Gibbs sampling method, and it incorporates novel features optimized for the task of recognizing the binding motif of MHC classes I and II. The method locates the binding motif in a set of sequences and characterizes the motif in terms of a weight-matrix. Subsequently, the weight-matrix can be applied to identifying effectively potential MHC binding peptides and to guiding the process of rational vaccine design. We apply the motif sampler method to the complex problem of MHC class II binding. The input to the method is amino acid peptide sequences extracted from the public databases of SYFPEITHI and MHCPEP and known to bind to the MHC class II complex HLA-DR4(B1*0401). Prior identification of information-rich (anchor) positions in the binding motif is shown to improve the predictive performance of the Gibbs sampler. Similarly, a consensus solution obtained from an ensemble average over suboptimal solutions is shown to outperform the use of a single optimal solution. In a large-scale benchmark calculation, the performance is quantified using relative operating characteristics curve (ROC) plots and we make a detailed comparison of the performance with that of both the TEPITOPE method and a weight-matrix derived using the conventional alignment algorithm of ClustalW. The calculation demonstrates that the predictive performance of the Gibbs sampler is higher than that of ClustalW and in most cases also higher than that of

  15. The oxidoreductase ERp57 efficiently reduces partially folded in preference to fully folded MHC class I molecules

    PubMed Central

    Antoniou, Antony N.; Ford, Stuart; Alphey, Magnus; Osborne, Andrew; Elliott, Tim; Powis, Simon J.

    2002-01-01

    The oxidoreductase ERp57 is an integral component of the peptide loading complex of major histocompatibility complex (MHC) class I molecules, formed during their chaperone-assisted assembly in the endoplasmic reticulum. Misfolded MHC class I molecules or those denied suitable peptides are retrotranslocated and degraded in the cytosol. The presence of ERp57 during class I assembly suggests it may be involved in the reduction of intrachain disulfides prior to retrotranslocation. We have studied the ability of ERp57 to reduce MHC class I molecules in vitro. Recombinant ERp57 specifically reduced partially folded MHC class I molecules, whereas it had little or no effect on folded and peptide-loaded MHC class I molecules. Reductase activity was associated with cysteines at positions 56 and 405 of ERp57, the N-terminal residues of the active CXXC motifs. Our data suggest that the reductase activity of ERp57 may be involved during the unfolding of MHC class I molecules, leading to targeting for degradation. PMID:12032078

  16. Prevalence of class-I, class-II and class-III obesity in Australian adults between 1995 and 2011-12.

    PubMed

    Keating, Catherine; Backholer, Kathryn; Gearon, Emma; Stevenson, Christopher; Swinburn, Boyd; Moodie, Marj; Carter, Rob; Peeters, Anna

    2015-01-01

    To compare the prevalence of class-I, II and III obesity in Australian adults between 1995, 2007-08 and 2011-12. Prevalence data for adults (aged 18+ years) were sourced from customised data from the nationally representative National Nutrition Survey (1995), the National Health Survey (2007-08), and the Australian Health Survey (2011-12) conducted by the Australian Bureau of Statistics. Obesity classifications were based on measured height and weight (class-I body mass index: 30.0-34.9 kg/m(2), class-II: 35.0-39.9 kg/m(2) and class-III: ≥ 40.0 kg/m(2)). Severe obesity was defined as class-II or class-III obesity. Between 1995 and 2011-12, the prevalence of obesity (all classes combined) increased from 19.1% to 27.2%. During this 17 year period, relative increases in class I, II and III obesity were 1.3, 1.7 and 2.2-fold respectively. In 2011-12, the prevalence of class I, II and III obesity was 19.4, 5.9 and 2.0 per cent respectively in men, and 16.1, 6.9 and 4.2 per cent respectively in women. One in every ten people was severely obese, increasing from one in twenty in 1995, and women were disproportionally represented in this population. Obesity prevalence increased with increasing levels of area-level socioeconomic disadvantage, particularly for the more severely obese classes. Severe obesity affected 6.2% and 13.4% in the least and most disadvantaged quintiles respectively. Over the last two decades, there have been substantial increases in the prevalence of obesity, particularly the more severe levels of obesity. This study highlights high risk groups who warrant targeted weight gain prevention interventions. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  17. Focusing Leaky Waves: A Class of Electromagnetic Localized Waves with Complex Spectra

    NASA Astrophysics Data System (ADS)

    Fuscaldo, Walter; Comite, Davide; Boesso, Alessandro; Baccarelli, Paolo; Burghignoli, Paolo; Galli, Alessandro

    2018-05-01

    Localized waves, i.e., the wide class of limited-diffraction, limited-dispersion solutions to the wave equation are generally characterized by real wave numbers. We consider the role played by localized waves with generally complex "leaky" wave numbers. First, the impact of the imaginary part of the wave number (i.e., the leakage constant) on the diffractive (spatial broadening) features of monochromatic localized solutions (i.e., beams) is rigorously evaluated. Then general conditions are derived to show that only a restricted class of spectra (either real or complex) allows for generating a causal localized wave. It turns out that backward leaky waves fall into this category. On this ground, several criteria for the systematic design of wideband radiators, namely, periodic radial waveguides based on backward leaky waves, are established in the framework of leaky-wave theory. An effective design method is proposed to minimize the frequency dispersion of the proposed class of devices and the impact of the "leakage" on the dispersive (temporal broadening) features of polychromatic localized solutions (i.e., pulses) is accounted for. Numerical results corroborate the concept, clearly highlighting the advantages and limitations of the leaky-wave approach for the generation of localized pulses at millimeter-wave frequencies, where energy focusing is in high demand in modern applications.

  18. The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model.

    PubMed

    Giblin, P A; Leahy, D J; Mennone, J; Kavathas, P B

    1994-03-01

    The CD8 dimer interacts with the alpha 3 domain of major histocompatibility complex class I molecules through two immunoglobulin variable-like domains. In this study a crystal structure-informed mutational analysis has been performed to identify amino acids in the CD8 alpha/alpha homodimer that are likely to be involved in binding to class I. Several key residues are situated on the top face of the dimer within loops analogous to the complementarity-determining regions (CDRs) of immunoglobulin. In addition, other important amino acids are located in the A and B beta-strands on the sides of the dimer. The potential involvement of amino acids on both the top and the side faces of the molecule is consistent with a bivalent model for the interaction between a single CD8 alpha/alpha homodimer and two class I molecules and may have important implications for signal transduction in class I-expressing cells. This study also demonstrates a role for the positive surface potential of CD8 in class I binding and complements previous work demonstrating the importance of a negatively charged loop on the alpha 3 domain of class I for CD8 alpha/alpha-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the alpha 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B beta-strands contact the alpha 2 domain of class I.

  19. Identification of MHC class I sequences in Chinese-origin rhesus macaques

    PubMed Central

    Karl, Julie A.; Wiseman, Roger W.; Campbell, Kevin J.; Blasky, Alex J.; Hughes, Austin L.; Ferguson, Betsy; Read, Daniel S.

    2010-01-01

    The rhesus macaque (Macaca mulatta) is an excellent model for human disease and vaccine research. Two populations exhibiting distinctive morphological and physiological characteristics, Indian- and Chinese-origin rhesus macaques, are commonly used in research. Genetic analysis has focused on the Indian macaque population, but the accessibility of these animals for research is limited. Due to their greater availability, Chinese rhesus macaques are now being used more frequently, particularly in vaccine and biodefense studies, although relatively little is known about their immunogenetics. In this study, we discovered major histocompatibility complex (MHC) class I cDNAs in 12 Chinese rhesus macaques and detected 41 distinct Mamu-A and Mamu-B sequences. Twenty-seven of these class I cDNAs were novel, while six and eight of these sequences were previously reported in Chinese and Indian rhesus macaques, respectively. We then performed microsatellite analysis on DNA from these 12 animals, as well as an additional 18 animals, and developed sequence specific primer PCR (PCR-SSP) assays for eight cDNAs found in multiple animals. We also examined our cohort for potential admixture of Chinese and Indian origin animals using a recently developed panel of single nucleotide polymorphisms (SNPs). The discovery of 27 novel MHC class I sequences in this analysis underscores the genetic diversity of Chinese rhesus macaques and contributes reagents that will be valuable for studying cellular immunology in this population. PMID:18097659

  20. Liquid class predictor for liquid handling of complex mixtures

    DOEpatents

    Seglke, Brent W [San Ramon, CA; Lekin, Timothy P [Livermore, CA

    2008-12-09

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

  1. Haemophilus ducreyi Cutaneous Ulcer Strains Diverged from Both Class I and Class II Genital Ulcer Strains: Implications for Epidemiological Studies

    PubMed Central

    Gangaiah, Dharanesh

    2016-01-01

    Background Haemophilus ducreyi has emerged as a major cause of cutaneous ulcers (CU) in yaws-endemic regions of the tropics in the South Pacific, South East Asia and Africa. H. ducreyi was once thought only to cause the genital ulcer (GU) disease chancroid; GU strains belong to 2 distinct classes, class I and class II. Using whole-genome sequencing of 4 CU strains from Samoa, 1 from Vanuatu and 1 from Papua New Guinea, we showed that CU strains diverged from the class I strain 35000HP and that one CU strain expressed β-lactamase. Recently, the Center for Disease Control and Prevention released the genomes of 11 additional CU strains from Vanuatu and Ghana; however, the evolutionary relationship of these CU strains to previously-characterized CU and GU strains is unknown. Methodology/Principal Findings We performed phylogenetic analysis of 17 CU and 10 GU strains. Class I and class II GU strains formed two distinct clades. The class I strains formed two subclades, one containing 35000HP and HD183 and the other containing the remainder of the class I strains. Twelve of the CU strains formed a subclone under the class I 35000HP subclade, while 2 CU strains formed a subclone under the other class I subclade. Unexpectedly, 3 of the CU strains formed a subclone under the class II clade. Phylogenetic analysis of dsrA-hgbA-ncaA sequences yielded a tree similar to that of whole-genome phylogenetic tree. Conclusions/Significance CU strains diverged from multiple lineages within both class I and class II GU strains. Multilocus sequence typing of dsrA-hgbA-ncaA could be reliably used for epidemiological investigation of CU and GU strains. As class II strains grow relatively poorly and are relatively more susceptible to vancomycin than class I strains, these findings have implications for methods to recover CU strains. Comparison of contemporary CU and GU isolates would help clarify the relationship between these entities. PMID:28027326

  2. Haemophilus ducreyi Cutaneous Ulcer Strains Diverged from Both Class I and Class II Genital Ulcer Strains: Implications for Epidemiological Studies.

    PubMed

    Gangaiah, Dharanesh; Spinola, Stanley M

    2016-12-01

    Haemophilus ducreyi has emerged as a major cause of cutaneous ulcers (CU) in yaws-endemic regions of the tropics in the South Pacific, South East Asia and Africa. H. ducreyi was once thought only to cause the genital ulcer (GU) disease chancroid; GU strains belong to 2 distinct classes, class I and class II. Using whole-genome sequencing of 4 CU strains from Samoa, 1 from Vanuatu and 1 from Papua New Guinea, we showed that CU strains diverged from the class I strain 35000HP and that one CU strain expressed β-lactamase. Recently, the Center for Disease Control and Prevention released the genomes of 11 additional CU strains from Vanuatu and Ghana; however, the evolutionary relationship of these CU strains to previously-characterized CU and GU strains is unknown. We performed phylogenetic analysis of 17 CU and 10 GU strains. Class I and class II GU strains formed two distinct clades. The class I strains formed two subclades, one containing 35000HP and HD183 and the other containing the remainder of the class I strains. Twelve of the CU strains formed a subclone under the class I 35000HP subclade, while 2 CU strains formed a subclone under the other class I subclade. Unexpectedly, 3 of the CU strains formed a subclone under the class II clade. Phylogenetic analysis of dsrA-hgbA-ncaA sequences yielded a tree similar to that of whole-genome phylogenetic tree. CU strains diverged from multiple lineages within both class I and class II GU strains. Multilocus sequence typing of dsrA-hgbA-ncaA could be reliably used for epidemiological investigation of CU and GU strains. As class II strains grow relatively poorly and are relatively more susceptible to vancomycin than class I strains, these findings have implications for methods to recover CU strains. Comparison of contemporary CU and GU isolates would help clarify the relationship between these entities.

  3. The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II

    PubMed Central

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

    2015-01-01

    ABSTRACT The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8+ cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8+ cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8+ cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4+ cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8+ and CD4+ T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8+ T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8+ T cells specific for

  4. Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

    PubMed Central

    Hawse, William F.; Gloor, Brian E.; Ayres, Cory M.; Kho, Kevin; Nuter, Elizabeth; Baker, Brian M.

    2013-01-01

    T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of substates in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the “altered self” mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity. PMID:23836912

  5. An Optimizing Compiler for Petascale I/O on Leadership Class Architectures

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Choudhary, Alok; Kandemir, Mahmut

    In high-performance computing systems, parallel I/O architectures usually have very complex hierarchies with multiple layers that collectively constitute an I/O stack, including high-level I/O libraries such as PnetCDF and HDF5, I/O middleware such as MPI-IO, and parallel file systems such as PVFS and Lustre. Our project explored automated instrumentation and compiler support for I/O intensive applications. Our project made significant progress towards understanding the complex I/O hierarchies of high-performance storage systems (including storage caches, HDDs, and SSDs), and designing and implementing state-of-the-art compiler/runtime system technology that targets I/O intensive HPC applications that target leadership class machine. This final report summarizesmore » the major achievements of the project and also points out promising future directions.« less

  6. 25 CFR 502.2 - Class I gaming.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 2 2011-04-01 2011-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

  7. 25 CFR 502.2 - Class I gaming.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

  8. 25 CFR 502.2 - Class I gaming.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 2 2012-04-01 2012-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

  9. 25 CFR 502.2 - Class I gaming.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 2 2013-04-01 2013-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

  10. 25 CFR 502.2 - Class I gaming.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 2 2014-04-01 2014-04-01 false Class I gaming. 502.2 Section 502.2 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS OF THIS CHAPTER § 502.2 Class I gaming. Class I gaming means: (a) Social games played solely for prizes of minimal value...

  11. Presence of strong association of the major histocompatibility complex (MHC) class I allele HLA-A*26:01 with idiopathic hypoparathyroidism.

    PubMed

    Goswami, Ravinder; Singh, Archana; Gupta, Nandita; Rani, Rajni

    2012-09-01

    The pathogenesis of isolated hypoparathyroidism, also referred to as idiopathic hypoparathyroidism (IH), is not clear. There is a paucity of information related to the immunogenetic basis of the disease due to its rarity. A recurrent theme of several autoimmune disorders is aberrant antigen presentation. We investigated for the association of alleles of the human leukocyte antigen (HLA) class I and II loci with IH. A total of 134 patients with IH and 902 healthy controls from the same ethnic background participated in the study. There was a significant increase of HLA class I alleles HLA-A*26:01 [P < 1.71 × 10(-34); odds ratio (OR) = 9.29; 95% confidence interval (CI) = 6.08-14.16] and HLA-B*08:01 (P < 8.19 × 10(-6); OR = 2.59; 95% CI = 1.63-4.04) in patients with IH compared to healthy controls. However, the association of A*26:01 was primary because B*08:01 was in linkage disequilibrium with A*26:01. Although the major histocompatibility complex (MHC) is very polymorphic, several alleles of HLA loci share key residues at anchor positions in the peptide binding pockets such that similar peptides may be presented by different MHC molecules encoded by the same locus. These allelic forms with similar anchoring amino acids have been clustered in supertypes. An analysis of HLA-A locus supertypes A01, A02, A03, and A04 revealed that supertype A01 was significantly increased (P < 9.18 × 10(-9); OR = 2.95) in IH compared to controls. However, this increase in the supertype A01 was contributed by A*26:01 because 68.7% of the A01 samples had A*26:01. Other alleles of the supertype did not show any significant differences. The strong association of HLA-A*26:01 suggests an important role of MHC class I-mediated presentation of autoantigenic peptides to CD8(+) cytotoxic T cells in the pathogenesis of IH. These data provide evidence for the autoimmune etiology of IH akin to other autoimmune disorders like type 1 diabetes and rheumatoid arthritis.

  12. Evolution by selection, recombination, and gene duplication in MHC class I genes of two Rhacophoridae species

    PubMed Central

    2013-01-01

    Background Comparison of major histocompatibility complex (MHC) genes across vertebrate species can reveal molecular mechanisms underlying the evolution of adaptive immunity-related proteins. As the first terrestrial tetrapods, amphibians deserve special attention because of their exposure to probably increased spectrum of microorganisms compared with ancestral aquatic fishes. Knowledge regarding the evolutionary patterns and mechanisms associated with amphibian MHC genes remains limited. The goal of the present study was to isolate MHC class I genes from two Rhacophoridae species (Rhacophorus omeimontis and Polypedates megacephalus) and examine their evolution. Results We identified 27 MHC class I alleles spanning the region from exon 2 to 4 in 38 tree frogs. The available evidence suggests that these 27 sequences all belong to classical MHC class I (MHC Ia) genes. Although several anuran species only display one MHC class Ia locus, at least two or three loci were observed in P. megacephalus and R. omeimontis, indicating that the number of MHC class Ia loci varies among anuran species. Recombination events, which mainly involve the entire exons, played an important role in shaping the genetic diversity of the 27 MHC class Ia alleles. In addition, signals of positive selection were found in Rhacophoridae MHC class Ia genes. Amino acid sites strongly suggested by program to be under positive selection basically accorded with the putative antigen binding sites deduced from crystal structure of human HLA. Phylogenetic relationships among MHC class I alleles revealed the presence of trans-species polymorphisms. Conclusions In the two Rhacophoridae species (1) there are two or three MHC class Ia loci; (2) recombination mainly occurs between the entire exons of MHC class Ia genes; (3) balancing selection, gene duplication and recombination all contribute to the diversity of MHC class Ia genes. These findings broaden our knowledge on the evolution of amphibian MHC systems

  13. A viral, transporter associated with antigen processing (TAP)-independent, high affinity ligand with alternative interactions endogenously presented by the nonclassical human leukocyte antigen E class I molecule.

    PubMed

    Lorente, Elena; Infantes, Susana; Abia, David; Barnea, Eilon; Beer, Ilan; García, Ruth; Lasala, Fátima; Jiménez, Mercedes; Mir, Carmen; Morreale, Antonio; Admon, Arie; López, Daniel

    2012-10-12

    The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8(+) lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide-binding site. These data expand the role of HLA-E as an antigen-presenting molecule.

  14. The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II.

    PubMed

    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

  15. Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

    PubMed Central

    Groll, Michael; Larionov, Oleg V.; Huber, Robert; de Meijere, Armin

    2006-01-01

    Most class I MHC ligands are generated from the vast majority of cellular proteins by proteolysis within the ubiquitin–proteasome pathway and are presented on the cell surface by MHC class I molecules. Here, we present the crystallographic analysis of yeast 20S proteasome in complex with the inhibitor homobelactosin C. The structure reveals a unique inhibitor-binding mode and provides information about the composition of proteasomal primed substrate-binding sites. IFN-γ inducible substitution of proteasomal constitutive subunits by immunosubunits modulates characteristics of generated peptides, thus producing fragments with higher preference for binding to MHC class I molecules. The structural data for the proteasome:homobelactosin C complex provide an explanation for involvement of immunosubunits in antigen generation and open perspectives for rational design of ligands, inhibiting exclusively constitutive proteasomes or immunoproteasomes. PMID:16537370

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

    PubMed

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

    2014-08-01

    Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. The Role of HLA Class I Gene Variation in Autoimmune Diabetes

    PubMed Central

    Sia, Charles; Weinem, Michael

    2005-01-01

    The use of DNA-based genetic typing has enabled the identification of type 1 diabetes mellitus (T1DM) susceptible and protective major histocompatibility complex (MHC) class II alleles and haplotypes. The application of this approach has also progressed to locate MHC class I alleles that contribute to the clinicopathology of T1DM. Recent studies have shown a widespread involvement of genes from the MHC class I gene region in the clinicopathology of T1DM. These genes are shown to be involved in contributing to progression from the preclinical stage of the disease, which is characterized by the occurrence of islet-specific antibodies, to clinical disease and also to the occurrence of autoimmunity. They can either contribute directly to disease development or indirectly in concert with other susceptible MHC class II alleles or haplotypes via linkage disequilibrium. Class I alleles may also be negatively associated with T1DM. These findings are useful for the development of future strategies in designing tolerogenic approaches for the prevention or even reversal of T1DM. In this article, the latest evidence for the different kinds of participation of HLA class I genes in the etiology of T1DM is reviewed. A meta-analysis which included existing association studies was also carried out in order to re-assess the relevance of class I genes in diabetes development. The analysis of an enlarged heterogeneous sample confirmed the involvement of previously detected serotypes in the etiology of T1DM, such as A24, B8 and B18, and revealed hitherto unknown associations with B60 and B62. The analysis points out that much of the conflicting results of previous association studies originate from inadequate sample sizes and accentuate the value of future investigations of larger samples for identifying linkage in multigenic diseases. PMID:17491685

  18. NetCTLpan: pan-specific MHC class I pathway epitope predictions

    PubMed Central

    Larsen, Mette Voldby; Lundegaard, Claus; Nielsen, Morten

    2010-01-01

    Reliable predictions of immunogenic peptides are essential in rational vaccine design and can minimize the experimental effort needed to identify epitopes. In this work, we describe a pan-specific major histocompatibility complex (MHC) class I epitope predictor, NetCTLpan. The method integrates predictions of proteasomal cleavage, transporter associated with antigen processing (TAP) transport efficiency, and MHC class I binding affinity into a MHC class I pathway likelihood score and is an improved and extended version of NetCTL. The NetCTLpan method performs predictions for all MHC class I molecules with known protein sequence and allows predictions for 8-, 9-, 10-, and 11-mer peptides. In order to meet the need for a low false positive rate, the method is optimized to achieve high specificity. The method was trained and validated on large datasets of experimentally identified MHC class I ligands and cytotoxic T lymphocyte (CTL) epitopes. It has been reported that MHC molecules are differentially dependent on TAP transport and proteasomal cleavage. Here, we did not find any consistent signs of such MHC dependencies, and the NetCTLpan method is implemented with fixed weights for proteasomal cleavage and TAP transport for all MHC molecules. The predictive performance of the NetCTLpan method was shown to outperform other state-of-the-art CTL epitope prediction methods. Our results further confirm the importance of using full-type human leukocyte antigen restriction information when identifying MHC class I epitopes. Using the NetCTLpan method, the experimental effort to identify 90% of new epitopes can be reduced by 15% and 40%, respectively, when compared to the NetMHCpan and NetCTL methods. The method and benchmark datasets are available at http://www.cbs.dtu.dk/services/NetCTLpan/. Electronic supplementary material The online version of this article (doi:10.1007/s00251-010-0441-4) contains supplementary material, which is available to authorized users. PMID

  19. On synchronisation of a class of complex chaotic systems with complex unknown parameters via integral sliding mode control

    NASA Astrophysics Data System (ADS)

    Tirandaz, Hamed; Karami-Mollaee, Ali

    2018-06-01

    Chaotic systems demonstrate complex behaviour in their state variables and their parameters, which generate some challenges and consequences. This paper presents a new synchronisation scheme based on integral sliding mode control (ISMC) method on a class of complex chaotic systems with complex unknown parameters. Synchronisation between corresponding states of a class of complex chaotic systems and also convergence of the errors of the system parameters to zero point are studied. The designed feedback control vector and complex unknown parameter vector are analytically achieved based on the Lyapunov stability theory. Moreover, the effectiveness of the proposed methodology is verified by synchronisation of the Chen complex system and the Lorenz complex systems as the leader and the follower chaotic systems, respectively. In conclusion, some numerical simulations related to the synchronisation methodology is given to illustrate the effectiveness of the theoretical discussions.

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

    USDA-ARS?s Scientific Manuscript database

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

  1. A HLA class I cis-regulatory element whose activity can be modulated by hormones.

    PubMed

    Sim, B C; Hui, K M

    1994-12-01

    To elucidate the basis of the down-regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA-binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis-regulatory element (NRE) has been identified using band-shift assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expression of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti-sense orientation. More interestingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MCF-7 cells but has no influence on the estrogen-mediated transcriptional activation of MCF-7 cells in the context of the reported estrogen-responsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans-activators are novel and suggest a versatile form of transcriptional control.

  2. Equus caballus Major Histocompatibility Complex Class I Is an Entry Receptor for Equine Herpesvirus Type 1▿

    PubMed Central

    Kurtz, Brian M.; Singletary, Lauren B.; Kelly, Sean D.; Frampton, Arthur R.

    2010-01-01

    In this study, Equus caballus major histocompatibility complex class I (MHC-I) was identified as a cellular entry receptor for the alphaherpesvirus equine herpesvirus type 1 (EHV-1). This novel EHV-1 receptor was discovered using a cDNA library from equine macrophages. cDNAs from this EHV-1-susceptible cell type were inserted into EHV-1-resistant B78H1 murine melanoma cells, these cells were infected with an EHV-1 lacZ reporter virus, and cells that supported virus infection were identified by X-Gal (5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside) staining. Positive cells were subjected to several rounds of purification to obtain homogeneous cell populations that were shown to be uniformly infected with EHV-1. cDNAs from these cell populations were amplified by PCR and then sequenced. The sequence data revealed that the EHV-1-susceptible cells had acquired an E. caballus MHC-I cDNA. Cell surface expression of this receptor was verified by confocal immunofluorescence microscopy. The MHC-I cDNA was cloned into a mammalian expression vector, and stable B78H1 cell lines were generated that express this receptor. These cell lines were susceptible to EHV-1 infection while the parental B78H1 cells remained resistant to infection. In addition, EHV-1 infection of the B78H1 MHC-I-expressing cell lines was inhibited in a dose-dependent manner by an anti-MHC-I antibody. PMID:20610718

  3. Hydrophobicity as a driver of MHC class I antigen processing

    PubMed Central

    Huang, Lan; Kuhls, Matthew C; Eisenlohr, Laurence C

    2011-01-01

    The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif. Dislocation of the TM domain during the natural process of endoplasmic reticulum-associated degradation (ERAD) similarly accelerated peptide production, but in the context of markedly prolonged processing that included nonnascent species. These insights into intracellular proteolytic pathways and their selective contributions to MHC class I-restricted peptide supply, may point to new approaches in rational vaccine design. PMID:21378750

  4. Hydrophobicity as a driver of MHC class I antigen processing.

    PubMed

    Huang, Lan; Kuhls, Matthew C; Eisenlohr, Laurence C

    2011-04-20

    The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif. Dislocation of the TM domain during the natural process of endoplasmic reticulum-associated degradation (ERAD) similarly accelerated peptide production, but in the context of markedly prolonged processing that included nonnascent species. These insights into intracellular proteolytic pathways and their selective contributions to MHC class I-restricted peptide supply, may point to new approaches in rational vaccine design.

  5. Structure and content of the major histocompatibility complex (MHC) class I regions of the great anthropoid apes.

    PubMed

    Venditti, C P; Lawlor, D A; Sharma, P; Chorney, M J

    1996-09-01

    The origins of the functional class I genes predated human speciation, a phenomenon known as trans-speciation. The retention of class Ia orthologues within the great apes, however, has not been paralleled by studies designed to examine the pseudogene content, organization, and structure of their class I regions. Therefore, we have begun the systematic characterization of the Old World primate MHCs. The numbers and sizes of fragments harboring class I sequences were similar among the chimpanzee, gorilla, and human genomes tested. Both of the gorillas included in our study possessed genomic fragments carrying orthologues of the recently evolved HLA-H pseudogene identical to those found in the human. The overall megabase restriction fragment patterns of humans and chimpanzees appeared slightly more similar to each other, although the HLA-A subregional megabase variants may have been generated following the emergence of Homo sapiens. Based on the results of this initial study, it is difficult to generate a firm species tree and to determine human's closest evolutionary neighbor. Nevertheless, an analysis of MHC subregional similarities and differences in the hominoid apes may ultimately aid in localizing and identifying MHC haplotype-associated disease genes such as idiopathic hemochromatosis.

  6. Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism

    PubMed Central

    Norman, Paul J.; Parham, Peter

    2012-01-01

    Pinnipeds, marine carnivores, diverged from terrestrial carnivores ~45 million years ago, before their adaptation to marine environments. This lifestyle change exposed pinnipeds to different microbiota and pathogens, with probable impact on their MHC class I genes. Investigating this question, genomic sequences were determined for 71 MHC class I variants: 27 from harbor seal and 44 from gray seal. These variants form three MHC class I gene lineages, one comprising a pseudogene. The second, a candidate nonclassical MHC class I gene, comprises a nonpolymorphic transcribed gene related to dog DLA-79 and giant panda Aime-1906. The third is the diversity lineage, which includes 62 of the 71 seal MHC class I variants. All are transcribed, and they minimally represent six harbor and 12 gray seal MHC class I genes. Besides species-specific differences in gene number, seal MHC class I haplotypes exhibit gene content variation and allelic polymorphism. Patterns of sequence variation, and of positions for positively selected sites, indicate the diversity lineage genes are the seals’ classical MHC class I genes. Evidence that expansion of diversity lineage genes began before gray and harbor seals diverged is the presence in both species of two distinctive sublineages of diversity lineage genes. Pointing to further expansion following the divergence are the presence of species-specific genes and greater MHC class I diversity in gray seals than harbor seals. The elaboration of a complex variable family of classical MHC class I genes in pinnipeds contrasts with the single, highly polymorphic classical MHC class I gene of dog and giant panda, terrestrial carnivores. PMID:23001684

  7. An Optimizing Compiler for Petascale I/O on Leadership-Class Architectures

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kandemir, Mahmut Taylan; Choudary, Alok; Thakur, Rajeev

    In high-performance computing (HPC), parallel I/O architectures usually have very complex hierarchies with multiple layers that collectively constitute an I/O stack, including high-level I/O libraries such as PnetCDF and HDF5, I/O middleware such as MPI-IO, and parallel file systems such as PVFS and Lustre. Our DOE project explored automated instrumentation and compiler support for I/O intensive applications. Our project made significant progress towards understanding the complex I/O hierarchies of high-performance storage systems (including storage caches, HDDs, and SSDs), and designing and implementing state-of-the-art compiler/runtime system technology that targets I/O intensive HPC applications that target leadership class machine. This final reportmore » summarizes the major achievements of the project and also points out promising future directions Two new sections in this report compared to the previous report are IOGenie and SSD/NVM-specific optimizations.« less

  8. Soluble Major Histocompatibility Complex Class I-Related Chain B Molecules Are Increased and Correlate With Clinical Outcomes During Rhinovirus Infection in Healthy Subjects

    PubMed Central

    Telcian, Aurica G.; Caramori, Gaetano; Laza-Stanca, Vasile; Message, Simon D.; Kebadze, Tatiana; Kon, Onn M.; Groh, Veronika; Papi, Alberto; Johnston, Sebastian L.; Mallia, Patrick; Stanciu, Luminita A.

    2014-01-01

    BACKGROUND: Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma. METHODS: Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection. RESULTS: RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma. CONCLUSIONS: RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections. PMID:24556715

  9. Comparison of second molar eruption patterns in patients with skeletal Class II and skeletal Class I malocclusions.

    PubMed

    Brin, Ilana; Camasuvi, Semin; Dali, Nasser; Aizenbud, Dror

    2006-12-01

    The eruptive positions of the second molars in Class I and Class II malocclusions were studied. Pretreatment records of 221 patients with a mean age of 11.3 years were evaluated. About 19% of them had skeletal Class I, 31% had skeletal maxillary Class II, and 50% had skeletal mandibular Class II malocclusions. The mean values of the dental and chronologic ages of the subjects were similar. The eruptive positions in relation to a reference line, the developmental stages of the patients' second molars and dental ages were recorded from the panoramic roentgenograms. The distribution of the various developmental stages in each malocclusion group was similar, and no association between skeletal malocclusion and dental developmental stage of the second molars was encountered. The eruptive position of the maxillary second molars was more occlusal only in the oldest maxillary Class II group, above 12 years of age (P = .02). These results support, in part, previous reports suggesting that the maxillary second molars may erupt earlier in patients with skeletal maxillary Class II malocclusions.

  10. Structural Definition of Duck Major Histocompatibility Complex Class I Molecules That Might Explain Efficient Cytotoxic T Lymphocyte Immunity to Influenza A Virus

    PubMed Central

    Wu, Yanan; Wang, Junya; Fan, Shuhua; Chen, Rong; Liu, Yanjie; Zhang, Jianhua; Yuan, Hongyu; Liang, Ruiying

    2017-01-01

    ABSTRACT A single dominantly expressed allele of major histocompatibility complex class I (MHC I) may be responsible for the duck's high tolerance to highly pathogenic influenza A virus (HP-IAV) compared to the chicken's lower tolerance. In this study, the crystal structures of duck MHC I (Anpl-UAA*01) and duck β2-microglobulin (β2m) with two peptides from the H5N1 strains were determined. Two remarkable features were found to distinguish the Anpl-UAA*01 complex from other known MHC I structures. A disulfide bond formed by Cys95 and Cys112 and connecting the β5 and β6 sheets at the bottom of peptide binding groove (PBG) in Anpl-UAA*01 complex, which can enhance IAV peptide binding, was identified. Moreover, the interface area between duck MHC I and β2m was found to be larger than in other species. In addition, the two IAV peptides that display distinctive conformations in the PBG, B, and F pockets act as the primary anchor sites. Thirty-one IAV peptides were used to verify the peptide binding motif of Anpl-UAA*01, and the results confirmed that the peptide binding motif is similar to that of HLA-A*0201. Based on this motif, approximately 600 peptides from the IAV strains were partially verified as the candidate epitope peptides for Anpl-UAA*01, which is a far greater number than those for chicken BF2*2101 and BF2*0401 molecules. Extensive IAV peptide binding should allow for ducks with this Anpl-UAA*01 haplotype to resist IAV infection. IMPORTANCE Ducks are natural reservoirs of influenza A virus (IAV) and are more resistant to the IAV than chickens. Both ducks and chickens express only one dominant MHC I locus providing resistance to the virus. To investigate how MHC I provides IAV resistance, crystal structures of the dominantly expressed duck MHC class I (pAnpl-UAA*01) with two IAV peptides were determined. A disulfide bond was identified in the peptide binding groove that can facilitate Anpl-UAA*01 binding to IAV peptides. Anpl-UAA*01 has a much wider

  11. Structural Definition of Duck Major Histocompatibility Complex Class I Molecules That Might Explain Efficient Cytotoxic T Lymphocyte Immunity to Influenza A Virus.

    PubMed

    Wu, Yanan; Wang, Junya; Fan, Shuhua; Chen, Rong; Liu, Yanjie; Zhang, Jianhua; Yuan, Hongyu; Liang, Ruiying; Zhang, Nianzhi; Xia, Chun

    2017-07-15

    A single dominantly expressed allele of major histocompatibility complex class I (MHC I) may be responsible for the duck's high tolerance to highly pathogenic influenza A virus (HP-IAV) compared to the chicken's lower tolerance. In this study, the crystal structures of duck MHC I ( Anpl -UAA*01) and duck β2-microglobulin (β2m) with two peptides from the H5N1 strains were determined. Two remarkable features were found to distinguish the Anpl -UAA*01 complex from other known MHC I structures. A disulfide bond formed by Cys 95 and Cys 112 and connecting the β5 and β6 sheets at the bottom of peptide binding groove (PBG) in Anpl -UAA*01 complex, which can enhance IAV peptide binding, was identified. Moreover, the interface area between duck MHC I and β2m was found to be larger than in other species. In addition, the two IAV peptides that display distinctive conformations in the PBG, B, and F pockets act as the primary anchor sites. Thirty-one IAV peptides were used to verify the peptide binding motif of Anpl -UAA*01, and the results confirmed that the peptide binding motif is similar to that of HLA-A*0201. Based on this motif, approximately 600 peptides from the IAV strains were partially verified as the candidate epitope peptides for Anpl -UAA*01, which is a far greater number than those for chicken BF2*2101 and BF2*0401 molecules. Extensive IAV peptide binding should allow for ducks with this Anpl -UAA*01 haplotype to resist IAV infection. IMPORTANCE Ducks are natural reservoirs of influenza A virus (IAV) and are more resistant to the IAV than chickens. Both ducks and chickens express only one dominant MHC I locus providing resistance to the virus. To investigate how MHC I provides IAV resistance, crystal structures of the dominantly expressed duck MHC class I (p Anpl -UAA*01) with two IAV peptides were determined. A disulfide bond was identified in the peptide binding groove that can facilitate Anpl -UAA*01 binding to IAV peptides. Anpl -UAA*01 has a much wider

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

    PubMed

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

    2016-08-01

    Trophoblast cells from bovine somatic cell nuclear transfer (SCNT) conceptuses express major histocompatibility complex class I (MHC-I) proteins early in gestation, and this may be one cause of the significant first-trimester embryonic mortality observed in these pregnancies. MHC-I homozygous-compatible (n = 9), homozygous-incompatible (n = 8), and heterozygous-incompatible (n = 5) SCNT pregnancies were established. The control group consisted of eight pregnancies produced by artificial insemination. Uterine and placental samples were collected on Day 35 ± 1 of pregnancy, and expression of MHC-I, leukocyte markers, and cytokines were examined by immunohistochemistry. Trophoblast cells from all SCNT pregnancies expressed MHC-I, while trophoblast cells from age-matched control pregnancies were negative for MHC-I expression. Expression of MHC-I antigens by trophoblast cells from SCNT pregnancies was associated with lymphocytic infiltration in the endometrium. Furthermore, MHC-I-incompatible conceptuses, particularly the heterozygous-incompatible ones, induced a more pronounced lymphocytic infiltration than MHC-I-compatible conceptuses. Cells expressing cluster of differentiation (CD) 3, gamma/deltaTCR, and MHC-II were increased in the endometrium of SCNT pregnancies compared to the control group. CD4(+) lymphocytes were increased in MHC-I-incompatible pregnancies compared to MHC-I-compatible and control pregnancies. CD8(+), FOXP3(+), and natural killer cells were increased in MHC-I heterozygous-incompatible SCNT pregnancies compared to homozygous SCNT and control pregnancies. © 2016 by the Society for the Study of Reproduction, Inc.

  13. Evolution of MHC class I genes in the endangered loggerhead sea turtle (Caretta caretta) revealed by 454 amplicon sequencing.

    PubMed

    Stiebens, Victor A; Merino, Sonia E; Chain, Frédéric J J; Eizaguirre, Christophe

    2013-04-30

    In evolutionary and conservation biology, parasitism is often highlighted as a major selective pressure. To fight against parasites and pathogens, genetic diversity of the immune genes of the major histocompatibility complex (MHC) are particularly important. However, the extensive degree of polymorphism observed in these genes makes it difficult to conduct thorough population screenings. We utilized a genotyping protocol that uses 454 amplicon sequencing to characterize the MHC class I in the endangered loggerhead sea turtle (Caretta caretta) and to investigate their evolution at multiple relevant levels of organization. MHC class I genes revealed signatures of trans-species polymorphism across several reptile species. In the studied loggerhead turtle individuals, it results in the maintenance of two ancient allelic lineages. We also found that individuals carrying an intermediate number of MHC class I alleles are larger than those with either a low or high number of alleles. Multiple modes of evolution seem to maintain MHC diversity in the loggerhead turtles, with relatively high polymorphism for an endangered species.

  14. 7 CFR 1001.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1001.51 Section 1001.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  15. 7 CFR 1033.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1033.51 Section 1033.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  16. 7 CFR 1131.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1131.51 Section 1131.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  17. 7 CFR 1131.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1131.51 Section 1131.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  18. 7 CFR 1032.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1032.51 Section 1032.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  19. 7 CFR 1033.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1033.51 Section 1033.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  20. 7 CFR 1032.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1032.51 Section 1032.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  1. 7 CFR 1032.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1032.51 Section 1032.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  2. 7 CFR 1126.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1126.51 Section 1126.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  3. 7 CFR 1001.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1001.51 Section 1001.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  4. 7 CFR 1033.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1033.51 Section 1033.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  5. 7 CFR 1001.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1001.51 Section 1001.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  6. 7 CFR 1131.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1131.51 Section 1131.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  7. 7 CFR 1126.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1126.51 Section 1126.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  8. 7 CFR 1126.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1126.51 Section 1126.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  9. MHC class I and MHC class II DRB gene variability in wild and captive Bengal tigers (Panthera tigris tigris).

    PubMed

    Pokorny, Ina; Sharma, Reeta; Goyal, Surendra Prakash; Mishra, Sudanshu; Tiedemann, Ralph

    2010-10-01

    Bengal tigers are highly endangered and knowledge on adaptive genetic variation can be essential for efficient conservation and management. Here we present the first assessment of allelic variation in major histocompatibility complex (MHC) class I and MHC class II DRB genes for wild and captive tigers from India. We amplified, cloned, and sequenced alpha-1 and alpha-2 domain of MHC class I and beta-1 domain of MHC class II DRB genes in 16 tiger specimens of different geographic origin. We detected high variability in peptide-binding sites, presumably resulting from positive selection. Tigers exhibit a low number of MHC DRB alleles, similar to other endangered big cats. Our initial assessment-admittedly with limited geographic coverage and sample size-did not reveal significant differences between captive and wild tigers with regard to MHC variability. In addition, we successfully amplified MHC DRB alleles from scat samples. Our characterization of tiger MHC alleles forms a basis for further in-depth analyses of MHC variability in this illustrative threatened mammal.

  10. 7 CFR 1124.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1124.51 Section 1124.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  11. 7 CFR 1124.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1124.51 Section 1124.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  12. 7 CFR 1030.51 - Class I differential and price.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.51 Class I differential and price. The Class I... 7 Agriculture 9 2013-01-01 2013-01-01 false Class I differential and price. 1030.51 Section 1030.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  13. 7 CFR 1030.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1030.51 Section 1030.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  14. 7 CFR 1030.51 - Class I differential and price.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.51 Class I differential and price. The Class I... 7 Agriculture 9 2011-01-01 2011-01-01 false Class I differential and price. 1030.51 Section 1030.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  15. 7 CFR 1124.51 - Class I differential and price.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.51 Class I differential and price. The Class I... 7 Agriculture 9 2012-01-01 2012-01-01 false Class I differential and price. 1124.51 Section 1124.51 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  16. Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia.

    PubMed

    Hernansanz-Agustín, Pablo; Ramos, Elena; Navarro, Elisa; Parada, Esther; Sánchez-López, Nuria; Peláez-Aguado, Laura; Cabrera-García, J Daniel; Tello, Daniel; Buendia, Izaskun; Marina, Anabel; Egea, Javier; López, Manuela G; Bogdanova, Anna; Martínez-Ruiz, Antonio

    2017-08-01

    Mitochondria use oxygen as the final acceptor of the respiratory chain, but its incomplete reduction can also produce reactive oxygen species (ROS), especially superoxide. Acute hypoxia produces a superoxide burst in different cell types, but the triggering mechanism is still unknown. Herein, we show that complex I is involved in this superoxide burst under acute hypoxia in endothelial cells. We have also studied the possible mechanisms by which complex I could be involved in this burst, discarding reverse electron transport in complex I and the implication of PTEN-induced putative kinase 1 (PINK1). We show that complex I transition from the active to 'deactive' form is enhanced by acute hypoxia in endothelial cells and brain tissue, and we suggest that it can trigger ROS production through its Na + /H + antiporter activity. These results highlight the role of complex I as a key actor in redox signalling in acute hypoxia. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Insights into MHC class I peptide loading from the structure of the tapasin/ERp57 heterodimer

    PubMed Central

    Dong, Gang; Wearsch, Pamela A.; Peaper, David R.; Cresswell, Peter; Reinisch, Karin M.

    2009-01-01

    SUMMARY Tapasin is a glycoprotein critical for loading Major Histocompatibility Complex (MHC) class I molecules with high affinity peptides. It functions within the multimeric peptide-loading complex (PLC) as a disulfide-linked, stable heterodimer with the thiol oxidoreductase ERp57, and this covalent interaction is required to support optimal PLC activity. Here we present the 2.6 Å resolution structure of the tapasin/ERp57 core of the PLC. The structure reveals the basis for the stable dimerization of tapasin and ERp57 and provides the first example of a protein disulfide isomerase family member interacting with a substrate. Mutational analysis identified a conserved surface on tapasin that interacts with MHC class I molecules and is critical for the peptide loading and editing function of the tapasin-ERp57 heterodimer. By combining the tapasin/ERp57 structure with those of other defined PLC components we present a molecular model that illuminates the processes involved in MHC class I peptide loading. PMID:19119025

  18. 7 CFR 1126.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1126.51 Section 1126.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1126.51 Class I differential and price. The Class I differential shall be the...

  19. 7 CFR 1131.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1131.51 Section 1131.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE ARIZONA MARKETING AREA Order Regulating Handling Class Prices § 1131.51 Class I differential and price. The Class I differential shall be the...

  20. 7 CFR 1126.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1126.51 Section 1126.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1126.51 Class I differential and price. The Class I differential shall be the...

  1. 7 CFR 1033.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1033.51 Section 1033.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE MIDEAST MARKETING AREA Order Regulating Handling Class Prices § 1033.51 Class I differential and price. The Class I differential shall be the...

  2. 7 CFR 1030.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1030.51 Section 1030.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE UPPER MIDWEST MARKETING AREA Order Regulating Handling Class Prices § 1030.51 Class I differential and price. The Class I differential shall be...

  3. 7 CFR 1001.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1001.51 Section 1001.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE NORTHEAST MARKETING AREA Order Regulating Handling Class Prices § 1001.51 Class I differential and price. The Class I differential shall be the...

  4. 7 CFR 1030.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1030.51 Section 1030.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE UPPER MIDWEST MARKETING AREA Order Regulating Handling Class Prices § 1030.51 Class I differential and price. The Class I differential shall be...

  5. 7 CFR 1124.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1124.51 Section 1124.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE PACIFIC NORTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1124.51 Class I differential and price. The Class I differential shall be...

  6. 7 CFR 1032.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1032.51 Section 1032.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE CENTRAL MARKETING AREA Order Regulating Handling Class Prices § 1032.51 Class I differential and price. The Class I differential shall be the...

  7. 7 CFR 1033.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1033.51 Section 1033.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE MIDEAST MARKETING AREA Order Regulating Handling Class Prices § 1033.51 Class I differential and price. The Class I differential shall be the...

  8. 7 CFR 1032.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1032.51 Section 1032.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE CENTRAL MARKETING AREA Order Regulating Handling Class Prices § 1032.51 Class I differential and price. The Class I differential shall be the...

  9. 7 CFR 1131.51 - Class I differential and price.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Class I differential and price. 1131.51 Section 1131.51... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE ARIZONA MARKETING AREA Order Regulating Handling Class Prices § 1131.51 Class I differential and price. The Class I differential shall be the...

  10. 7 CFR 1124.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1124.51 Section 1124.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE PACIFIC NORTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1124.51 Class I differential and price. The Class I differential shall be...

  11. 7 CFR 1001.51 - Class I differential and price.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Class I differential and price. 1001.51 Section 1001.51... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE NORTHEAST MARKETING AREA Order Regulating Handling Class Prices § 1001.51 Class I differential and price. The Class I differential shall be the...

  12. Class I Microcins: Their Structures, Activities, and Mechanisms of Resistance

    NASA Astrophysics Data System (ADS)

    Severinov, Konstantin; Semenova, Ekaterina; Kazakov, Teymur

    Microcin J25, microcin B17, and microcin C7-C51 are the three known members of class I posttranslationally modified microcins (heavily posttranslationally modified antibacterial peptides produced by Enterobacteriaceae with molecular weights of less than 5 kDa). The three microcins are unrelated to each other; they have structures that are highly atypical for ribosomally synthesized peptides and target essential molecular machines that are validated drug targets. In this chapter, available data on mechanisms of action, structure-activity relationships, and immunity mechanisms for class I microcins and related compounds are discussed.

  13. X-ray emitting class I protostars in the Serpens dark cloud

    NASA Astrophysics Data System (ADS)

    Preibisch, T.

    2004-12-01

    We analyze a set of three individual XMM-Newton X-ray observation of the Serpens dark cloud. In addition to the 45 sources already reported in the analysis of the first of these XMM-Newton observations by Preibisch (\\cite{Preibisch2003), the complete combined data set leads to the detection of X-ray emission from four of the 19 known class I protostars in the region. The set of three observations allows us to study the variability of the sources on timescales from minutes to several months. The lightcurves of two of the four X-ray detected class I protostars show evidence for significant variability; the data suggest at least four flare-like events on these objects. This relatively high level of variability in the X-ray emission from the class I protostars is in qualitative agreement with the result by Imanishi et al. (\\cite{Imanishi2001}), who found that the class I protostars in the ρ Ophiuchi dark cloud show a higher level of variability than that of more evolved class II and class III young stellar objects. This may support non-coronal X-ray emission mechanisms for class I protostars and is in agreement with the predictions of models that assume magnetic interactions between the protostar and its surrounding disk as a source of high-energy emission. We also find a strong variation (by a factor of ˜10) in the X-ray luminosity of the class II object EC 74 between the three observations, which may be explained by a long duration flare or by rotational modulation. Finally, we find no evidence for X-ray emission from the five class 0 protostars in the region.

  14. Resonance Properties of Class I and Class II Neurons Differentially Modulated by Channel Noise

    NASA Astrophysics Data System (ADS)

    Wang, Lei

    2018-01-01

    Resonance properties of two different neuron types (Class I and Class II) induced by channel noise are investigated in this study. It is found that for Class I neuron, spiking activity is enhanced when certain noise intensity is presented, especially under weak current stimuli -- a typical phenomenon of stochastic resonance (SR); while for Class II neuron, in addition to perform the SR, certain noise intensity would inhibit neuronal activity under some current stimuli -- a typical phenomenon of inverse stochastic resonance (ISR). Moreover, we show that only sodium channel noise or potassium channel noise variation can achieve the similar phenomena. Consequently, the model results suggest that channel noise may exert differential roles in modulating the resonance properties of Class I and Class II neurons.

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

    PubMed Central

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

    1997-01-01

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

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

    PubMed

    Singh, G D; McNamara, J A; Lozanoff, S

    1997-11-01

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

  17. Fingerprinting of HLA class I genes for improved selection of unrelated bone marrow donors.

    PubMed

    Martinelli, G; Farabegoli, P; Buzzi, M; Panzica, G; Zaccaria, A; Bandini, G; Calori, E; Testoni, N; Rosti, G; Conte, R; Remiddi, C; Salvucci, M; De Vivo, A; Tura, S

    1996-02-01

    The degree of matching of HLA genes between the selected donor and recipient is an important aspect of the selection of unrelated donors for allogeneic bone marrow transplantation (UBMT). The most sensitive methods currently used are serological typing of HLA class I genes, mixed lymphocyte culture (MLC), IEF and molecular genotyping of HLA class II genes by direct sequencing of PCR products. Serological typing of class I antigenes (A, B and C) fails to detect minor differences demonstrated by direct sequencing of DNA polymorphic regions. Molecular genotyping of HLA class I genes by DNA analysis is costly and work-intensive. To improve compatibility between donor and recipient, we have set up a new rapid and non-radioisotopic application of the 'fingerprinting PCR' technique for the analysis of the polymorphic second exon of the HLA class I A, B and C genes. This technique is based on the formation of specific patterns (PCR fingerprints) of homoduplexes and heteroduplexes between heterologous amplified DNA sequences. After an electrophoretic run on non-denaturing polyacrylamide gel, different HLA class I types give allele-specific banding patterns. HLA class I matching is performed, after the gel has been soaked in ethidium bromide or silver-stained, by visual comparison of patients' fingerprints with those of donors. Identity can be confirmed by mixing donor and recipient DNAs in an amplification cross-match. To assess the technique, 10 normal samples, 22 related allogeneic bone marrow transplanted pairs and 10 unrelated HLA-A and HLA-B serologically matched patient-donor pairs were analysed for HLA class I polymorphic regions. In all the related pairs and in 1/10 unrelated pairs, matched donor-recipient patterns were identified. This new application of PCR fingerprinting may confirm the HLA class I serological selection of unrelated marrow donors.

  18. The Emerging Role of the Major Histocompatibility Complex Class I in Amyotrophic Lateral Sclerosis

    PubMed Central

    Chiarotto, Gabriela Bortolança; Trolese, Maria Chiara; França, Marcondes Cavalcante; Bendotti, Caterina

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motoneurons (MNs). The etiology of the disease is still unknown for most patients with sporadic ALS, while in 5–10% of the familial cases, several gene mutations have been linked to the disease. Mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1), reproducing in animal models a pathological scenario similar to that found in ALS patients, have allowed for the identification of mechanisms relevant to the ALS pathogenesis. Among them, neuroinflammation mediated by glial cells and systemic immune activation play a key role in the progression of the disease, through mechanisms that can be either neuroprotective or neurodetrimental depending on the type of cells and the MN compartment involved. In this review, we will examine and discuss the involvement of major histocompatibility complex class I (MHCI) in ALS concerning its function in the adaptive immunity and its role in modulating the neural plasticity in the central and peripheral nervous system. The evidence indicates that the overexpression of MHCI into MNs protect them from astrocytes’ toxicity in the central nervous system (CNS) and promote the removal of degenerating motor axons accelerating collateral reinnervation of muscles. PMID:29104236

  19. The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity.

    PubMed

    Sullivan, L C; Clements, C S; Rossjohn, J; Brooks, A G

    2008-11-01

    The non-classical major histocompatibility complex (MHC) class I molecule human leucocyte antigen (HLA)-E is the least polymorphic of all the MHC class I molecules and acts as a ligand for receptors of both the innate and the adaptive immune systems. The recognition of self-peptides complexed to HLA-E by the CD94-NKG2A receptor expressed by natural killer (NK) cells represents a crucial checkpoint for immune surveillance by NK cells. However, HLA-E can also be recognised by the T-cell receptor expressed by alphabeta CD8 T cells and therefore can play a role in the adaptive immune response to invading pathogens. The recent resolution of HLA-E in complex with both innate and adaptive ligands has provided insight into the dual role of this molecule in immunity.

  20. 7 CFR 1131.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1131.52 Section 1131.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  1. 7 CFR 1007.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1007.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1007.52 Section 1007.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  2. 7 CFR 1033.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1033.52 Section 1033.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  3. 7 CFR 1006.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1006.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1006.52 Section 1006.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  4. 7 CFR 1032.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1032.52 Section 1032.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  5. 7 CFR 1005.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1005.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1005.52 Section 1005.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  6. 7 CFR 1131.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1131.52 Section 1131.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  7. 7 CFR 1030.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1030.52 Section 1030.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  8. 7 CFR 1124.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1124.52 Section 1124.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  9. 7 CFR 1007.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1007.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1007.52 Section 1007.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  10. 7 CFR 1005.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1005.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1005.52 Section 1005.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  11. 7 CFR 1124.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1124.52 Section 1124.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  12. 7 CFR 1030.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1030.52 Section 1030.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  13. 7 CFR 1126.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1126.52 Section 1126.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  14. 7 CFR 1005.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1005.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1005.52 Section 1005.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  15. 7 CFR 1124.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1124.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1124.52 Section 1124.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  16. 7 CFR 1001.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1001.52 Section 1001.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  17. 7 CFR 1001.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1001.52 Section 1001.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  18. 7 CFR 1032.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1032.52 Section 1032.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  19. 7 CFR 1033.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1033.52 Section 1033.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  20. 7 CFR 1030.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MARKETING AREA Order Regulating Handling Class Prices § 1030.52 Adjusted Class I differentials. See § 1000... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1030.52 Section 1030.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  1. 7 CFR 1006.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1006.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1006.52 Section 1006.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  2. 7 CFR 1131.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1131.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1131.52 Section 1131.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  3. 7 CFR 1126.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1126.52 Section 1126.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  4. 7 CFR 1001.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1001.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1001.52 Section 1001.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  5. 7 CFR 1032.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1032.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1032.52 Section 1032.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  6. 7 CFR 1007.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1007.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1007.52 Section 1007.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  7. 7 CFR 1033.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AREA Order Regulating Handling Class Prices § 1033.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2012-01-01 2012-01-01 false Adjusted Class I differentials. 1033.52 Section 1033.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  8. 7 CFR 1006.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AREA Order Regulating Handling Class Prices § 1006.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2011-01-01 2011-01-01 false Adjusted Class I differentials. 1006.52 Section 1006.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  9. 7 CFR 1126.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AREA Order Regulating Handling Class Prices § 1126.52 Adjusted Class I differentials. See § 1000.52. ... 7 Agriculture 9 2013-01-01 2013-01-01 false Adjusted Class I differentials. 1126.52 Section 1126.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING...

  10. The relationship between Class I and Class II methanol masers at high angular resolution

    NASA Astrophysics Data System (ADS)

    McCarthy, T. P.; Ellingsen, S. P.; Voronkov, M. A.; Cimò, G.

    2018-06-01

    We have used the Australia Telescope Compact Array (ATCA) to make the first high-resolution observations of a large sample of class I methanol masers in the 95-GHz (80-71A+) transition. The target sources consist of a statistically complete sample of 6.7-GHz class II methanol masers with an associated 95-GHz class I methanol maser, enabling a detailed study of the relationship between the two methanol maser classes at arcsecond angular resolution. These sources have been previously observed at high resolution in the 36- and 44-GHz transitions, allowing comparison between all three class I maser transitions. In total, 172 95-GHz maser components were detected across the 32 target sources. We find that at high resolution, when considering matched maser components, a 3:1 flux density ratio is observed between the 95- and 44-GHz components, consistent with a number of previous lower angular resolution studies. The 95-GHz maser components appear to be preferentially located closer to the driving sources and this may indicate that this transition is more strongly inverted nearby to background continuum sources. We do not observe an elevated association rate between 95-GHz maser emission and more evolved sources, as indicated by the presence of 12.2-GHz class II masers. We find that in the majority of cases where both class I and class II methanol emission is observed, some component of the class I emission is associated with a likely outflow candidate.

  11. 7 CFR 1124.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1124.52 Section 1124.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE PACIFIC NORTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1124.52 Adjusted Class I differentials. See § 1000.52. ...

  12. 7 CFR 1030.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1030.52 Section 1030.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE UPPER MIDWEST MARKETING AREA Order Regulating Handling Class Prices § 1030.52 Adjusted Class I differentials. See § 1000.52. ...

  13. 7 CFR 1124.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1124.52 Section 1124.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE PACIFIC NORTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1124.52 Adjusted Class I differentials. See § 1000.52. ...

  14. 7 CFR 1007.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1007.52 Section 1007.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHEAST MARKETING AREA Order Regulating Handling Class Prices § 1007.52 Adjusted Class I differentials. See § 1000.52. ...

  15. 7 CFR 1007.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1007.52 Section 1007.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHEAST MARKETING AREA Order Regulating Handling Class Prices § 1007.52 Adjusted Class I differentials. See § 1000.52. ...

  16. 7 CFR 1006.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1006.52 Section 1006.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE FLORIDA MARKETING AREA Order Regulating Handling Class Prices § 1006.52 Adjusted Class I differentials. See § 1000.52. ...

  17. 7 CFR 1126.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1126.52 Section 1126.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1126.52 Adjusted Class I differentials. See § 1000.52. ...

  18. 7 CFR 1006.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1006.52 Section 1006.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE FLORIDA MARKETING AREA Order Regulating Handling Class Prices § 1006.52 Adjusted Class I differentials. See § 1000.52. ...

  19. 7 CFR 1005.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1005.52 Section 1005.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE APPALACHIAN MARKETING AREA Order Regulating Handling Class Prices § 1005.52 Adjusted Class I differentials. See § 1000.52. ...

  20. 7 CFR 1131.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1131.52 Section 1131.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE ARIZONA MARKETING AREA Order Regulating Handling Class Prices § 1131.52 Adjusted Class I differentials. See § 1000.52. ...

  1. 7 CFR 1126.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1126.52 Section 1126.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE SOUTHWEST MARKETING AREA Order Regulating Handling Class Prices § 1126.52 Adjusted Class I differentials. See § 1000.52. ...

  2. 7 CFR 1131.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1131.52 Section 1131.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE ARIZONA MARKETING AREA Order Regulating Handling Class Prices § 1131.52 Adjusted Class I differentials. See § 1000.52. ...

  3. 7 CFR 1001.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1001.52 Section 1001.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE NORTHEAST MARKETING AREA Order Regulating Handling Class Prices § 1001.52 Adjusted Class I differentials. See § 1000.52. ...

  4. 7 CFR 1032.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1032.52 Section 1032.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE CENTRAL MARKETING AREA Order Regulating Handling Class Prices § 1032.52 Adjusted Class I differentials. See § 1000.52. ...

  5. 7 CFR 1033.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1033.52 Section 1033.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE MIDEAST MARKETING AREA Order Regulating Handling Class Prices § 1033.52 Adjusted Class I differentials. See § 1000.52. ...

  6. 7 CFR 1033.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1033.52 Section 1033.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE MIDEAST MARKETING AREA Order Regulating Handling Class Prices § 1033.52 Adjusted Class I differentials. See § 1000.52. ...

  7. 7 CFR 1005.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1005.52 Section 1005.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE APPALACHIAN MARKETING AREA Order Regulating Handling Class Prices § 1005.52 Adjusted Class I differentials. See § 1000.52. ...

  8. 7 CFR 1030.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1030.52 Section 1030.52... Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE UPPER MIDWEST MARKETING AREA Order Regulating Handling Class Prices § 1030.52 Adjusted Class I differentials. See § 1000.52. ...

  9. 7 CFR 1032.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Adjusted Class I differentials. 1032.52 Section 1032.52... AGREEMENTS AND ORDERS; MILK), DEPARTMENT OF AGRICULTURE MILK IN THE CENTRAL MARKETING AREA Order Regulating Handling Class Prices § 1032.52 Adjusted Class I differentials. See § 1000.52. ...

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

    PubMed Central

    Alcaide, Miguel; Liu, Mark

    2013-01-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nolen, B.; Tomasevic, N; Russell, A

    2009-01-01

    Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2more » and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.« less

  12. Differential Transmembrane Domain GXXXG Motif Pairing Impacts Major Histocompatibility Complex (MHC) Class II Structure*

    PubMed Central

    Dixon, Ann M.; Drake, Lisa; Hughes, Kelly T.; Sargent, Elizabeth; Hunt, Danielle; Harton, Jonathan A.; Drake, James R.

    2014-01-01

    Major histocompatibility complex (MHC) class II molecules exhibit conformational heterogeneity, which influences their ability to stimulate CD4 T cells and drive immune responses. Previous studies suggest a role for the transmembrane domain of the class II αβ heterodimer in determining molecular structure and function. Our previous studies identified an MHC class II conformer that is marked by the Ia.2 epitope. These Ia.2+ class II conformers are lipid raft-associated and able to drive both tyrosine kinase signaling and efficient antigen presentation to CD4 T cells. Here, we establish that the Ia.2+ I-Ak conformer is formed early in the class II biosynthetic pathway and that differential pairing of highly conserved transmembrane domain GXXXG dimerization motifs is responsible for formation of Ia.2+ versus Ia.2− I-Ak class II conformers and controlling lipid raft partitioning. These findings provide a molecular explanation for the formation of two distinct MHC class II conformers that differ in their inherent ability to signal and drive robust T cell activation, providing new insight into the role of MHC class II in regulating antigen-presenting cell-T cell interactions critical to the initiation and control of multiple aspects of the immune response. PMID:24619409

  13. HLA class-I and class-II allele frequencies and two-locus haplotypes in Melanesians of Vanuatu and New Caledonia.

    PubMed

    Maitland, K; Bunce, M; Harding, R M; Barnardo, M C N M; Clegg, J B; Welsh, K; Bowden, D K; Williams, T N

    2004-12-01

    HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity.

  14. Assembly and function of the major histocompatibility complex (MHC) I peptide-loading complex are conserved across higher vertebrates.

    PubMed

    Hinz, Andreas; Jedamzick, Johanna; Herbring, Valentina; Fischbach, Hanna; Hartmann, Jessica; Parcej, David; Koch, Joachim; Tampé, Robert

    2014-11-28

    Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Recognition of Human Histocompatibility Leukocyte Antigen (HLA)-E Complexed with HLA Class I Signal Sequence–derived Peptides by CD94/NKG2 Confers Protection from Natural Killer Cell–mediated Lysis

    PubMed Central

    Borrego, Francisco; Ulbrecht, Matthias; Weiss, Elisabeth H.; Coligan, John E.; Brooks, Andrew G.

    1998-01-01

    Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical HLA class I molecule, the gene for which is transcribed in most tissues. It has recently been reported that this molecule binds peptides derived from the signal sequence of HLA class I proteins; however, no function for HLA-E has yet been described. We show that natural killer (NK) cells can recognize target cells expressing HLA-E molecules on the cell surface and this interaction results in inhibition of the lytic process. Furthermore, HLA-E recognition is mediated primarily through the CD94/NKG2-A heterodimer, as CD94-specific, but not killer cell inhibitory receptor (KIR)–specific mAbs block HLA-E–mediated protection of target cells. Cell surface HLA-E could be increased by incubation with synthetic peptides corresponding to residues 3–11 from the signal sequences of a number of HLA class I molecules; however, only peptides which contained a Met at position 2 were capable of conferring resistance to NK-mediated lysis, whereas those having Thr at position 2 had no effect. Interestingly, HLA class I molecules previously correlated with CD94/NKG2 recognition all have Met at residue 4 of the signal sequence (position 2 of the HLA-E binding peptide), whereas those which have been reported not to interact with CD94/NKG2 have Thr at this position. Thus, these data show a function for HLA-E and suggest an alternative explanation for the apparent broad reactivity of CD94/NKG2 with HLA class I molecules; that CD94/NKG2 interacts with HLA-E complexed with signal sequence peptides derived from “protective” HLA class I alleles rather than directly interacting with classical HLA class I proteins. PMID:9480992

  16. Generalists and Specialists: A New View of How MHC Class I Molecules Fight Infectious Pathogens.

    PubMed

    Kaufman, Jim

    2018-05-01

    In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems. This review discusses the new concept that poorly expressed promiscuous class I alleles act as generalists to protect against a wide variety of infectious pathogens, while highly expressed fastidious class I alleles can act as specialists to protect against new and dangerous pathogens. Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved.

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

    PubMed Central

    Yoshihama, Sayuri; Roszik, Jason; Downs, Isaac; Meissner, Torsten B.; Vijayan, Saptha; Chapuy, Bjoern; Sidiq, Tabasum; Shipp, Margaret A.; Lizee, Gregory A.; Kobayashi, Koichi S.

    2016-01-01

    Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as “NLRC5” [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8+ cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers. PMID:27162338

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

    PubMed

    Yoshihama, Sayuri; Roszik, Jason; Downs, Isaac; Meissner, Torsten B; Vijayan, Saptha; Chapuy, Bjoern; Sidiq, Tabasum; Shipp, Margaret A; Lizee, Gregory A; Kobayashi, Koichi S

    2016-05-24

    Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.

  19. Teaching the Public Relations Case Studies/Campaigns Class.

    ERIC Educational Resources Information Center

    Cottone, Laura Perkins

    The public relations case studies/campaigns class entails teaching students how to die and then come back to life. As students must learn to take a critical look at complex public and social issues, teachers should create an environment in which the students feel comfortable with the process of psychological reconstruction. Students must be taught…

  20. Comparison of psychosocial status in treatment-seeking women with class III vs. class I-II obesity.

    PubMed

    Wadden, Thomas A; Butryn, Meghan L; Sarwer, David B; Fabricatore, Anthony N; Crerand, Canice E; Lipschutz, Patti E; Faulconbridge, Lucy; Raper, Steven; Williams, Noel N

    2006-01-01

    This study compared the psychosocial status and weight loss expectations of women with extreme (class III) obesity who sought bariatric surgery with those of women with class I-II obesity who enrolled in a research study on behavioral weight control. Before treatment, all participants completed the Beck Depression Inventory-II and the Weight and Lifestyle Inventory. This latter questionnaire assesses several domains including symptoms of depression and low self-esteem, history of psychiatric complications, current stressors, and weight loss expectations. Women with class III obesity, as compared with class I-II, reported significantly more symptoms of depression. Fully 25% of women in the former group appeared to have a significant mood disorder that would benefit from treatment. As compared with women with class I-II obesity, significantly more women with class III obesity also reported a history of psychiatric complications, which included physical and sexual abuse and greater stress related to their physical health and financial/legal matters. Both groups of women had unrealistic weight loss expectations. Those who sought surgery expected to lose 47.6 +/- 9.3% of initial weight, compared with 24.8 +/- 8.7% for those who enrolled in behavioral weight control. These findings suggest that women with extreme obesity who seek bariatric surgery should be screened for psychosocial complications. Those determined to have significant psychiatric distress should be referred for behavioral or pharmacological treatment to alleviate their suffering. Long-term studies are needed to provide definitive guidance concerning the relationship between preoperative psychopathology and the outcome of bariatric surgery.

  1. Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques.

    PubMed

    Semler, Matthew R; Wiseman, Roger W; Karl, Julie A; Graham, Michael E; Gieger, Samantha M; O'Connor, David H

    2018-06-01

    Pig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to that of rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to infer Mane-A and Mane-B haplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313 Mane-A, Mane-B, and Mane-I sequences that defined 86 Mane-A and 106 Mane-B MHC-I haplotypes. Pacific Biosciences technology allows us to resolve these Mane-A and Mane-B haplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease.

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

    PubMed Central

    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

  3. Single Amino Acid Residue in the A2 Domain of Major Histocompatibility Complex Class I Is Involved in the Efficiency of Equine Herpesvirus-1 Entry*

    PubMed Central

    Sasaki, Michihito; Kim, Eunmi; Igarashi, Manabu; Ito, Kimihito; Hasebe, Rie; Fukushi, Hideto; Sawa, Hirofumi; Kimura, Takashi

    2011-01-01

    Equine herpesvirus-1 (EHV-1), an α-herpesvirus of the family Herpesviridae, causes respiratory disease, abortion, and encephalomyelitis in horses. EHV-1 utilizes equine MHC class I molecules as entry receptors. However, hamster MHC class I molecules on EHV-1-susceptible CHO-K1 cells play no role in EHV-1 entry. To identify the MHC class I molecule region that is responsible for EHV-1 entry, domain exchange and site-directed mutagenesis experiments were performed, in which parts of the extracellular region of hamster MHC class I (clone C5) were replaced with corresponding sequences from equine MHC class I (clone A68). Substitution of alanine for glutamine at position 173 (Q173A) within the α2 domain of the MHC class I molecule enabled hamster MHC class I C5 to mediate EHV-1 entry into cells. Conversely, substitution of glutamine for alanine at position 173 (A173Q) in equine MHC class I A68 resulted in loss of EHV-1 receptor function. Equine MHC class I clone 3.4, which possesses threonine at position 173, was unable to act as an EHV-1 receptor. Substitution of alanine for threonine at position 173 (T173A) enabled MHC class I 3.4 to mediate EHV-1 entry into cells. These results suggest that the amino acid residue at position 173 of the MHC class I molecule is involved in the efficiency of EHV-1 entry. PMID:21949188

  4. Changes in Cranial Base Morphology in Class I and Class II Division 1 Malocclusions

    PubMed Central

    Agarwal, Anirudh; Pandey, Harsh; Bajaj, Kamal; Pandey, Lavesh

    2013-01-01

    Introduction: The cranial base plays a key role in craniofacial growth; it helps to integrate spatially and functionally different patterns of growth in various adjoining regions of the skull such as components of the brain, the nasal and oral cavity and the pharynx. The aim of this study was to evaluate the difference in cranial base flexure between skeletal and dental Class I and Class II division 1. Materials & Methods: Lateral cephalometric radiograph, of Class I and Class II with an average growth pattern were analyzed and compared. A total of 103 patients having class I (n=52) and class II (n=51) malocclusion, were taken from Department of Orthodontics, Rajasthan Dental College & Hospital, Jaipur. Cranial base angle (N-S-Ar) and ANB were measured on pre treatment lateral cephalograms. Results: In this study cranial base angle did not show statistically significant difference between the two groups studied. Conclusion: In the assessment of orthodontic problems involving anteroposterior malrelationships of the jaws, the problem is usually the result of size, form and position of the jaw. The present study failed to find any differences in cranial base angle between sagittal malocclusions. How to cite this article: Agarwal A, Pandey H, Bajaj K, Pandey L. Changes in Cranial Base Morphology in Class I and Class II Division 1 Malocclusion. J Int Oral Health 2013; 5(1):39-42. PMID:24155576

  5. Crystal structure of a TAPBPR–MHC I complex reveals the mechanism of peptide editing in antigen presentation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jiang, Jiansheng; Natarajan, Kannan; Boyd, Lisa F.

    Central to CD8+ T cell–mediated immunity is the recognition of peptide–major histocompatibility complex class I (p–MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein–related), a tapasin homolog. TAPBPR remodels the peptide-binding groove of MHC I, resulting in the release of low-affinity peptide. Changes include groove relaxation, modifications of keymore » binding pockets, and domain adjustments. This structure captures a peptide-receptive state of MHC I and provides insights into the mechanism of peptide editing by TAPBPR and, by analogy, tapasin.« less

  6. Antigen-B Cell Receptor Complexes Associate with Intracellular major histocompatibility complex (MHC) Class II Molecules*

    PubMed Central

    Barroso, Margarida; Tucker, Heidi; Drake, Lisa; Nichol, Kathleen; Drake, James R.

    2015-01-01

    Antigen processing and MHC class II-restricted antigen presentation by antigen-presenting cells such as dendritic cells and B cells allows the activation of naïve CD4+ T cells and cognate interactions between B cells and effector CD4+ T cells, respectively. B cells are unique among class II-restricted antigen-presenting cells in that they have a clonally restricted antigen-specific receptor, the B cell receptor (BCR), which allows the cell to recognize and respond to trace amounts of foreign antigen present in a sea of self-antigens. Moreover, engagement of peptide-class II complexes formed via BCR-mediated processing of cognate antigen has been shown to result in a unique pattern of B cell activation. Using a combined biochemical and imaging/FRET approach, we establish that internalized antigen-BCR complexes associate with intracellular class II molecules. We demonstrate that the M1-paired MHC class II conformer, shown previously to be critical for CD4 T cell activation, is incorporated selectively into these complexes and loaded selectively with peptide derived from BCR-internalized cognate antigen. These results demonstrate that, in B cells, internalized antigen-BCR complexes associate with intracellular MHC class II molecules, potentially defining a site of class II peptide acquisition, and reveal a selective role for the M1-paired class II conformer in the presentation of cognate antigen. These findings provide key insights into the molecular mechanisms used by B cells to control the source of peptides charged onto class II molecules, allowing the immune system to mount an antibody response focused on BCR-reactive cognate antigen. PMID:26400081

  7. Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope.

    PubMed

    Raafat, Nermin; Sadowski-Cron, Charlotte; Mengus, Chantal; Heberer, Michael; Spagnoli, Giulio C; Zajac, Paul

    2012-09-01

    Herpes simplex virus protein ICP47, encoded by US12 gene, strongly downregulates major histocompatibility complex (MHC) class-I antigen restricted presentation by blocking transporter associated with antigen processing (TAP) protein. To decrease viral vector antigenic immunodominance and MHC class-I driven clearance, we engineered recombinant vaccinia viruses (rVV) expressing ICP47 alone (rVV-US12) or together with endoplasmic reticulum (ER)-targeted Melan-A/MART-1(27-35) model tumor epitope (rVV-MUS12). In this study, we show that antigen presenting cells (APC), infected with rVV-US12, display a decreased ability to present TAP dependent MHC class-I restricted viral antigens to CD8+ T-cells. While HLA class-I cell surface expression is strongly downregulated, other important immune related molecules such as CD80, CD44 and, most importantly, MHC class-II are unaffected. Characterization of rVV-MUS12 infected cells demonstrates that over-expression of a TAP-independent peptide, partially compensates for ICP47 induced surface MHC class-I downregulation (30% vs. 70% respectively). Most importantly, in conditions where clearance of infected APC by virus-specific CTL represents a limiting factor, a significant enhancement of CTL responses to the tumor epitope can be detected in cultures stimulated with rVV-MUS12, as compared to those stimulated by rVV-MART alone. Such reagents could become of high relevance in multiple boost protocols required for cancer immunotherapy, to limit vector-specific responsiveness. Copyright © 2011 UICC.

  8. In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function.

    PubMed

    Follin, Elna; Karlsson, Maria; Lundegaard, Claus; Nielsen, Morten; Wallin, Stefan; Paulsson, Kajsa; Westerdahl, Helena

    2013-04-01

    The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1-α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate their functional and genetic relationships. We found more pronounced clustering of the MHC class I allomorphs (allele specific proteins) in regards to their function (peptide-binding specificities) compared to their genetic relationships (amino acid sequences), indicating that the high number of alleles is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein function, possibly driven by selection from shared pathogens, has resulted in allomorphs with similar peptide-binding repertoires, although trans-species evolution in combination with gene conversion cannot be ruled out.

  9. Thin-plate spline analysis of craniofacial growth in Class I and Class II subjects.

    PubMed

    Franchi, Lorenzo; Baccetti, Tiziano; Stahl, Franka; McNamara, James A

    2007-07-01

    To compare the craniofacial growth characteristics of untreated subjects with Class II division 1 malocclusion with those of subjects with normal (Class I) occlusion from the prepubertal through the postpubertal stages of development. The Class II division 1 sample consisted of 17 subjects (11 boys and six girls). The Class I sample also consisted of 17 subjects (13 boys and four girls). Three craniofacial regions (cranial base, maxilla, and mandible) were analyzed on the lateral cephalograms of the subjects in both groups by means of thin-plate spline analysis at T1 (prepubertal) and T2 (postpubertal). Both cross-sectional and longitudinal comparisons were performed on both size and shape differences between the two groups. The results showed an increased cranial base angulation as a morphological feature of Class II malocclusion at the prepubertal developmental phase. Maxillary changes in either shape or size were not significant. Subjects with Class II malocclusion exhibited a significant deficiency in the size of the mandible at the completion of active craniofacial growth as compared with Class I subjects. A significant deficiency in the size of the mandible became apparent in Class II subjects during the circumpubertal period and it was still present at the completion of active craniofacial growth.

  10. Major histocompatibility complex (MHC) class I and II alleles which confer susceptibility or protection in the Morphea in Adults and Children (MAC) cohort

    PubMed Central

    Jacobe, Heidi; Ahn, Chul; Arnett, Frank; Reveille, John D.

    2014-01-01

    Objective To determine human leukocyte antigen class I (HLA-class I) and II (HLA-class II) alleles associated with morphea (localized scleroderma) in the Morphea in Adults and Children (MAC) cohort by a nested case–control association study. Methods Morphea patients were included from MAC cohort and matched controls from the NIH/NIAMS Scleroderma Family Registry and DNA Repository and Division of Rheumatology at the University of Texas Health Science Center at Houston. HLA- Class II genotyping and SSCP typing was performed of HLA-A, -B, -C alleles. Associations between HLA-Class I and II alleles and morphea as well as its subphenotypes were determined. Results There were 211 cases available for HLA-class I typing with 726 matched controls and 158 cases available for HLA Class-II typing with 1108 matched controls. The strongest associations were found with DRB1*04:04 (OR 2.3, 95% CI 1.4–4.0 P=0.002) and HLA-B*37 conferred the highest OR among Class I alleles (3.3, 95% CI 1.6–6.9, P= 0.0016). Comparison with risk alleles in systemic sclerosis determined using the same methods and control population revealed one common allele (DRB*04:04). Conclusion Results of the present study demonstrate specific HLA Class I and II alleles are associated with morphea and likely generalized and linear subtypes. The associated morphea alleles are different than in scleroderma, implicating morphea is also immunogenetically distinct. Risk alleles in morphea are also associated with conditions such as rheumatoid arthritis (RA) and other autoimmune conditions. Population based studies indicate patients with RA have increased risk of morphea, implicating a common susceptibility allele. PMID:25223600

  11. HLA Class I and Genetic Susceptibility to Type 1 Diabetes

    PubMed Central

    Noble, Janelle A.; Valdes, Ana Maria; Varney, Michael D.; Carlson, Joyce A.; Moonsamy, Priscilla; Fear, Anna Lisa; Lane, Julie A.; Lavant, Eva; Rappner, Rebecca; Louey, Anthony; Concannon, Patrick; Mychaleckyj, Josyf C.; Erlich, Henry A.

    2010-01-01

    OBJECTIVE We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. RESEARCH DESIGN AND METHODS Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. RESULTS Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10−11) and B*3906 (10.31; P = 4 × 10−10). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403). CONCLUSIONS These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes. PMID:20798335

  12. Calreticulin is expressed on the cell surface of activated human peripheral blood T lymphocytes in association with major histocompatibility complex class I molecules.

    PubMed

    Arosa, F A; de Jesus, O; Porto, G; Carmo, A M; de Sousa, M

    1999-06-11

    Calreticulin is an endoplasmic reticulum resident molecule known to be involved in the folding and assembly of major histocompatibility complex (MHC) class I molecules. In the present study, expression of calreticulin was analyzed in human peripheral blood T lymphocytes. Pulse-chase experiments in [35S]methionine-labeled T cell blasts showed that calreticulin was associated with several proteins in the endoplasmic reticulum and suggested that it was expressed at the cell surface. Indeed, the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells together with a protein with an apparent molecular mass of 46 kDa. Cell surface expression of calreticulin by activated T lymphocytes was further confirmed by immunofluorescence and flow cytometry, studies that showed that both CD8+ and CD4+ T cells expressed calreticulin in the plasma membrane. Low amounts of cell surface calreticulin were detected in resting T lymphocytes. By sequential immunoprecipitation using the conformation independent monoclonal antibody HC-10, we provided evidence that the cell surface 46-kDa protein co-precipitated with calreticulin is unfolded MHC I. These results show for the first time that after T cell activation, significant amounts of calreticulin are expressed on the T cell surface, where they are found in physical association with a pool of beta2-free MHC class I molecules.

  13. NetMHCcons: a consensus method for the major histocompatibility complex class I predictions.

    PubMed

    Karosiene, Edita; Lundegaard, Claus; Lund, Ole; Nielsen, Morten

    2012-03-01

    A key role in cell-mediated immunity is dedicated to the major histocompatibility complex (MHC) molecules that bind peptides for presentation on the cell surface. Several in silico methods capable of predicting peptide binding to MHC class I have been developed. The accuracy of these methods depends on the data available characterizing the binding specificity of the MHC molecules. It has, moreover, been demonstrated that consensus methods defined as combinations of two or more different methods led to improved prediction accuracy. This plethora of methods makes it very difficult for the non-expert user to choose the most suitable method for predicting binding to a given MHC molecule. In this study, we have therefore made an in-depth analysis of combinations of three state-of-the-art MHC-peptide binding prediction methods (NetMHC, NetMHCpan and PickPocket). We demonstrate that a simple combination of NetMHC and NetMHCpan gives the highest performance when the allele in question is included in the training and is characterized by at least 50 data points with at least ten binders. Otherwise, NetMHCpan is the best predictor. When an allele has not been characterized, the performance depends on the distance to the training data. NetMHCpan has the highest performance when close neighbours are present in the training set, while the combination of NetMHCpan and PickPocket outperforms either of the two methods for alleles with more remote neighbours. The final method, NetMHCcons, is publicly available at www.cbs.dtu.dk/services/NetMHCcons , and allows the user in an automatic manner to obtain the most accurate predictions for any given MHC molecule.

  14. MHC class I chain-related gene a diversity in patients with cutaneous malignant melanoma from southeastern Spain.

    PubMed

    Campillo, José Antonio; López-Hernández, Ruth; Martínez-Banaclocha, Helios; Bolarín, José Miguel; Gimeno, Lourdes; Mrowiec, Anna; López, Manuela; Las Heras, Beatriz; Minguela, Alfredo; Moya-Quiles, Maria Rosa; Legáz, Isabel; Frías-Iniesta, José Francisco; García-Alonso, Ana María; Álvarez-López, María Rocío; Martínez-Escribano, Jorge Antonio; Muro, Manuel

    2015-01-01

    A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA(*)009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA(*)009 and HLA-B(*)51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA(*)009 nor the combination MICA(*)009/HLA-B(*)51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.

  15. Molecular and functional evolution of class I chitinases for plant carnivory in the caryophyllales.

    PubMed

    Renner, Tanya; Specht, Chelsea D

    2012-10-01

    Proteins produced by the large and diverse chitinase gene family are involved in the hydrolyzation of glycosidic bonds in chitin, a polymer of N-acetylglucosamines. In flowering plants, class I chitinases are important pathogenesis-related proteins, functioning in the determent of herbivory and pathogen attack by acting on insect exoskeletons and fungal cell walls. Within the carnivorous plants, two subclasses of class I chitinases have been identified to play a role in the digestion of prey. Members of these two subclasses, depending on the presence or absence of a C-terminal extension, can be secreted from specialized digestive glands found within the morphologically diverse traps that develop from carnivorous plant leaves. The degree of homology among carnivorous plant class I chitinases and the method by which these enzymes have been adapted for the carnivorous habit has yet to be elucidated. This study focuses on understanding the evolution of carnivory and chitinase genes in one of the major groups of plants that has evolved the carnivorous habit: the Caryophyllales. We recover novel class I chitinase homologs from species of genera Ancistrocladus, Dionaea, Drosera, Nepenthes, and Triphyophyllum, while also confirming the presence of two subclasses of class I chitinases based upon sequence homology and phylogenetic affinity to class I chitinases available from sequenced angiosperm genomes. We further detect residues under positive selection and reveal substitutions specific to carnivorous plant class I chitinases. These substitutions may confer functional differences as indicated by protein structure homology modeling.

  16. A modern approach for epitope prediction: identification of foot-and-mouth disease virus peptides binding bovine leukocyte antigen (BoLA) class I molecules

    USDA-ARS?s Scientific Manuscript database

    Major histocompatibility complex (MHC) class I molecules regulate adaptive immune responses through the presentation of antigenic peptides to CD8positive T-cells. Polymorphisms in the peptide binding region of class I molecules determine peptide binding affinity and stability during antigen presenta...

  17. 49 CFR 1241.11 - Annual reports of class I railroads.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Annual reports of class I railroads. 1241.11... class I railroads. (a) Commencing with reports for the year ended December 31, 1973, and thereafter, until further order, all line-haul railroad companies of class I, as defined in § 1240.1 of this chapter...

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

    PubMed

    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.

  19. Toxoplasma gondii peptide ligands open the gate of the HLA class I binding groove

    PubMed Central

    McMurtrey, Curtis; Trolle, Thomas; Sansom, Tiffany; Remesh, Soumya G; Kaever, Thomas; Bardet, Wilfried; Jackson, Kenneth; McLeod, Rima; Sette, Alessandro; Nielsen, Morten; Zajonc, Dirk M; Blader, Ira J; Peters, Bjoern; Hildebrand, William

    2016-01-01

    HLA class I presentation of pathogen-derived peptide ligands is essential for CD8+ T-cell recognition of Toxoplasma gondii infected cells. Currently, little data exist pertaining to peptides that are presented after T. gondii infection. Herein we purify HLA-A*02:01 complexes from T. gondii infected cells and characterize the peptide ligands using LCMS. We identify 195 T. gondii encoded ligands originating from both secreted and cytoplasmic proteins. Surprisingly, T. gondii ligands are significantly longer than uninfected host ligands, and these longer pathogen-derived peptides maintain a canonical N-terminal binding core yet exhibit a C-terminal extension of 1–30 amino acids. Structural analysis demonstrates that binding of extended peptides opens the HLA class I F’ pocket, allowing the C-terminal extension to protrude through one end of the binding groove. In summary, we demonstrate that unrealized structural flexibility makes MHC class I receptive to parasite-derived ligands that exhibit unique C-terminal peptide extensions. DOI: http://dx.doi.org/10.7554/eLife.12556.001 PMID:26824387

  20. Marsupials and monotremes possess a novel family of MHC class I genes that is lost from the eutherian lineage.

    PubMed

    Papenfuss, Anthony T; Feng, Zhi-Ping; Krasnec, Katina; Deakin, Janine E; Baker, Michelle L; Miller, Robert D

    2015-07-22

    Major histocompatibility complex (MHC) class I genes are found in the genomes of all jawed vertebrates. The evolution of this gene family is closely tied to the evolution of the vertebrate genome. Family members are frequently found in four paralogous regions, which were formed in two rounds of genome duplication in the early vertebrates, but in some species class Is have been subject to additional duplication or translocation, creating additional clusters. The gene family is traditionally grouped into two subtypes: classical MHC class I genes that are usually MHC-linked, highly polymorphic, expressed in a broad range of tissues and present endogenously-derived peptides to cytotoxic T-cells; and non-classical MHC class I genes generally have lower polymorphism, may have tissue-specific expression and have evolved to perform immune-related or non-immune functions. As immune genes can evolve rapidly and are subject to different selection pressure, we hypothesised that there may be divergent, as yet unannotated or uncharacterised class I genes. Application of a novel method of sensitive genome searching of available vertebrate genome sequences revealed a new, extensive sub-family of divergent MHC class I genes, denoted as UT, which has not previously been characterized. These class I genes are found in both American and Australian marsupials, and in monotremes, at an evolutionary chromosomal breakpoint, but are not present in non-mammalian genomes and have been lost from the eutherian lineage. We show that UT family members are expressed in the thymus of the gray short-tailed opossum and in other immune tissues of several Australian marsupials. Structural homology modelling shows that the proteins encoded by this family are predicted to have an open, though short, antigen-binding groove. We have identified a novel sub-family of putatively non-classical MHC class I genes that are specific to marsupials and monotremes. This family was present in the ancestral mammal and

  1. TAPBPR bridges UDP-glucose:glycoprotein glucosyltransferase 1 onto MHC class I to provide quality control in the antigen presentation pathway

    PubMed Central

    Neerincx, Andreas; Hermann, Clemens; Antrobus, Robin; van Hateren, Andy; Cao, Huan; Trautwein, Nico; Stevanović, Stefan; Elliott, Tim; Deane, Janet E; Boyle, Louise H

    2017-01-01

    Recently, we revealed that TAPBPR is a peptide exchange catalyst that is important for optimal peptide selection by MHC class I molecules. Here, we asked whether any other co-factors associate with TAPBPR, which would explain its effect on peptide selection. We identify an interaction between TAPBPR and UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1), a folding sensor in the calnexin/calreticulin quality control cycle that is known to regenerate the Glc1Man9GlcNAc2 moiety on glycoproteins. Our results suggest the formation of a multimeric complex, dependent on a conserved cysteine at position 94 in TAPBPR, in which TAPBPR promotes the association of UGT1 with peptide-receptive MHC class I molecules. We reveal that the interaction between TAPBPR and UGT1 facilities the reglucosylation of the glycan on MHC class I molecules, promoting their recognition by calreticulin. Our results suggest that in addition to being a peptide editor, TAPBPR improves peptide optimisation by promoting peptide-receptive MHC class I molecules to associate with the peptide-loading complex. DOI: http://dx.doi.org/10.7554/eLife.23049.001 PMID:28425917

  2. The Viral Transcription Group Determines the HLA Class I Cellular Immune Response Against Human Respiratory Syncytial Virus*

    PubMed Central

    Johnstone, Carolina; Lorente, Elena; Barriga, Alejandro; Barnea, Eilon; Infantes, Susana; Lemonnier, François A.; David, Chella S.; Admon, Arie; López, Daniel

    2015-01-01

    The cytotoxic T-lymphocyte-mediated killing of virus-infected cells requires previous recognition of short viral antigenic peptides bound to human leukocyte antigen class I molecules that are exposed on the surface of infected cells. The cytotoxic T-lymphocyte response is critical for the clearance of human respiratory syncytial virus infection. In this study, naturally processed viral human leukocyte antigen class I ligands were identified with mass spectrometry analysis of complex human leukocyte antigen-bound peptide pools isolated from large amounts of human respiratory syncytial virus-infected cells. Acute antiviral T-cell response characterization showed that viral transcription determines both the immunoprevalence and immunodominance of the human leukocyte antigen class I response to human respiratory syncytial virus. These findings have clear implications for antiviral vaccine design. PMID:25635267

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

    PubMed

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

    2004-11-21

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

  4. Peer Victimisation and Its Relation to Class Relational Climate and Class Moral Disengagement among School Children

    ERIC Educational Resources Information Center

    Thornberg, Robert; Wänström, Linda; Pozzoli, Tiziana

    2017-01-01

    The aim of the present study was to examine whether class climate and class moral disengagement each contribute to explain different levels of victimisation among classes. Eight-hundred-and-ninety-nine children from 43 Swedish elementary school classes participated in the current study. Class moral disengagement, class relational climate and peer…

  5. MHC class I diversity of olive baboons (Papio anubis) unravelled by next-generation sequencing.

    PubMed

    van der Wiel, Marit K H; Doxiadis, Gaby G M; de Groot, N; Otting, N; de Groot, N G; Poirier, N; Blancho, G; Bontrop, R E

    2018-02-24

    The olive baboon represents an important model system to study various aspects of human biology and health, including the origin and diversity of the major histocompatibility complex. After screening of a group of related animals for polymorphisms associated with a well-defined microsatellite marker, subsequent MHC class I typing of a selected population of 24 animals was performed on two distinct next-generation sequencing (NGS) platforms. A substantial number of 21 A and 80 B transcripts were discovered, about half of which had not been previously reported. Per animal, from one to four highly transcribed A alleles (majors) were observed, in addition to ones characterised by low transcripion levels (minors), such as members of the A*14 lineage. Furthermore, in one animal, up to 13 B alleles with differential transcription level profiles may be present. Based on segregation profiles, 16 Paan-AB haplotypes were defined. A haplotype encodes in general one or two major A and three to seven B transcripts, respectively. A further peculiarity is the presence of at least one copy of a B*02 lineage on nearly every haplotype, which indicates that B*02 represents a separate locus with probably a specialistic function. Haplotypes appear to be generated by recombination-like events, and the breakpoints map not only between the A and B regions but also within the B region itself. Therefore, the genetic makeup of the olive baboon MHC class I region appears to have been subject to a similar or even more complex expansion process than the one documented for macaque species.

  6. CXA La Paloma, LLC: UIC Class I Permit No.CA10710001

    EPA Pesticide Factsheets

    Documents related to La Paloma Generating Company, LLC's (LPGC) application for a UIC permit renewal (of permit #CA199000001) to operate a Class I injection well facility to dispose of non-hazardous wastewater from the La Paloma Generating Plant.

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

    PubMed

    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.

  8. Limited MHC class I intron 2 repertoire variation in bonobos.

    PubMed

    de Groot, Natasja G; Heijmans, Corrine M C; Helsen, Philippe; Otting, Nel; Pereboom, Zjef; Stevens, Jeroen M G; Bontrop, Ronald E

    2017-10-01

    Common chimpanzees (Pan troglodytes) experienced a selective sweep, probably caused by a SIV-like virus, which targeted their MHC class I repertoire. Based on MHC class I intron 2 data analyses, this selective sweep took place about 2-3 million years ago. As a consequence, common chimpanzees have a skewed MHC class I repertoire that is enriched for allotypes that are able to recognise conserved regions of the SIV proteome. The bonobo (Pan paniscus) shared an ancestor with common chimpanzees approximately 1.5 to 2 million years ago. To investigate whether the signature of this selective sweep is also detectable in bonobos, the MHC class I gene repertoire of two bonobo panels comprising in total 29 animals was investigated by Sanger sequencing. We identified 14 Papa-A, 20 Papa-B and 11 Papa-C alleles, of which eight, five and eight alleles, respectively, have not been reported previously. Within this pool of MHC class I variation, we recovered only 2 Papa-A, 3 Papa-B and 6 Papa-C intron 2 sequences. As compared to humans, bonobos appear to have an even more diminished MHC class I intron 2 lineage repertoire than common chimpanzees. This supports the notion that the selective sweep may have predated the speciation of common chimpanzees and bonobos. The further reduction of the MHC class I intron 2 lineage repertoire observed in bonobos as compared to the common chimpanzee may be explained by a founding effect or other subsequent selective processes.

  9. 18 CFR 415.20 - Class I projects.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 2 2011-04-01 2011-04-01 false Class I projects. 415.20 Section 415.20 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION ADMINISTRATIVE MANUAL BASIN REGULATIONS-FLOOD PLAIN REGULATIONS Types of Projects and Jurisdiction § 415.20 Class...

  10. Monitoring human leukocyte antigen class I molecules by micro-Raman spectroscopy at single-cell level

    NASA Astrophysics Data System (ADS)

    Das, Gobind; La Rocca, Rosanna; Lakshmikanth, Tadepally; Gentile, Francesco; Tallerico, Rossana; Zambetti, Lia P.; Devitt, J.; Candeloro, Patrizio; de Angelis, Francesco; Carbone, Ennio; di Fabrizio, Enzo

    2010-03-01

    Human leukocyte antigen (HLA) class I molecules are formed by three immunoglobulin-like domains (α1, α2, and α3) once folded by peptide and β2-microglobulin show the presence of two α-helix streams and one β-sheet limiting the pocket for the antigenic peptide. The loss of HLA class I expression in tumors and virus-infected cells, on one hand, prevents T cell recognition, while on the other hand, it leads to natural killer (NK) cell mediated cytotoxicity. We propose the possibility of using Raman spectroscopy to measure the relative expression of HLA class I molecules at the single-cell level. Raman spectra are recorded for three cell lines (K562, T2, and T3) and monomers (HLA class I folded, unfolded and peptide+β2-microlobulin refolded) using 830 nm laser line. Our data are consistent with the hypothesis that in the Raman spectra, ranging from 1600 to 1800 cm-1, the intensity variation of cells associated with HLA class I molecules could be measured.

  11. The viral transcription group determines the HLA class I cellular immune response against human respiratory syncytial virus.

    PubMed

    Johnstone, Carolina; Lorente, Elena; Barriga, Alejandro; Barnea, Eilon; Infantes, Susana; Lemonnier, François A; David, Chella S; Admon, Arie; López, Daniel

    2015-04-01

    The cytotoxic T-lymphocyte-mediated killing of virus-infected cells requires previous recognition of short viral antigenic peptides bound to human leukocyte antigen class I molecules that are exposed on the surface of infected cells. The cytotoxic T-lymphocyte response is critical for the clearance of human respiratory syncytial virus infection. In this study, naturally processed viral human leukocyte antigen class I ligands were identified with mass spectrometry analysis of complex human leukocyte antigen-bound peptide pools isolated from large amounts of human respiratory syncytial virus-infected cells. Acute antiviral T-cell response characterization showed that viral transcription determines both the immunoprevalence and immunodominance of the human leukocyte antigen class I response to human respiratory syncytial virus. These findings have clear implications for antiviral vaccine design. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Sequence, distribution and chromosomal context of class I and class II pilin genes of Neisseria meningitidis identified in whole genome sequences

    PubMed Central

    2014-01-01

    Background Neisseria meningitidis expresses type four pili (Tfp) which are important for colonisation and virulence. Tfp have been considered as one of the most variable structures on the bacterial surface due to high frequency gene conversion, resulting in amino acid sequence variation of the major pilin subunit (PilE). Meningococci express either a class I or a class II pilE gene and recent work has indicated that class II pilins do not undergo antigenic variation, as class II pilE genes encode conserved pilin subunits. The purpose of this work was to use whole genome sequences to further investigate the frequency and variability of the class II pilE genes in meningococcal isolate collections. Results We analysed over 600 publically available whole genome sequences of N. meningitidis isolates to determine the sequence and genomic organization of pilE. We confirmed that meningococcal strains belonging to a limited number of clonal complexes (ccs, namely cc1, cc5, cc8, cc11 and cc174) harbour a class II pilE gene which is conserved in terms of sequence and chromosomal context. We also identified pilS cassettes in all isolates with class II pilE, however, our analysis indicates that these do not serve as donor sequences for pilE/pilS recombination. Furthermore, our work reveals that the class II pilE locus lacks the DNA sequence motifs that enable (G4) or enhance (Sma/Cla repeat) pilin antigenic variation. Finally, through analysis of pilin genes in commensal Neisseria species we found that meningococcal class II pilE genes are closely related to pilE from Neisseria lactamica and Neisseria polysaccharea, suggesting horizontal transfer among these species. Conclusions Class II pilins can be defined by their amino acid sequence and genomic context and are present in meningococcal isolates which have persisted and spread globally. The absence of G4 and Sma/Cla sequences adjacent to the class II pilE genes is consistent with the lack of pilin subunit variation in these

  13. Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer

    PubMed Central

    Goeppert, Benjamin; Frauenschuh, Lena; Zucknick, Manuela; Roessler, Stephanie; Mehrabi, Arianeb; Hafezi, Mohammadreza; Stenzinger, Albrecht; Warth, Arne; Pathil, Anita; Renner, Marcus; Schirmacher, Peter; Weichert, Wilko

    2015-01-01

    Background: Biliary tract cancers (BTC) are rare malignant tumours with a poor prognosis. Previously, we have presented a detailed characterisation of the inflammatory infiltrate in BTC. Here, we analysed the impact of the expression of major histocompatibility complex class I (MHC I) on patient survival and the quantity, as well as the quality of tumour-infiltrating immune cell types in BTC. Methods: MHC I expression was assessed semi-quantitatively in 334 BTC, including extrahepatic (n=129) and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder (n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. Results were correlated with data on antitumour inflammation and investigated with respect to their association with clinicopathological variables and patient survival. Results: BTC showed a wide spectrum of different MHC I expression patterns ranging from complete negativity in some tumours to strong homogenous expression in others. In BilIN 3, significantly higher MHC I expression levels were seen compared to invasive tumours (P=0.004). Patients with strong tumoural MHC I expression had a significantly higher overall survival probability (median survival benefit: 8 months; P=0.006). MHC I expression strongly correlated with the number of tumour-infiltrating T-lymphocytes (CD4+ and CD8+) and macrophages. Conclusions: Differences of MHC I expression predict patient outcome and show correlations with specific components of the inflammatory infiltrate in BTC. These findings contribute to a better understanding of immune response and immune escape phenomena in cholangiocarcinogenesis. PMID:26461054

  14. Toward the prediction of class I and II mouse major histocompatibility complex-peptide-binding affinity: in silico bioinformatic step-by-step guide using quantitative structure-activity relationships.

    PubMed

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

    2007-01-01

    Quantitative structure-activity relationship (QSAR) analysis is a cornerstone of modern informatics. Predictive computational models of peptide-major histocompatibility complex (MHC)-binding affinity based on QSAR technology have now become important components of modern computational immunovaccinology. Historically, such approaches have been built around semiqualitative, classification methods, but these are now giving way to quantitative regression methods. We review three methods--a 2D-QSAR additive-partial least squares (PLS) and a 3D-QSAR comparative molecular similarity index analysis (CoMSIA) method--which can identify the sequence dependence of peptide-binding specificity for various class I MHC alleles from the reported binding affinities (IC50) of peptide sets. The third method is an iterative self-consistent (ISC) PLS-based additive method, which is a recently developed extension to the additive method for the affinity prediction of class II peptides. The QSAR methods presented here have established themselves as immunoinformatic techniques complementary to existing methodology, useful in the quantitative prediction of binding affinity: current methods for the in silico identification of T-cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate computational prediction of peptide-MHC affinity. We have reviewed various human and mouse class I and class II allele models. Studied alleles comprise HLA-A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3101, HLA-A*6801, HLA-A*6802, HLA-B*3501, H2-K(k), H2-K(b), H2-D(b) HLA-DRB1*0101, HLA-DRB1*0401, HLA-DRB1*0701, I-A(b), I-A(d), I-A(k), I-A(S), I-E(d), and I-E(k). In this chapter we show a step-by-step guide into predicting the reliability and the resulting models to represent an advance on existing methods. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method

  15. Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

    PubMed Central

    Ziegler, Mary E.; Souda, Puneet; Jin, Yi-Ping; Whitelegge, Julian P.; Reed, Elaine F.

    2012-01-01

    Background Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood. Methodology and Principal Findings The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin. Conclusions/Significance Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

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

    1986-03-05

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

  17. A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice.

    PubMed

    Harrison, L C; Honeyman, M C; Trembleau, S; Gregori, S; Gallazzi, F; Augstein, P; Brusic, V; Hammer, J; Adorini, L

    1997-03-17

    The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.

  18. 46 CFR 173.057 - Permitted locations for Class I watertight doors.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... STABILITY SPECIAL RULES PERTAINING TO VESSEL USE School Ships § 173.057 Permitted locations for Class I watertight doors. (a) Class I doors are permitted in any location on a sailing school vessel which has a mean... 46 Shipping 7 2013-10-01 2013-10-01 false Permitted locations for Class I watertight doors. 173...

  19. 46 CFR 173.057 - Permitted locations for Class I watertight doors.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... STABILITY SPECIAL RULES PERTAINING TO VESSEL USE School Ships § 173.057 Permitted locations for Class I watertight doors. (a) Class I doors are permitted in any location on a sailing school vessel which has a mean... 46 Shipping 7 2011-10-01 2011-10-01 false Permitted locations for Class I watertight doors. 173...

  20. 46 CFR 173.057 - Permitted locations for Class I watertight doors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... STABILITY SPECIAL RULES PERTAINING TO VESSEL USE School Ships § 173.057 Permitted locations for Class I watertight doors. (a) Class I doors are permitted in any location on a sailing school vessel which has a mean... 46 Shipping 7 2010-10-01 2010-10-01 false Permitted locations for Class I watertight doors. 173...

  1. 46 CFR 173.057 - Permitted locations for Class I watertight doors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... STABILITY SPECIAL RULES PERTAINING TO VESSEL USE School Ships § 173.057 Permitted locations for Class I watertight doors. (a) Class I doors are permitted in any location on a sailing school vessel which has a mean... 46 Shipping 7 2014-10-01 2014-10-01 false Permitted locations for Class I watertight doors. 173...

  2. 46 CFR 173.057 - Permitted locations for Class I watertight doors.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... STABILITY SPECIAL RULES PERTAINING TO VESSEL USE School Ships § 173.057 Permitted locations for Class I watertight doors. (a) Class I doors are permitted in any location on a sailing school vessel which has a mean... 46 Shipping 7 2012-10-01 2012-10-01 false Permitted locations for Class I watertight doors. 173...

  3. Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells.

    PubMed

    Nakajima, Nakako Izumi; Niimi, Atsuko; Isono, Mayu; Oike, Takahiro; Sato, Hiro; Nakano, Takashi; Shibata, Atsushi

    2017-08-01

    Immunotherapy is expected to be promising as a next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such levels of ligand expression are not effectively recognized by the native immune system due to tumor microenvironmental adaptation. Studies have demonstrated that natural-killer group 2, member D (NKG2D), a major activating immunoreceptor, responds to DNA damage. The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) (members of NKG2D ligands) expression after DNA damage is associated with NK cell-mediated killing of cancer cells. However, the regulation of DNA damage-induced MICA/B expression has not been fully elucidated in the context of the types of cancer cell lines. In the present study, we found that MICA/B expression varied between cancer cell lines after DNA damage. Screening in terms of chromatin remodeling identified that inhibitors related to chromatin relaxation via post-translational modification on histone H3K9, i.e. HDAC, Suv39 or G9a inhibition, restored DNA damage-dependent MICA/B expression in insensitive cells. In addition, we revealed that the restored MICA/B expression was dependent on ATR as well as E2F1, a transcription factor. We further revealed that low‑dose treatment of an HDAC inhibitor was sufficient to restore MICA/B expression in insensitive cells. Finally, we demonstrated that HDAC inhibition restored DNA damage‑dependent cytotoxic NK activity against insensitive cells. Thus, the present study revealed that DNA damage‑dependent MICA/B expression in insensitive cancer cells can be restored by chromatin relaxation via the HDAC/Suv39/G9a pathway. Collectively, manipulation of chromatin status by therapeutic cancer drugs may potentiate the antitumor effect by enhancing immune activation following radiotherapy and DNA damage-associated chemotherapy.

  4. KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand with a Bw6 Motif

    PubMed Central

    Colantonio, Arnaud D.; Bimber, Benjamin N.; Neidermyer, William J.; Reeves, R. Keith; Alter, Galit; Altfeld, Marcus; Johnson, R. Paul; Carrington, Mary; O'Connor, David H.; Evans, David T.

    2011-01-01

    Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05+ macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets. PMID:21423672

  5. Structure-activity relationships in cytotoxic Au(I)/Au(III) complexes derived from 2-(2'-pyridyl)benzimidazole.

    PubMed

    Maiore, Laura; Aragoni, Maria Carla; Deiana, Carlo; Cinellu, Maria Agostina; Isaia, Francesco; Lippolis, Vito; Pintus, Anna; Serratrice, Maria; Arca, Massimiliano

    2014-04-21

    Gold(I) and gold(III) complexes derived from 2-(2'-pyridyl)benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV-vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au(III) complexes [(pbi)AuX2] (X = Cl (1), AcO (2)), the four mononuclear Au(I) derivatives [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)]PF6 ((4(+))(PF6(-))), [(pbi)Au(PPh3)] (5), and [(pbi)Au(TPA)] (6), the three mixed-valence Au(III)/Au(I) complexes [(μ-pbi)Au2Cl3] (7), [(Ph3P)Au(μ-pbi)AuX2]PF6 (X = Cl ((8(+))(PF6(-))), AcO ((9(+))(PF6(-)))), and the binuclear Au(I)-Au(I) compound [(μ-pbi)Au2(PPh3)2]PF6 ((10(+))(PF6(-))). All complexes feature irreversible reduction processes related to the Au(III)/Au(I) or Au(I)/Au(0) processes and peculiar luminescent emission at about 360-370 nm in CH2Cl2, with quantum yields that are remarkably lower ((0.7-14.5) × 10(-2)) in comparison to that determined for the free pbiH ligand (31.5 × 10(-2)) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH2Cl2 implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn-Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure-activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs.

  6. 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.

    PubMed

    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.

  7. Selective inhibition of deactivated mitochondrial complex I by biguanides.

    PubMed

    Matsuzaki, Satoshi; Humphries, Kenneth M

    2015-03-24

    Biguanides are widely used antihyperglycemic agents for diabetes mellitus and prediabetes treatment. Complex I is the rate-limiting step of the mitochondrial electron transport chain (ETC), a major source of mitochondrial free radical production, and a known target of biguanides. Complex I has two reversible conformational states, active and de-active. The deactivated state is promoted in the absence of substrates but is rapidly and fully reversed to the active state in the presence of NADH. The objective of this study was to determine the relative sensitivity of active/de-active complex I to biguanide-mediated inhibition and resulting superoxide radical (O₂(•⁻)) production. Using isolated rat heart mitochondria, we show that deactivation of complex I sensitizes it to metformin and phenformin (4- and 3-fold, respectively), but not to other known complex I inhibitors, such as rotenone. Mitochondrial O₂(•⁻) production by deactivated complex I was measured fluorescently by NADH-dependent 2-hydroxyethidium formation at alkaline pH to impede reactivation. Superoxide production was 260.4% higher than in active complex I at pH 9.4. However, phenformin treatment of de-active complex I decreased O₂(•⁻) production by 14.9%, while rotenone increased production by 42.9%. Mitochondria isolated from rat hearts subjected to cardiac ischemia, a condition known to induce complex I deactivation, were sensitized to phenformin-mediated complex I inhibition. This supports the idea that the effects of biguanides are likely to be influenced by the complex I state in vivo. These results demonstrate that the complex I active and de-active states are a determinant in biguanide-mediated inhibition.

  8. MHC class I loci of the Bar-Headed goose (Anser indicus)

    PubMed Central

    2010-01-01

    MHC class I proteins mediate functions in anti-pathogen defense. MHC diversity has already been investigated by many studies in model avian species, but here we chose the bar-headed goose, a worldwide migrant bird, as a non-model avian species. Sequences from exons encoding the peptide-binding region (PBR) of MHC class I molecules were isolated from liver genomic DNA, to investigate variation in these genes. These are the first MHC class I partial sequences of the bar-headed goose to be reported. A preliminary analysis suggests the presence of at least four MHC class I genes, which share great similarity with those of the goose and duck. A phylogenetic analysis of bar-headed goose, goose and duck MHC class I sequences using the NJ method supports the idea that they all cluster within the anseriforms clade. PMID:21637434

  9. HLA class I molecules consistently present internal influenza epitopes.

    PubMed

    Wahl, Angela; Schafer, Fredda; Bardet, Wilfried; Buchli, Rico; Air, Gillian M; Hildebrand, William H

    2009-01-13

    Cytotoxic T lymphocytes (CTL) limit influenza virus replication and prevent morbidity and mortality upon recognition of HLA class I presented epitopes on the surface of virus infected cells, yet the number and origin of the viral epitopes that decorate the infected cell are unknown. To understand the presentation of influenza virus ligands by human MHC class I molecules, HLA-B*0702-presented viral peptides were directly identified following influenza infection. After transfection with soluble class I molecules, peptide ligands unique to infected cells were eluted from isolated MHC molecules and identified by comparative mass spectrometry (MS). Then CTL were gathered following infection with influenza and viral peptides were tested for immune recognition. We found that the class I molecule B*0702 presents 3-6 viral ligands following infection with different strains of influenza. Peptide ligands derived from the internal viral nucleoprotein (NP(418-426) and NP(473-481)) and from the internal viral polymerase subunit PB1 (PB1(329-337)) were presented by B*0702 following infection with each of 3 different influenza strains; ligands NP(418-426), NP(473-481), and PB1(329-337) derived from internal viral proteins were consistently revealed by class I HLA. In contrast, ligands derived from hemagglutinin (HA) and matrix protein (M1) were presented intermittently on a strain-by-strain basis. When tested for immune recognition, HLA-B*0702 transgenic mice responded to NP(418-426) and PB1(329-337) consistently and NP(473-481) intermittently while ligands from HA and M1 were not recognized. These data demonstrate an emerging pattern whereby class I HLA reveal a handful of internal viral ligands and whereby CTL recognize consistently presented influenza ligands.

  10. HLA class I molecules consistently present internal influenza epitopes

    PubMed Central

    Wahl, Angela; Schafer, Fredda; Bardet, Wilfried; Buchli, Rico; Air, Gillian M.; Hildebrand, William H.

    2009-01-01

    Cytotoxic T lymphocytes (CTL) limit influenza virus replication and prevent morbidity and mortality upon recognition of HLA class I presented epitopes on the surface of virus infected cells, yet the number and origin of the viral epitopes that decorate the infected cell are unknown. To understand the presentation of influenza virus ligands by human MHC class I molecules, HLA-B*0702-presented viral peptides were directly identified following influenza infection. After transfection with soluble class I molecules, peptide ligands unique to infected cells were eluted from isolated MHC molecules and identified by comparative mass spectrometry (MS). Then CTL were gathered following infection with influenza and viral peptides were tested for immune recognition. We found that the class I molecule B*0702 presents 3–6 viral ligands following infection with different strains of influenza. Peptide ligands derived from the internal viral nucleoprotein (NP418–426 and NP473–481) and from the internal viral polymerase subunit PB1 (PB1329–337) were presented by B*0702 following infection with each of 3 different influenza strains; ligands NP418–426, NP473–481, and PB1329–337 derived from internal viral proteins were consistently revealed by class I HLA. In contrast, ligands derived from hemagglutinin (HA) and matrix protein (M1) were presented intermittently on a strain-by-strain basis. When tested for immune recognition, HLA-B*0702 transgenic mice responded to NP418–426 and PB1329–337 consistently and NP473–481 intermittently while ligands from HA and M1 were not recognized. These data demonstrate an emerging pattern whereby class I HLA reveal a handful of internal viral ligands and whereby CTL recognize consistently presented influenza ligands. PMID:19122146

  11. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class II...

  12. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class II...

  13. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class II...

  14. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class II...

  15. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class II...

  16. Structure of a Class I Tagatose-1,6-bisphosphate Aldolase

    PubMed Central

    LowKam, Clotilde; Liotard, Brigitte; Sygusch, Jurgen

    2010-01-01

    Tagatose-1,6-bisphosphate aldolase from Streptococcus pyogenes is a class I aldolase that exhibits a remarkable lack of chiral discrimination with respect to the configuration of hydroxyl groups at both C3 and C4 positions. The enzyme catalyzes the reversible cleavage of four diastereoisomers (fructose 1,6-bisphosphate (FBP), psicose 1,6-bisphosphate, sorbose 1,6-bisphosphate, and tagatose 1,6-bisphosphate) to dihydroxyacetone phosphate (DHAP) and d-glyceraldehyde 3-phosphate with high catalytic efficiency. To investigate its enzymatic mechanism, high resolution crystal structures were determined of both native enzyme and native enzyme in complex with dihydroxyacetone-P. The electron density map revealed a (α/β)8 fold in each dimeric subunit. Flash-cooled crystals of native enzyme soaked with dihydroxyacetone phosphate trapped a covalent intermediate with carbanionic character at Lys205, different from the enamine mesomer bound in stereospecific class I FBP aldolase. Structural analysis indicates extensive active site conservation with respect to class I FBP aldolases, including conserved conformational responses to DHAP binding and conserved stereospecific proton transfer at the DHAP C3 carbon mediated by a proximal water molecule. Exchange reactions with tritiated water and tritium-labeled DHAP at C3 hydrogen were carried out in both solution and crystalline state to assess stereochemical control at C3. The kinetic studies show labeling at both pro-R and pro-S C3 positions of DHAP yet detritiation only at the C3 pro-S-labeled position. Detritiation of the C3 pro-R label was not detected and is consistent with preferential cis-trans isomerism about the C2–C3 bond in the carbanion as the mechanism responsible for C3 epimerization in tagatose-1,6-bisphosphate aldolase. PMID:20427286

  17. HLA class I associations with EBV+ post-transplant lymphoproliferative disorder.

    PubMed

    Jones, Kimberley; Wockner, Leesa; Thornton, Alycia; Gottlieb, David; Ritchie, David S; Seymour, John F; Kumarasinghe, Gayathri; Gandhi, Maher K

    2015-03-01

    Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation. Copyright © 2015. Published by Elsevier B.V.

  18. Complex I-complex II ratio strongly differs in various organs of Arabidopsis thaliana.

    PubMed

    Peters, Katrin; Niessen, Markus; Peterhänsel, Christoph; Späth, Bettina; Hölzle, Angela; Binder, Stefan; Marchfelder, Anita; Braun, Hans-Peter

    2012-06-01

    In most studies, amounts of protein complexes of the oxidative phosphorylation (OXPHOS) system in different organs or tissues are quantified on the basis of isolated mitochondrial fractions. However, yield of mitochondrial isolations might differ with respect to tissue type due to varying efficiencies of cell disruption during organelle isolation procedures or due to tissue-specific properties of organelles. Here we report an immunological investigation on the ratio of the OXPHOS complexes in different tissues of Arabidopsis thaliana which is based on total protein fractions isolated from five Arabidopsis organs (leaves, stems, flowers, roots and seeds) and from callus. Antibodies were generated against one surface exposed subunit of each of the five OXPHOS complexes and used for systematic immunoblotting experiments. Amounts of all complexes are highest in flowers (likewise with respect to organ fresh weight or total protein content of the flower fraction). Relative amounts of protein complexes in all other fractions were determined with respect to their amounts in flowers. Our investigation reveals high relative amounts of complex I in green organs (leaves and stems) but much lower amounts in non-green organs (roots, callus tissue). In contrast, complex II only is represented by low relative amounts in green organs but by significantly higher amounts in non-green organs, especially in seeds. In fact, the complex I-complex II ratio differs by factor 37 between callus and leaf, indicating drastic differences in electron entry into the respiratory chain in these two fractions. Variation in amounts concerning complexes III, IV and V was less pronounced in different Arabidopsis tissues (quantification of complex V in leaves was not meaningful due to a cross-reaction of the antibody with the chloroplast form of this enzyme). Analyses were complemented by in gel activity measurements for the protein complexes of the OXPHOS system and comparative 2D blue native/SDS PAGE

  19. A novel role of HLA class I in the pathology of medulloblastoma.

    PubMed

    Smith, Courtney; Santi, Mariarita; Rajan, Bhargavi; Rushing, Elisabeth J; Choi, Mi Rim; Rood, Brian R; Cornelison, Robert; MacDonald, Tobey J; Vukmanovic, Stanislav

    2009-07-12

    MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma. We investigated expression of four essential components of MHC class I (heavy chain, beta2m, TAP1 and TAP2) in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro. The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of beta2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells. MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or beta2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility.

  20. Techniques to improve the direct ex vivo detection of low frequency antigen-specific CD8+ T cells with peptide-major histocompatibility complex class I tetramers

    PubMed Central

    Chattopadhyay, Pratip K.; Melenhorst, J. Joseph; Ladell, Kristin; Gostick, Emma; Scheinberg, Philip; Barrett, A. John; Wooldridge, Linda; Roederer, Mario; Sewell, Andrew K.; Price, David A.

    2008-01-01

    The ability to quantify and characterize antigen-specific CD8+ T cells irrespective of functional readouts using fluorochrome-conjugated tetrameric peptide-MHC class I (pMHCI) complexes in conjunction with flow cytometry has transformed our understanding of cellular immune responses over the past decade. In the case of prevalent CD8+ T cell populations that engage cognate pMHCI tetramers with high avidities, direct ex vivo identification and subsequent data interpretation is relatively straightforward. However, the accurate identification of low frequency antigen-specific CD8+ T cell populations can be complicated, especially in situations where TCR-mediated tetramer binding occurs at low avidities. Here, we highlight a few simple techniques that can be employed to improve the visual resolution, and hence the accurate quantification, of tetramer-binding CD8+ T cell populations by flow cytometry. These methodological modifications enhance signal intensity, especially in the case of specific CD8+ T cell populations that bind cognate antigen with low avidity, minimize background noise and enable improved discrimination of true pMHCI tetramer binding events from nonspecific uptake. PMID:18836993

  1. Association of HLA class I alleles with aloplecia areata in Chinese Hans.

    PubMed

    Xiao, Feng-Li; Yang, Sen; Yan, Kai-lin; Cui, Yong; Liang, Yan-Hua; Zhou, Fu-Sheng; Du, Wen-Hui; Gao, Min; Sun, Liang-Dan; Fan, Xing; Chen, Jian-Jun; Wang, Pei-Guang; Zhu, Ya-Gang; Zhou, Shun-Ming; Zhang, Xue-Jun

    2006-02-01

    Some studies suggested that human HLA status may potentiate development of the AA phenotype and exists ethic differences. No report has been published about HLA class I alleles associated with AA in Chinese Hans. To study the distribution of HLA class I alleles and haplotypes in Chinese Hans AA patients and the relation of HLA class I profile with age of onset, severity, duration of current attack, past history and family history. The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA class I alleles in 192 patients with AA and 252 healthy controls in Chinese Hans. The frequencies of HLA-A*02, -A*03, -B*18, -B*27, -B*52 and -Cw*0704 were significantly higher in patients than in controls. The A*2-B*18, A*2-B*27, A*2-B*52, A*2-Cw*0704, B*18-Cw*0704, B*27-Cw*0704, B*52-Cw*0704 were found as high-risk haplotypes in developing AA in this study. The HLA-A*02 and -A*03 were observed increased frequencies in patients less than 50% hair loss, and HLA-B*27 equally in patients of 50-99% hair loss, alopecia totalis and alopecia universalis. The frequencies of HLA-A*02 and -B*27 were significantly raised in recurrent patients, and ones of HLA-A*02, -A*03 and -B*27 similarly in patients without a positive family history. This study demonstrated the positive association of HLA class I alleles and haplotypes with AA. There may be differences in genetic background in patients with different age of onset, grade of scalp hair loss, duration of current attack, a past history and a family history.

  2. Class I ADP-Ribosylation Factors Are Involved in Enterovirus 71 Replication

    PubMed Central

    Wang, Jianmin; Du, Jiang; Jin, Qi

    2014-01-01

    Enterovirus 71 is one of the major causative agents of hand, foot, and mouth disease in infants and children. Replication of enterovirus 71 depends on host cellular factors. The viral replication complex is formed in novel, cytoplasmic, vesicular compartments. It has not been elucidated which cellular pathways are hijacked by the virus to create these vesicles. Here, we investigated whether proteins associated with the cellular secretory pathway were involved in enterovirus 71 replication. We used a loss-of-function assay, based on small interfering RNA. We showed that enterovirus 71 RNA replication was dependent on the activity of Class I ADP-ribosylation factors. Simultaneous depletion of ADP-ribosylation factors 1 and 3, but not three others, inhibited viral replication in cells. We also demonstrated with various techniques that the brefeldin-A-sensitive guanidine nucleotide exchange factor, GBF1, was critically important for enterovirus 71 replication. Our results suggested that enterovirus 71 replication depended on GBF1-mediated activation of Class I ADP-ribosylation factors. These results revealed a connection between enterovirus 71 replication and the cellular secretory pathway; this pathway may represent a novel target for antiviral therapies. PMID:24911624

  3. An MHC class I immune evasion gene of Marek׳s disease virus.

    PubMed

    Hearn, Cari; Preeyanon, Likit; Hunt, Henry D; York, Ian A

    2015-01-15

    Marek׳s disease virus (MDV) is a widespread α-herpesvirus of chickens that causes T cell tumors. Acute, but not latent, MDV infection has previously been shown to lead to downregulation of cell-surface MHC class I (Virology 282:198-205 (2001)), but the gene(s) involved have not been identified. Here we demonstrate that an MDV gene, MDV012, is capable of reducing surface expression of MHC class I on chicken cells. Co-expression of an MHC class I-binding peptide targeted to the endoplasmic reticulum (bypassing the requirement for the TAP peptide transporter) partially rescued MHC class I expression in the presence of MDV012, suggesting that MDV012 is a TAP-blocking MHC class I immune evasion protein. This is the first unique non-mammalian MHC class I immune evasion gene identified, and suggests that α-herpesviruses have conserved this function for at least 100 million years. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    PubMed

    Parasar, Parveen; Wilhelm, Amanda; Rutigliano, Heloisa M; Thomas, Aaron J; Teng, Lihong; Shi, Bi; Davis, William C; Suarez, Carlos E; New, Daniel D; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-classical MHC-I isoforms, we expressed the MHC proteins in murine P815 and human K562 (MHC-I deficient) cells. Following antibiotic selection, stably transfected cell lines were stained with H1A or W6/32 antibodies to detect expression of the MHC-I proteins by flow cytometry. Two non-classical proteins (BoLA-NC1*00501 and BoLA-NC3*00101) were expressed on the cell surface in both cell lines. Surprisingly, the BoLA-NC4*00201 protein was expressed on the cell membrane of human K562 but not mouse P815 cells. Two non-classical proteins (BoLA-NC1*00401, which lacks a transmembrane domain, and BoLA-NC2*00102) did not exhibit cell surface expression. Nevertheless, Western blot analyses demonstrated expression of the MHC-I heavy chain in all transfected cell lines. Ammonium-sulfate precipitation of proteins from culture supernatants showed that BoLA-NC1*00401 was secreted and that all surface expressed proteins where shed from the cell membrane by the transfected cells. Interestingly, the surface expressed MHC-I proteins were present in culture supernatants at a much higher concentration than BoLA-NC1*00401. This comprehensive study shows that bovine non-classical MHC-I proteins BoLA-NC1*00501, BoLA-NC3*00101, and BoLA-NC4*00201 are expressed as surface isoforms with the latter reaching the cell membrane only in K562 cells. Furthermore, it demonstrated that BoLA-NC1*00401 is a secreted isoform and that significant quantities of membrane associated MHC-I proteins can be shed from the cell membrane. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. In vivo immunologic selection of class I major histocompatibility complex gene deletion variants from the B16-BL6 melanoma.

    PubMed

    Talmadge, J E; Talmadge, C B; Zbar, B; McEwen, R; Meeker, A K; Tribble, H

    1987-06-01

    The mechanism by which tumor allografts escape host immunologic attack was investigated. B16-BL6 cells (the bladder 6 subline of the B16 melanoma) (H-2b) were transfected with a gene (Dd) encoding an allogeneic class I major histocompatibility complex antigen. Clones that expressed Dd antigen were injected into the footpads of nonimmune syngeneic mice, syngeneic immune mice, and nude mice. Under conditions of immunologic selection a clone that contained multiple copies of the transfected gene formed variants that lacked the transfected gene. Primary tumors and pulmonary metastases of immunized mice and pulmonary metastases of nonimmunized mice had lost the Dd gene and, in most cases, all of the associated plasmid. In contrast, in immunodeficient nude mice, primary tumors and pulmonary metastases retained the Dd gene and the associated plasmid. Deletion of genes encoding cell surface antigens may be one of the mechanisms by which allogeneic tumors escape immunologic attack.

  6. HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection.

    PubMed

    McAulay, Karen A; Higgins, Craig D; Macsween, Karen F; Lake, Annette; Jarrett, Ruth F; Robertson, Faye L; Williams, Hilary; Crawford, Dorothy H

    2007-10-01

    Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence.

  7. HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

    PubMed Central

    McAulay, Karen A.; Higgins, Craig D.; Macsween, Karen F.; Lake, Annette; Jarrett, Ruth F.; Robertson, Faye L.; Williams, Hilary; Crawford, Dorothy H.

    2007-01-01

    Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence. PMID:17909631

  8. MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

    PubMed Central

    Nelson, P. Austin; Sage, Jennifer R.; Wood, Suzanne C.; Davenport, Christopher M.; Anagnostaras, Stephan G.; Boulanger, Lisa M.

    2013-01-01

    Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In β2m−/−TAP−/−mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of β2m−/−TAP−/−mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain. PMID:23959708

  9. A novel role of HLA class I in the pathology of medulloblastoma

    PubMed Central

    Smith, Courtney; Santi, Mariarita; Rajan, Bhargavi; Rushing, Elisabeth J; Choi, Mi Rim; Rood, Brian R; Cornelison, Robert; MacDonald, Tobey J; Vukmanovic, Stanislav

    2009-01-01

    Background MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma. Methods We investigated expression of four essential components of MHC class I (heavy chain, β2m, TAP1 and TAP2) in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro. Results The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of β2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells. Conclusion MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or β2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility. PMID:19594892

  10. NetMHCstab – predicting stability of peptide–MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery

    PubMed Central

    Jørgensen, Kasper W; Rasmussen, Michael; Buus, Søren; Nielsen, Morten

    2014-01-01

    Major histocompatibility complex class I (MHC-I) molecules play an essential role in the cellular immune response, presenting peptides to cytotoxic T lymphocytes (CTLs) allowing the immune system to scrutinize ongoing intracellular production of proteins. In the early 1990s, immunogenicity and stability of the peptide–MHC-I (pMHC-I) complex were shown to be correlated. At that time, measuring stability was cumbersome and time consuming and only small data sets were analysed. Here, we investigate this fairly unexplored area on a large scale compared with earlier studies. A recent small-scale study demonstrated that pMHC-I complex stability was a better correlate of CTL immunogenicity than peptide–MHC-I affinity. We here extended this study and analysed a total of 5509 distinct peptide stability measurements covering 10 different HLA class I molecules. Artificial neural networks were used to construct stability predictors capable of predicting the half-life of the pMHC-I complex. These predictors were shown to predict T-cell epitopes and MHC ligands from SYFPEITHI and IEDB to form significantly more stable MHC-I complexes compared with affinity-matched non-epitopes. Combining the stability predictions with a state-of-the-art affinity predictions NetMHCcons significantly improved the performance for identification of T-cell epitopes and ligands. For the HLA alleles included in the study, we could identify distinct sub-motifs that differentiate between stable and unstable peptide binders and demonstrate that anchor positions in the N-terminal of the binding motif (primarily P2 and P3) play a critical role for the formation of stable pMHC-I complexes. A webserver implementing the method is available at http://www.cbs.dtu.dk/services/NetMHCstab. PMID:23927693

  11. Up-regulation of MHC class I in transgenic mice results in reduced force-generating capacity in slow-twitch muscle

    PubMed Central

    Salomonsson, Stina; Grundtman, Cecilia; Zhang, Shi-Jin; Lanner, Johanna T.; Li, Charles; Katz, Abram; Wedderburn, Lucy R.; Nagaraju, Kanneboyina; Lundberg, Ingrid E.; Westerblad, Håkan

    2008-01-01

    Expression of major histocompatibility complex (MHC) class I in skeletal muscle fibers is an early and consistent finding in inflammatory myopathies. To test if MHC class I has a primary role in muscle impairment; we used transgenic mice with inducible over-expression of MHC class I in their skeletal muscle cells. Contractile function was studied in isolated extensor digitorum longus (EDL, fast-twitch) and soleus (slow-twitch) muscles. We found that EDL was smaller, whereas soleus muscle was slightly larger. Both muscles generated less absolute force in myopathic compared to control mice, however when force was expressed per cross-sectional area, only soleus muscle generated less force. Inflammation was markedly increased, but no changes were found in the activities of key mitochondrial and glycogenolytic enzymes in myopathic mice. The induction of MHC class I results in muscle atrophy and an intrinsic decrease in force-generation capacity. These observations may have important implications for our understanding of the pathophysiological processes of muscle weakness seen in inflammatory myopathies. PMID:19229963

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

    PubMed Central

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

    1989-01-01

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

  13. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  14. Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion

    PubMed Central

    Aune, Sverre E.; Herr, Daniel J.; Mani, Santhosh K.; Menick, Donald R.

    2014-01-01

    While inhibition of class I/IIb histone deacetylases (HDACs) protects the mammalian heart from ischemia reperfusion (IR) injury, class selective effects remain unexamined. We hypothesized that selective inhibition of class I HDACs would preserve left ventricular contractile function following IR in isolated hearts. Male Sprague Dawley rats (n=6 per group) were injected with vehicle (dimethylsulfoxide, 0.63 mg/kg), the class I/IIb HDAC inhibitor trichostatin A (1 mg/kg), the class I HDAC inhibitor entinostat (MS-275, 10 mg/kg), or the HDAC6 (class IIb) inhibitor tubastatin A (10 mg/kg). After 24 h, hearts were isolated and perfused in Langendorff mode for 30 min (Sham) or subjected to 30 min global ischemia and 120 min global reperfusion (IR). A saline filled balloon attached to a pressure transducer was placed in the LV to monitor contractile function. After perfusion, LV tissue was collected for measurements of antioxidant protein levels and infarct area. At the conclusion of IR, MS-275 pretreatment was associated with significant preservation of developed pressure, rate of pressure generation, rate of pressure relaxation and rate pressure product, as compared to vehicle treated hearts. There was significant reduction of infarct area with MS-275 pretreatment. Contractile function was not significantly restored in hearts treated with trichostatin A or tubastatin A. Mitochondrial superoxide dismutase (SOD2) and catalase protein and mRNA in hearts from animals pretreated with MS-275 were increased following IR, as compared to Sham. This was associated with a dramatic enrichment of nuclear FOXO3a transcription factor, which mediates the expression of SOD2 and catalase. Tubastatin A treatment was associated with significantly decreased catalase levels after IR. Class I HDAC inhibition elicits protection of contractile function following IR, which is associated with increased expression of endogenous antioxidant enzymes. Class I/IIb HDAC inhibition with trichostatin A

  15. The effects of forehead and neck position on esthetics of class I, II and III profiles.

    PubMed

    Salehi, Parisa; Oshagh, Morteza; Aleyasin, Zeinab S; Pakshir, Hamid Reza

    2014-01-01

    All parts of the face, other than jaw relationships, should be considered in orthodontic treatment planning. The role of forehead and neck in facial esthetics is well known; however, the majority of conventional facial analysis methods have not considered them. Neck and forehead may confer mutual effects on equilibrium and on esthetics of other facial components, and may change the overall convexity/concavity view of the profile. Therefore, the aim of this study was to assess the effect of anteroposterior position of the forehead and neck on the esthetics of skeletal class I, II and III jaw relationships using profile silhouettes. Class II and III jaw relationships were constructed on the silhouette of a class I normal profile by altering the mandibular position. Retruded, normal and protruded positions were also applied for the forehead and neck. Three hundred Iranian laypeople (150 men, 150 women) scored the esthetics of profile silhouettes from 1 to 7. Half of the participants were told to consider the profiles as a man, and the other half were told to consider them as a woman. Data were analyzed using non-parametric methods. Class I jaw relation was found to be the most beautiful profile followed by class II and III respectively. Esthetics of different positions of the neck and forehead were significantly different (P < 0.05). In subjects with a normal neck and forehead position, and those with a retruded neck, the best esthetic relationship was class I, and the worst was class III. For protruded foreheads, the best jaw relationship was class II for females and class I for males, and the worst was class III for both. In a retruded forehead position, the most preferred jaw relationship was class I, and the worst was class II. For profiles with a protruded neck, the best esthetics was found to be in class III jaw relationship, and the worst was in class II. There was a small difference in scoring for male and female profiles (P < 0.05); there were also small

  16. Differences in antigen presentation to MHC class I-and class II- restricted influenza virus-specific cytolytic T lymphocyte clones

    PubMed Central

    1986-01-01

    We have examined requirements for antigen presentation to a panel of MHC class I-and class II-restricted, influenza virus-specific CTL clones by controlling the form of virus presented on the target cell surface. Both H-2K/D- and I region-restricted CTL recognize target cells exposed to infectious virus, but only the I region-restricted clones efficiently lysed histocompatible target cells pulsed with inactivated virus preparations. The isolated influenza hemagglutinin (HA) polypeptide also could sensitize target cells for recognition by class II-restricted, HA-specific CTL, but not by class I-restricted, HA- specific CTL. Inhibition of nascent viral protein synthesis abrogated the ability of target cells to present viral antigen relevant for class I-restricted CTL recognition. Significantly, presentation for class II- restricted recognition was unaffected in target cells exposed to preparations of either inactivated or infectious virus. This differential sensitivity suggested that these H-2I region-restricted CTL recognized viral polypeptides derived from the exogenously introduced virions, rather than viral polypeptides newly synthesized in the infected cell. In support of this contention, treatment of the target cells with the lysosomotropic agent chloroquine abolished recognition of infected target cells by class II-restricted CTL without diminishing class I-restricted recognition of infected target cells. Furthermore, when the influenza HA gene was introduced into target cells without exogenous HA polypeptide, the target cells that expressed the newly synthesized protein product of the HA gene were recognized only by H-2K/D-restricted CTL. These observations suggest that important differences may exist in requirements for antigen presentation between H-2K/D and H-2I region-restricted CTL. These differences may reflect the nature of the antigenic epitopes recognized by these two CTL subsets. PMID:3485173

  17. 46 CFR 108.173 - Class I, Division 2 locations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... m (10 ft.) of a possible source of gas release; or (3) Within 1.5 m (5 ft.) of the boundaries of any...) Within 1.5 m (5 ft.) of a semi-enclosed Class I, Division 1 location indicated in § 108.171(b); or (2) Within 1.5 m (5 ft.) of a Class I, Division 1 space indicated in § 108.171(e). (d) A semi-enclosed area...

  18. 46 CFR 108.173 - Class I, Division 2 locations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... m (10 ft.) of a possible source of gas release; or (3) Within 1.5 m (5 ft.) of the boundaries of any...) Within 1.5 m (5 ft.) of a semi-enclosed Class I, Division 1 location indicated in § 108.171(b); or (2) Within 1.5 m (5 ft.) of a Class I, Division 1 space indicated in § 108.171(e). (d) A semi-enclosed area...

  19. 46 CFR 108.173 - Class I, Division 2 locations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... m (10 ft.) of a possible source of gas release; or (3) Within 1.5 m (5 ft.) of the boundaries of any...) Within 1.5 m (5 ft.) of a semi-enclosed Class I, Division 1 location indicated in § 108.171(b); or (2) Within 1.5 m (5 ft.) of a Class I, Division 1 space indicated in § 108.171(e). (d) A semi-enclosed area...

  20. 46 CFR 108.173 - Class I, Division 2 locations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... m (10 ft.) of a possible source of gas release; or (3) Within 1.5 m (5 ft.) of the boundaries of any...) Within 1.5 m (5 ft.) of a semi-enclosed Class I, Division 1 location indicated in § 108.171(b); or (2) Within 1.5 m (5 ft.) of a Class I, Division 1 space indicated in § 108.171(e). (d) A semi-enclosed area...

  1. MHC class I loaded ligands from breast cancer cell lines: A potential HLA-I-typed antigen collection

    PubMed Central

    Rozanov, Dmitri V.; Rozanov, Nikita D.; Chiotti, Kami; Reddy, Ashok; Wilmarth, Phillip A.; David, Larry L.; Cha, Seung W.; Woo, Sunghee; Pevzner, Pavel; Bafna, Vineet; Burrows, Gregory G.; Rantala, Juha K.; Levin, Trevor; Anur, Pavana; Johnson-Camacho, Katie; Tabatabaei, Shaadi; Munson, Daniel J.; Bruno, Tullia C.; Slansky, Jill E.; Kappler, John W.; Hirano, Naoto; Boegel, Sebastian; Fox, Bernard A.; Egelston, Colt; Simons, Diana L.; Jimenez, Grecia; Lee, Peter P.; Gray, Joe W.; Spellman, Paul T.

    2018-01-01

    Breast cancer therapy based on amplifying a patient’s antitumor immune response depends on the availability of appropriate MHC class I-restricted, breast cancer-specific epitopes. To build a catalog of peptides presented by breast cancer cells, we undertook systematic MHC class I immunoprecipitation followed by elution of MHC class I-loaded peptides in breast cancer cell lines. We determined the sequence of 3,196 MHC class I-bound peptides representing 1,921 proteins from a panel of 20 breast cancer cell lines including basal, luminal, and claudin-low subtypes. The data has been deposited to the ProteomeXchange with identifier PXD006406. After removing duplicate peptides, i.e., the same peptide eluted from more than one cell line, the total number of unique peptides was 2,740. Of the unique peptides eluted, more than 1,750 had been previously identified, and of these, sixteen have been shown to be immunogenic. Importantly, only 3 of these immunogenic peptides have been identified in breast cancer cells in earlier studies. MHC class I binding probability of eluted peptides was used to plot the distribution of MHC class I allele-specific peptides in accordance with the binding score for each breast cancer cell line. We also determined that the tested breast cancer cells presented 89 mutation-containing peptides and peptides derived from aberrantly translated genes, 7 of which were shared between four or two different cell lines. Overall, the high throughput identification of MHC class I-loaded peptides is an effective strategy for systematic characterization of cancer peptides, and could be employed for design of multi-peptide anticancer vaccines. PMID:29331515

  2. Genomic localization of the human gene encoding Dr1, a negative modulator of transcription of class II and class III genes.

    PubMed

    Purrello, M; Di Pietro, C; Rapisarda, A; Viola, A; Corsaro, C; Motta, S; Grzeschik, K H; Sichel, G

    1996-01-01

    Dr1 is a nuclear protein of 19 kDa that exists in the nucleoplasm as a homotetramer. By binding to TBP (the DNA-binding subunit of TFIID, and also a subunit of SL1 and TFIIIB), the protein blocks class II and class III preinitiation complex assembly, thus repressing the activity of the corresponding promoters. Since transcription of class I genes is unaffected by Dr1. it has been proposed that the protein may coordinate the expression of class I, class II and class III genes. By somatic cell genetics and fluorescence in situ hybridization, we have localized the gene (DR1), present in the genome of higher eukaryotes as a single copy, to human chromosome region 1p21-->p13. The nucleotide sequence conservation of the coding segment of the gene, as determined by Noah's ark blot analysis, and its ubiquitous transcription suggest that Dr1 has an important biological role, which could be related to the negative control of cell proliferation.

  3. Ethnic Related Selection for an ADH Class I Variant within East Asia

    PubMed Central

    Li, Hui; Gu, Sheng; Cai, Xiaoyun; Speed, William C.; Pakstis, Andrew J.; Golub, Efim I.; Kidd, Judith R.; Kidd, Kenneth K.

    2008-01-01

    Background The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region. Methodology/Principal Findings Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best. Conclusions/Significance The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region

  4. Ethnic related selection for an ADH Class I variant within East Asia.

    PubMed

    Li, Hui; Gu, Sheng; Cai, Xiaoyun; Speed, William C; Pakstis, Andrew J; Golub, Efim I; Kidd, Judith R; Kidd, Kenneth K

    2008-04-02

    The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region. Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best. The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B diversities

  5. Somatic HLA Mutations Expose the Role of Class I-Mediated Autoimmunity in Aplastic Anemia and its Clonal Complications.

    PubMed

    Babushok, Daria V; Duke, Jamie L; Xie, Hongbo M; Stanley, Natasha; Atienza, Jamie; Perdigones, Nieves; Nicholas, Peter; Ferriola, Deborah; Li, Yimei; Huang, Hugh; Ye, Wenda; Morrissette, Jennifer J D; Kearns, Jane; Porter, David L; Podsakoff, Gregory M; Eisenlohr, Laurence C; Biegel, Jaclyn A; Chou, Stella T; Monos, Dimitrios S; Bessler, Monica; Olson, Timothy S

    2017-10-10

    Acquired aplastic anemia (aAA) is an acquired deficiency of early hematopoietic cells, characterized by inadequate blood production, and a predisposition to myelodysplastic syndrome (MDS) and leukemia. Although its exact pathogenesis is unknown, aAA is thought to be driven by Human Leukocyte Antigen (HLA)-restricted T cell immunity, with earlier studies favoring HLA class II-mediated pathways. Using whole exome sequencing (WES), we recently identified two aAA patients with somatic mutations in HLA class I genes. We hypothesized that HLA class I mutations are pathognomonic for autoimmunity in aAA, but were previously underappreciated because the Major Histocompatibility Complex (MHC) region is notoriously difficult to analyze by WES. Using a combination of targeted deep sequencing of HLA class I genes and single nucleotide polymorphism array (SNP-A) genotyping we screened 66 aAA patients for somatic HLA class I loss. We found somatic HLA loss in eleven patients (17%), with thirteen loss-of-function mutations in HLA-A *33:03, HLA-A *68:01, HLA-B *14:02 and HLA-B *40:02 alleles. Three patients had more than one mutation targeting the same HLA allele. Interestingly, HLA-B *14:02 and HLA-B *40:02 were significantly overrepresented in aAA patients, compared to ethnicity-matched controls. Patients who inherited the targeted HLA alleles, regardless of HLA mutation status, had a more severe disease course with more frequent clonal complications as assessed by WES, SNP-A, and metaphase cytogenetics, and more frequent secondary MDS. The finding of recurrent HLA class I mutations provides compelling evidence for a predominant HLA class I-driven autoimmunity in aAA, and establishes a novel link between aAA patients' immunogenetics and clonal evolution.

  6. Selective Inhibition of Deactivated Mitochondrial Complex I by Biguanides †

    PubMed Central

    Matsuzaki, Satoshi; Humphries, Kenneth M.

    2015-01-01

    Biguanides are widely used antihyperglycemic agents for diabetes mellitus and prediabetes treatment. Complex I is the rate limiting step of the mitochondrial electron transport chain (ETC), a major source of mitochondrial free radical production, and a known target of biguanides. Complex I has two reversible conformational states, active and de-active. The deactivated state is promoted in the absence of substrates, but is rapidly and fully reversed to the active state in the presence of NADH. The objective of this study was to determine the relative sensitivity of active/de-active complex I to biguanide-mediated inhibition and resulting superoxide radical (O2•−) production. Using isolated rat heart mitochondria, we show that deactivation of complex I sensitizes it to metformin and phenformin (4- and 3-fold, respectively), but not to other known complex I inhibitors, such as rotenone. Mitochondrial O2•− production by deactivated complex I was measured fluorescently by the NADH-dependent 2-hydroxyethidium formation at alkaline pH to impede reactivation. Superoxide production was 260.4% higher than in active complex I at pH 9.4. However, phenformin treatment of de-active complex I decreased O2•− production by 14.9% while rotenone increased production by 42.9%. Mitochondria isolated from rat hearts subjected to cardiac ischemia, a condition known to induce complex I deactivation, were sensitized to phenformin:mediated complex I inhibition. This supports that the effects of biguanides are likely to be influenced by the complex I state in vivo. These results demonstrate that the complex I active/de-active states are a determinant in biguanide-mediated inhibition. PMID:25719498

  7. Characterization of MHC class I and II genes in a subantarctic seabird, the blue petrel, Halobaena caerulea (Procellariiformes).

    PubMed

    Strandh, Maria; Lannefors, Mimi; Bonadonna, Francesco; Westerdahl, Helena

    2011-10-01

    The great polymorphism observed in the major histocompatibility complex (MHC) genes is thought to be maintained by pathogen-mediated selection possibly combined with MHC-disassortative mating, guided by MHC-determined olfactory cues. Here, we partly characterize the MHC class I and II B of the blue petrel, Halobaena caerulea (Procellariiformes), a bird with significant olfactory abilities that lives under presumably low pathogen burdens in Subantarctica. Blue petrels are long-lived, monogamous birds which suggest the necessity of an accurate mate choice process. The species is ancestral to songbirds (Passeriformes; many MHC loci), although not to gamefowls (Galliformes; few MHC loci). Considering the phylogenetic relationships and the low subantarctic pathogen burden, we expected few rather than many MHC loci in the blue petrel. However, when we analysed partial MHC class I and class II B cDNA and gDNA sequences we found evidence for as many as at least eight MHC class I loci and at least two class II B loci. These class I and II B sequences showed classical MHC characteristics, e.g. high nucleotide diversity, especially in putative peptide-binding regions where signatures of positive selection was detected. Trans-species polymorphism was found between MHC class II B sequences of the blue petrel and those of thin-billed prion, Pachyptila belcheri, two species that diverged ∼25 MYA. The observed MHC allele richness in the blue petrel may well serve as a basis for mate choice, especially since olfactory discrimination of MHC types may be possible in this species.

  8. The Total Gaussian Class of Quasiprobabilities and its Relation to Squeezed-State Excitations

    NASA Technical Reports Server (NTRS)

    Wuensche, Alfred

    1996-01-01

    The class of quasiprobabilities obtainable from the Wigner quasiprobability by convolutions with the general class of Gaussian functions is investigated. It can be described by a three-dimensional, in general, complex vector parameter with the property of additivity when composing convolutions. The diagonal representation of this class of quasiprobabilities is connected with a generalization of the displaced Fock states in direction of squeezing. The subclass with real vector parameter is considered more in detail. It is related to the most important kinds of boson operator ordering. The properties of a specific set of discrete excitations of squeezed coherent states are given.

  9. 49 CFR 369.4 - Annual reports of Class I carriers of passengers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Annual reports of Class I carriers of passengers. 369.4 Section 369.4 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS REPORTS OF MOTOR CARRIERS § 369.4 Annual...

  10. Dynamics of the Major Histocompatibility Complex Class I Processing and Presentation Pathway in the Course of Malaria Parasite Development in Human Hepatocytes: Implications for Vaccine Development

    PubMed Central

    Ma, Jinxia; Trop, Stefanie; Baer, Samantha; Rakhmanaliev, Elian; Arany, Zita; Dumoulin, Peter; Zhang, Hao; Romano, Julia; Coppens, Isabelle; Levitsky, Victor; Levitskaya, Jelena

    2013-01-01

    Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver. PMID:24086507

  11. Patterns of genetic differentiation at MHC class I genes and microsatellites identify conservation units in the giant panda.

    PubMed

    Zhu, Ying; Wan, Qiu-Hong; Yu, Bin; Ge, Yun-Fa; Fang, Sheng-Guo

    2013-10-22

    Evaluating patterns of genetic variation is important to identify conservation units (i.e., evolutionarily significant units [ESUs], management units [MUs], and adaptive units [AUs]) in endangered species. While neutral markers could be used to infer population history, their application in the estimation of adaptive variation is limited. The capacity to adapt to various environments is vital for the long-term survival of endangered species. Hence, analysis of adaptive loci, such as the major histocompatibility complex (MHC) genes, is critical for conservation genetics studies. Here, we investigated 4 classical MHC class I genes (Aime-C, Aime-F, Aime-I, and Aime-L) and 8 microsatellites to infer patterns of genetic variation in the giant panda (Ailuropoda melanoleuca) and to further define conservation units. Overall, we identified 24 haplotypes (9 for Aime-C, 1 for Aime-F, 7 for Aime-I, and 7 for Aime-L) from 218 individuals obtained from 6 populations of giant panda. We found that the Xiaoxiangling population had the highest genetic variation at microsatellites among the 6 giant panda populations and higher genetic variation at Aime-MHC class I genes than other larger populations (Qinling, Qionglai, and Minshan populations). Differentiation index (FST)-based phylogenetic and Bayesian clustering analyses for Aime-MHC-I and microsatellite loci both supported that most populations were highly differentiated. The Qinling population was the most genetically differentiated. The giant panda showed a relatively higher level of genetic diversity at MHC class I genes compared with endangered felids. Using all of the loci, we found that the 6 giant panda populations fell into 2 ESUs: Qinling and non-Qinling populations. We defined 3 MUs based on microsatellites: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. We also recommended 3 possible AUs based on MHC loci: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. Furthermore, we recommend

  12. Polymorphisms and Tissue Expression of the Feline Leukocyte Antigen Class I Loci FLAI-E, -H and -K

    PubMed Central

    Holmes, Jennifer C.; Holmer, Savannah G.; Ross, Peter; Buntzman, Adam S.; Frelinger, Jeffrey A.; Hess, Paul R.

    2013-01-01

    Cytotoxic CD8+ T-cell immunosurveillance for intracellular pathogens, such as viruses, is controlled by classical major histocompatibility complex (MHC) class Ia molecules, and ideally, these antiviral T-cell populations are defined by the specific peptide and restricting MHC allele. Surprisingly, despite the utility of the cat in modeling human viral immunity, little is known about the Feline Leukocyte Antigen class I complex (FLAI). Only a few coding sequences with uncertain locus origin and expression patterns have been reported. Of 19 class I genes, 3 loci - FLAI-E, -H and -K – are predicted to encode classical molecules, and our objective was to evaluate their status by analyzing polymorphisms and tissue expression. Using locus-specific, PCR-based genotyping, we amplified 33 FLAI-E, -H, and -K alleles from 12 cats of various breeds, identifying, for the first time, alleles across 3 distinct loci in a feline species. Alleles shared the expected polymorphic and invariant sites in the α1/α2 domains, and full-length cDNA clones possessed all characteristic class Ia exons. Alleles could be assigned to a specific locus with reasonable confidence, although there was evidence of potentially confounding interlocus recombination between FLAI-E and -K. Only FLAI-E, -H and -K-origin alleles were amplified from cDNAs of multiple tissue types. We also defined hypervariable regions across these genes, which permitted the assignment of names to both novel and established alleles. As predicted, FLAI-E, -H, and -K fulfill the major criteria of class Ia genes. These data represent a necessary prerequisite for studying epitope-specific antiviral CD8+ T-cell responses in cats. PMID:23812210

  13. A Latent Class Analysis of Weight-Related Health Behaviors among 2-and 4-Year College Students and Associated Risk of Obesity

    ERIC Educational Resources Information Center

    Mathur, Charu; Stigler, Melissa; Lust, Katherine; Laska, Melissa

    2014-01-01

    Little is known about the complex patterning of weight-related health behaviors in 2-and 4-year college students. The objective of this study was to identify and describe unique classes of weight-related health behaviors among college students. Latent class analysis was used to identify homogenous, mutually exclusive classes of nine health…

  14. Arginine (Di)methylated Human Leukocyte Antigen Class I Peptides Are Favorably Presented by HLA-B*07.

    PubMed

    Marino, Fabio; Mommen, Geert P M; Jeko, Anita; Meiring, Hugo D; van Gaans-van den Brink, Jacqueline A M; Scheltema, Richard A; van Els, Cécile A C M; Heck, Albert J R

    2017-01-06

    Alterations in protein post-translational modification (PTM) are recognized hallmarks of diseases. These modifications potentially provide a unique source of disease-related human leukocyte antigen (HLA) class I-presented peptides that can elicit specific immune responses. While phosphorylated HLA peptides have already received attention, arginine methylated HLA class I peptide presentation has not been characterized in detail. In a human B-cell line we detected 149 HLA class I peptides harboring mono- and/or dimethylated arginine residues by mass spectrometry. A striking preference was observed in the presentation of arginine (di)methylated peptides for HLA-B*07 molecules, likely because the binding motifs of this allele resemble consensus sequences recognized by arginine methyl-transferases. Moreover, HLA-B*07-bound peptides preferentially harbored dimethylated groups at the P3 position, thus consecutively to the proline anchor residue. Such a proline-arginine sequence has been associated with the arginine methyl-transferases CARM1 and PRMT5. Making use of the specific neutral losses in fragmentation spectra, we found most of the peptides to be asymmetrically dimethylated, most likely by CARM1. These data expand our knowledge of the processing and presentation of arginine (di)methylated HLA class I peptides and demonstrate that these types of modified peptides can be presented for recognition by T-cells. HLA class I peptides with mono- and dimethylated arginine residues may therefore offer a novel target for immunotherapy.

  15. Bap31 enhances the ER export and quality control of human class I MHC molecules

    PubMed Central

    Ladasky, John J.; Boyle, Sarah; Seth, Malini; Li, Hewang; Pentcheva, Tsvetelina; Abe, Fumiyoshi; Steinberg, Steven J.; Edidin, Michael

    2006-01-01

    The assembly of class I MHC molecules and their export from the endoplasmic reticulum is governed by chaperones and accessory proteins. We present evidence that the putative cargo receptor protein Bap31 participates in the transport and the quality control of human class I molecules. Transfection of the human adenocarcinoma cell line HeLa with YFP-Bap31 chimeras increased surface levels of class I in a dose-dependent manner, by as much as 3.7-fold. The increase in surface class I resulted from an increase in the rate of export of newly-synthesized class I molecules to the cell surface and from an increase in the stability of the exported molecules. We propose that Bap31 performs quality control on class I molecules in two distinct phases: first, by exporting peptide-loaded class I molecules to the ERGIC and second, by retrieving class I molecules which have lost peptides in the acidic post-ER environment. This function of Bap31 is conditional or redundant, since we find that Bap31 deficiency does not reduce surface class I levels. Overexpression of the Bap31 homolog, Bap29, decreases surface class levels in HeLa, indicating that it does not substitute for Bap31. PMID:17056546

  16. The antiporter-like subunit constituent of the universal adaptor of complex I, group 4 membrane-bound [NiFe]-hydrogenases and related complexes.

    PubMed

    Batista, Ana P; Marreiros, Bruno C; Pereira, Manuela M

    2013-05-01

    We have recently investigated the long-recognized relationship between complex I and group 4 [NiFe] hydrogenases and we have established the so-called Energy-converting hydrogenase related (Ehr) complex as a new member of the family. We have also observed that four subunits, homologues to NuoB, D, H and L, are common to the members of the family. We have designated this common group of subunits the universal adaptor. Taking into account the similarity of the Na(+)/H(+) antiporter-like subunits of complex I (NuoL, NuoM and NuoN) and the unique structural characteristic of the long amphipathic α helix part of NuoL, the nature of the antiporter-like subunit of the universal adaptor was questioned. Thus, in this work we further explore the properties of the universal adaptor, investigating which antiporter-like subunit is part of the universal adaptor. We observe that the universal adaptor contains an antiporter-like subunit with a long amphipathic α helix, similar to NuoL. Consequently, the long helix is a common denominator that has been conserved in all members of the family. Such conservation surely reflects the key role of such helix in the energy transduction mechanism of this family of enzymes.

  17. Repression of class I transcription by cadmium is mediated by the protein phosphatase 2A

    PubMed Central

    Zhou, Lei; Le Roux, Gwenaëlle; Ducrot, Cécile; Chédin, Stéphane; Labarre, Jean; Riva, Michel; Carles, Christophe

    2013-01-01

    Toxic metals are part of our environment, and undue exposure to them leads to a variety of pathologies. In response, most organisms adapt their metabolism and have evolved systems to limit this toxicity and to acquire tolerance. Ribosome biosynthesis being central for protein synthesis, we analyzed in yeast the effects of a moderate concentration of cadmium (Cd2+) on Pol I transcription that represents >60% of the transcriptional activity of the cells. We show that Cd2+ rapidly and drastically shuts down the expression of the 35S rRNA. Repression does not result from a poisoning of any of the components of the class I transcriptional machinery by Cd2+, but rather involves a protein phosphatase 2A (PP2A)-dependent cellular signaling pathway that targets the formation/dissociation of the Pol I–Rrn3 complex. We also show that Pol I transcription is repressed by other toxic metals, such as Ag+ and Hg2+, which likewise perturb the Pol I–Rrn3 complex, but through PP2A-independent mechanisms. Taken together, our results point to a central role for the Pol I–Rrn3 complex as molecular switch for regulating Pol I transcription in response to toxic metals. PMID:23640330

  18. Performance of exhaust-protective (class I) biological 'safety' cabinets.

    PubMed Central

    Newsom, S W

    1979-01-01

    Nineteen open-fronted (class I) safety cabinets were subjected to spore containment and airflow tests, which suggested that a flow of 0.75 m/s was the minimum required for safe operation; further tests on three of the cabinets were repeated at different air speeds and confirmed this. The airflow is required to overcome the effect of laboratory or external air currents. Contamination of surfaces (including the operator's hands) by aerosols liberated inside the cabinets was investigated and found to depend more on turbulence within the cabinet (as from a restricted front opening) than on the number of air changes. The findings suggest that the product protection provided by a well-designed class I cabinet might equal that of a class II (laminar flow) unit. Images Fig. 6 PMID:469014

  19. Facial attractiveness of skeletal class I and class II malocclusion as perceived by laypeople, patients and clinicians.

    PubMed

    Pace, Michela; Cioffi, Iacopo; D'antò, Vincenzo; Valletta, Alessandra; Valletta, Rosa; Amato, Massimo

    2018-06-01

    Physical attractiveness is dependent on facial appearance. The facial profile plays a crucial role in facial attractiveness and can be improved with orthodontic treatment. The aesthetic assessment of facial appearance may be influenced by the cultural background and education of the assessor and dependent upon the experience level of dental professionals. This study aimed to evaluate how the sagittal jaw relationship in Class I and Class II individuals affects facial attractiveness, and whether the assessor's professional education and background affect the perception of facial attractiveness. Facial silhouettes simulating mandibular retrusion, maxillary protrusion, mandibular retrusion combined with maxillary protrusion, bimaxillary protrusion and severe bimaxillary protrusion in class I and class II patients were assessed by five groups of people with different backgrounds and education levels (i.e., 23 expert orthodontists, 21 orthodontists, 15 maxillofacial surgeons, 19 orthodontic patients and 28 laypeople). Straight facial profiles were judged to be more attractive than convex profiles due to severe mandibular retrusion and to mandibular retrusion combined with maxillary protrusion (all P<0.05). Convex profiles due to a slightly retruded position of the mandible were judged less attractive by clinicians than by patients and laypeople (all P<0.05). Convex facial profiles are less attractive than Class I profiles. The assessment of facial attractiveness is dependent on the assessor's education and background. Laypeople and patients are considerably less sensitive to abnormal sagittal jaw relationships than orthodontists.

  20. Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro.

    PubMed

    Phumyen, Achara; Jantasorn, Siriporn; Jumnainsong, Amonrat; Leelayuwat, Chanvit

    2014-01-01

    Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain-related A (MICA) in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC) chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox) on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC) and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82%) could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage) remained the binding activity against MICA. Dox-phage was more efficient than free drugs in killing all the cell lines tested. The half maximal inhibitory concentration (IC50) values of Dox-phage were lower than those of free drugs at approximately 1.6-6 times depending on MICA expressions and the cell lines tested. Evidently, the application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide chemistry is effective to conjugate doxorubicin and major coat protein of bacteriophages without destroying binding activity of MICA antibodies. Dox-carrying bacteriophages targeting MICA have been

  1. Academic Achievement Differences between Title I Students Enrolled in Music Classes and Title I Students Who Are Not

    ERIC Educational Resources Information Center

    McDaniel, Brian

    2011-01-01

    Purpose. The purpose of the study was to determine academic achievement differences between those Title I students enrolled in music classes and Title I students who are not enrolled in music classes. A second purpose was to determine educators' perceptions regarding the educational justice implications of excluding nonproficient Title I students…

  2. Availability of endogenous peptides limits expression of an M3a-Ld major histocompatibility complex class I chimera

    PubMed Central

    1994-01-01

    Taking advantage of our understanding of the peptide specificity of the major histocompatibility complex class I-b molecule M3a, we sought to determine why these molecules are poorly represented on the cell surface. To this end we constructed a chimeric molecule with the alpha 1 and alpha 2 domains of M3a and alpha 3 of Ld thereby allowing use of available monoclonal antibodies to quantify surface expression. Transfected, but not control, B10.CAS2 (H-2M3b) cells were lysed readily by M3a-restricted monoclonal cytotoxic T lymphocytes. Thus, the chimera bound, trafficked, and presented endogenous mitochondrial peptides. However, despite high levels of M3a-Ld mRNA, transfectants were negative by surface staining. This finding was consistent with inefficient trafficking to the cell surface. Incubation at 26 degrees C, thought to permit trafficking of unoccupied heavy (H) chains, resulted in detectable cell surface expression of chimeric molecules. Incubation with exogenous peptide at 26 degrees C (but not at 37 degrees C) greatly enhanced expression of M3a-Ld molecules in a dose- dependent manner, suggesting stabilization of unoccupied molecules. Stable association of beta 2-microglobulin with the chimeric H chain was observed in labeled cell lysates only in the presence of exogenous specific peptide, indicating that peptide is required for the formation of a ternary complex. These results indicate that surface expression of M3a-Ld is limited largely by the steady-state availability of endogenous peptides. Since most known M3a-binding peptides are N- formylated, native M3a may normally be expressed at high levels only during infection by intracellular bacteria. PMID:8270862

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

    PubMed

    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.

  4. Anteroposterior condylar position: a comparative study between subjects with normal occlusion and patients with Class I, Class II Division 1, and Class III malocclusions.

    PubMed

    Fraga, Marcelo Reis; Rodrigues, Andréia Fialho; Ribeiro, Luiz Claudio; Campos, Marcio José da Silva; Vitral, Robert Willer Farinazzo

    2013-10-29

    The present study aimed to determine and compare the anteroposterior position of the condyle in the mandibular fossa between groups of asymptomatic subjects with normal occlusion and asymptomatic subjects with Class I, Class II Division 1, and Class III malocclusions. Thirty persons with normal occlusion, 30 with Class I malocclusion, 30 with Class II Division 1, and 30 with Class III had computed tomography scans of their temporomandibular joints. The anterior joint space/posterior joint space (AJS/PJS) ratio was determined for the right and left joints. The paired t test was used to analyze the AJS/PJS ratio between both sides for each group. The ANOVA test was applied to verify the differences between the groups for the measurements of the right and left sides. In case the ANOVA test confirmed significance, the Dunnett's t test was performed to compare the groups of malocclusion with that of normal occlusion. The paired t test between the AJS/PJS relationships in the right and left sides showed the following p values: Class I (0.168), Class II Division 1 (0.662), Class III (0.991), and normal occlusion (0.390). The ANOVA test showed a p value of 0.445 for the comparisons of the right side and 0.040 for the left side. The Dunnett's t test demonstrated a statistically significant difference between the Class II group and the normal occlusion group (p value of 0.026) in the joints of the left side. Bilateral symmetry and lack of condyle centralization were common characteristics among all groups. The greatest condylar decentralization was observed in the Class II group, whereas the least condylar decentralization was found in the normal occlusion group.

  5. P-I class metalloproteinase from Bothrops moojeni venom is a post-proline cleaving peptidase with kininogenase activity: insights into substrate selectivity and kinetic behavior.

    PubMed

    Okamoto, Débora N; Kondo, Marcia Y; Oliveira, Lilian C G; Honorato, Rodrigo V; Zanphorlin, Leticia M; Coronado, Monika A; Araújo, Mariana S; da Motta, Guacyara; Veronez, Camila L; Andrade, Sheila S; Oliveira, Paulo S L; Arni, Raghuvir K; Cintra, Adelia C O; Sampaio, Suely V; Juliano, Maria A; Juliano, Luiz; Murakami, Mário T; Gouvea, Iuri E

    2014-03-01

    Snake venom metalloproteinases (SVMPs) belonging to P-I class are able to hydrolyze extracellular matrix proteins and coagulation factors triggering local and systemic reactions by multiple molecular mechanisms that are not fully understood. BmooMPα-I, a P-I class SMVP from Bothrops moojeni venom, was active upon neuro- and vaso-active peptides including angiotensin I, bradykinin, neurotensin, oxytocin and substance P. Interestingly, BmooMPα-I showed a strong bias towards hydrolysis after proline residues, which is unusual for most of characterized peptidases. Moreover, the enzyme showed kininogenase activity similar to that observed in plasma and cells by kallikrein. FRET peptide assays indicated a relative promiscuity at its S2-S'2 subsites, with proline determining the scissile bond. This unusual post-proline cleaving activity was confirmed by the efficient hydrolysis of the synthetic combinatorial library MCA-GXXPXXQ-EDDnp, described as resistant for canonical peptidases, only after Pro residues. Structural analysis of the tripeptide LPL complexed with BmooMPα-I, generated by molecular dynamics simulations, assisted in defining the subsites and provided the structural basis for subsite preferences such as the restriction of basic residues at the S2 subsite due to repulsive electrostatic effects and the steric impediment for large aliphatic or aromatic side chains at the S1 subsite. These new functional and structural findings provided a further understanding of the molecular mechanisms governing the physiological effects of this important class of enzymes in envenomation process. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding

    PubMed Central

    Chappell, Paul E; Meziane, El Kahina; Harrison, Michael; Magiera, Łukasz; Hermann, Clemens; Mears, Laura; Wrobel, Antoni G; Durant, Charlotte; Nielsen, Lise Lotte; Buus, Søren; Ternette, Nicola; Mwangi, William; Butter, Colin; Nair, Venugopal; Ahyee, Trudy; Duggleby, Richard; Madrigal, Alejandro; Roversi, Pietro; Lea, Susan M; Kaufman, Jim

    2015-01-01

    Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We report that breadth of peptide presentation and level of cell surface expression of class I molecules are inversely correlated in both chickens and humans. This relationship correlates with protective responses against infectious pathogens including Marek's disease virus leading to lethal tumours in chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose that differences in peptide binding repertoire define two groups of MHC class I molecules strategically evolved as generalists and specialists for different modes of pathogen resistance. We suggest that differences in cell surface expression level ensure the development of optimal peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently a fundamental property of MHC molecules, with ramifications extending beyond immunology and medicine to evolutionary biology and conservation. DOI: http://dx.doi.org/10.7554/eLife.05345.001 PMID:25860507

  7. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles

    PubMed Central

    Lucena, M. Isabel; Molokhia, Mariam; Shen, Yufeng; Urban, Thomas J.; Aithal, Guruprasad P.; Andrade, Raúl J.; Day, Christopher P.; Ruiz-Cabello, Francisco; Donaldson, Peter T.; Stephens, Camilla; Pirmohamed, Munir; Romero-Gomez, Manuel; Navarro, Jose Maria; Fontana, Robert J.; Miller, Michael; Groome, Max; Bondon-Guitton, Emmanuelle; Conforti, Anita; Stricker, Bruno H. C.; Carvajal, Alfonso; Ibanez, Luisa; Yue, Qun-Ying; Eichelbaum, Michel; Floratos, Aris; Pe’er, Itsik; Daly, Mark J.; Goldstein, David B.; Dillon, John F.; Nelson, Matthew R.; Watkins, Paul B.; Daly, Ann K.

    2011-01-01

    Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values. PMID:21570397

  8. CIITA promoter I CARD-deficient mice express functional MHC class II genes in myeloid and lymphoid compartments.

    PubMed

    Zinzow-Kramer, W M; Long, A B; Youngblood, B A; Rosenthal, K M; Butler, R; Mohammed, A-U-R; Skountzou, I; Ahmed, R; Evavold, B D; Boss, J M

    2012-06-01

    Three distinct promoters control the master regulator of major histocompatibility complex (MHC) class II expression, class II transactivator (CIITA), in a cell type-specific manner. Promoter I (pI) CIITA, expressed primarily by dendritic cells (DCs) and macrophages, expresses a unique isoform that contains a caspase-recruitment domain (CARD). The activity and function of this isoform are not understood, but are believed to enhance the function of CIITA in antigen-presenting cells. To determine whether isoform I of CIITA has specific functions, CIITA mutant mice were created in which isoform I was replaced with isoform III sequences. Mice in which pI and the CARD-encoding exon were deleted were also created. No defect in the formation of CD4 T cells, the ability to respond to a model antigen or bacterial or viral challenge was observed in mice lacking CIITA isoform I. Although CIITA and MHC-II expression was decreased in splenic DCs, pI knockout animals expressed CIITA from downstream promoters, suggesting that control of pI activity is mediated by unknown distal elements that could act at pIII, the B-cell promoter. Thus, no critical function is linked to the CARD domain of CIITA isoform I with respect to basic immune system development, function and challenge.

  9. Using complex auditory-visual samples to produce emergent relations in children with autism.

    PubMed

    Groskreutz, Nicole C; Karsina, Allen; Miguel, Caio F; Groskreutz, Mark P

    2010-03-01

    Six participants with autism learned conditional relations between complex auditory-visual sample stimuli (dictated words and pictures) and simple visual comparisons (printed words) using matching-to-sample training procedures. Pre- and posttests examined potential stimulus control by each element of the complex sample when presented individually and emergence of additional conditional relations and oral labeling. Tests revealed class-consistent performance for all participants following training.

  10. Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India.

    PubMed

    Alter, Andrea; Huong, Nguyen Thu; Singh, Meenakshi; Orlova, Marianna; Van Thuc, Nguyen; Katoch, Kiran; Gao, Xiaojiang; Thai, Vu Hong; Ba, Nguyen Ngoc; Carrington, Mary; Abel, Laurent; Mehra, Narinder; Alcaïs, Alexandre; Schurr, Erwin

    2011-05-01

    Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10⁻⁹)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10⁻⁷ and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.

  11. Human Leukocyte Antigen Class I Region Single-Nucleotide Polymorphisms are Associated with Leprosy Susceptibility in Vietnam and India

    PubMed Central

    Alter, Andrea; Huong, Nguyen Thu; Singh, Meenakshi; Orlova, Marianna; Van Thuc, Nguyen; Katoch, Kiran; Gao, Xiaojiang; Thai, Vu Hong; Ba, Nguyen Ngoc; Carrington, Mary; Abel, Laurent; Mehra, Narinder; Alcaïs, Alexandre

    2011-01-01

    Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10−9)—rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10−7 and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis. PMID:21459816

  12. Dental cavity liners for Class I and Class II resin-based composite restorations.

    PubMed

    Schenkel, Andrew B; Peltz, Ivy; Veitz-Keenan, Analia

    2016-10-25

    Resin-based composite (RBC) is currently accepted as a viable material for the restoration of caries for posterior permanent teeth requiring surgical treatment. Despite the fact that the thermal conductivity of the RBC restorative material closely approximates that of natural tooth structure, postoperative hypersensitivity is sometimes still an issue. Dental cavity liners have historically been used to protect the pulp from the toxic effects of some dental restorative materials and to prevent the pain of thermal conductivity by placing an insulating layer between restorative material and the remaining tooth structure. The objective of this review was to assess the effects of using dental cavity liners in the placement of Class I and Class II resin-based composite posterior restorations in permanent teeth in children and adults. Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 25 May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library (searched 25 May 2016), MEDLINE Ovid (1946 to 25 May 2016), Embase Ovid (1980 to 25 May 2016) and LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 25 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. We included randomized controlled trials assessing the effects of the use of liners under Class I and Class II posterior resin-based composite restorations in permanent teeth (in both adults and children). We included both parallel and split-mouth designs. We utilized standard methodological procedures prescribed by Cochrane for data collection and analysis. Two review authors screened the search results and assessed the eligibility of studies for

  13. Class dependency of fuzzy relational database using relational calculus and conditional probability

    NASA Astrophysics Data System (ADS)

    Deni Akbar, Mohammad; Mizoguchi, Yoshihiro; Adiwijaya

    2018-03-01

    In this paper, we propose a design of fuzzy relational database to deal with a conditional probability relation using fuzzy relational calculus. In the previous, there are several researches about equivalence class in fuzzy database using similarity or approximate relation. It is an interesting topic to investigate the fuzzy dependency using equivalence classes. Our goal is to introduce a formulation of a fuzzy relational database model using the relational calculus on the category of fuzzy relations. We also introduce general formulas of the relational calculus for the notion of database operations such as ’projection’, ’selection’, ’injection’ and ’natural join’. Using the fuzzy relational calculus and conditional probabilities, we introduce notions of equivalence class, redundant, and dependency in the theory fuzzy relational database.

  14. The insecticide target in the PSST subunit of complex I.

    PubMed

    Schuler, F; Casida, J E

    2001-10-01

    Current insecticides have been selected by sifting and winnowing hundreds of thousands of synthetic chemicals and natural products to obtain commercial preparations of optimal effectiveness and safety. This process has often ended up with compounds of high potency as inhibitors of the electron transport chain and more specifically of complex I (NADH:ubiquinone oxidoreductase). Many classes of chemicals are involved and the enzyme is one of the most complicated known, with 43 subunits catalyzing electron transfer from NADH to ubiquinone through flavin mononucleotide and up to eight iron-sulfur clusters. We used a potent photoaffinity ligand, (trifluoromethyl)diazirinyl[3H]pyridaben, to localize the insecticide target to a single high-affinity site in the PSST subunit that couples electron transfer from iron-sulfur cluster N2 to ubiquinone. Most importantly, all of the potent complex I-inhibiting pesticides, despite their great structural diversity, compete for this same specific binding domain in PSST. Finding their common mode of action and target provides insight into shared toxicological features and potential selection for resistant pests.

  15. Potential future impacts on visual air quality for Class I areas

    Treesearch

    Gurule Nochumson; Mona J. Wecksung

    1979-01-01

    Visual air quality is most sensitive to degradation by air pollution in areas with good visibility. The protection of visual air quality in mandatory Class I Federal areas has been declared a national goal by Congress. Impacts on visual air quality are calculated for 154 Class I areas where visual air quality is considered an important value. These impacts are...

  16. Alveolar bone thickness and lower incisor position in skeletal Class I and Class II malocclusions assessed with cone-beam computed tomography

    PubMed Central

    Ucar, Faruk Izzet; Buyuk, Suleyman Kutalmis; Ozer, Torun; Uysal, Tancan

    2013-01-01

    Objective To evaluate lower incisor position and bony support between patients with Class II average- and high-angle malocclusions and compare with the patients presenting Class I malocclusions. Methods CBCT records of 79 patients were divided into 2 groups according to sagittal jaw relationships: Class I and II. Each group was further divided into average- and high-angle subgroups. Six angular and 6 linear measurements were performed. Independent samples t-test, Kruskal-Wallis, and Dunn post-hoc tests were performed for statistical comparisons. Results Labial alveolar bone thickness was significantly higher in Class I group compared to Class II group (p = 0.003). Lingual alveolar bone angle (p = 0.004), lower incisor protrusion (p = 0.007) and proclination (p = 0.046) were greatest in Class II average-angle patients. Spongious bone was thinner (p = 0.016) and root apex was closer to the labial cortex in high-angle subgroups when compared to the Class II average-angle subgroup (p = 0.004). Conclusions Mandibular anterior bony support and lower incisor position were different between average- and high-angle Class II patients. Clinicians should be aware that the range of lower incisor movement in high-angle Class II patients is limited compared to average- angle Class II patients. PMID:23814708

  17. Alveolar bone thickness and lower incisor position in skeletal Class I and Class II malocclusions assessed with cone-beam computed tomography.

    PubMed

    Baysal, Asli; Ucar, Faruk Izzet; Buyuk, Suleyman Kutalmis; Ozer, Torun; Uysal, Tancan

    2013-06-01

    To evaluate lower incisor position and bony support between patients with Class II average- and high-angle malocclusions and compare with the patients presenting Class I malocclusions. CBCT records of 79 patients were divided into 2 groups according to sagittal jaw relationships: Class I and II. Each group was further divided into average- and high-angle subgroups. Six angular and 6 linear measurements were performed. Independent samples t-test, Kruskal-Wallis, and Dunn post-hoc tests were performed for statistical comparisons. Labial alveolar bone thickness was significantly higher in Class I group compared to Class II group (p = 0.003). Lingual alveolar bone angle (p = 0.004), lower incisor protrusion (p = 0.007) and proclination (p = 0.046) were greatest in Class II average-angle patients. Spongious bone was thinner (p = 0.016) and root apex was closer to the labial cortex in high-angle subgroups when compared to the Class II average-angle subgroup (p = 0.004). Mandibular anterior bony support and lower incisor position were different between average- and high-angle Class II patients. Clinicians should be aware that the range of lower incisor movement in high-angle Class II patients is limited compared to average- angle Class II patients.

  18. Lower incisor dentoalveolar compensation and symphysis dimensions among Class I and III malocclusion patients with different facial vertical skeletal patterns.

    PubMed

    Molina-Berlanga, Núria; Llopis-Perez, Jaume; Flores-Mir, Carlos; Puigdollers, Andreu

    2013-11-01

    To compare lower incisor dentoalveolar compensation and mandible symphysis morphology among Class I and Class III malocclusion patients with different facial vertical skeletal patterns. Lower incisor extrusion and inclination, as well as buccal (LA) and lingual (LP) cortex depth, and mandibular symphysis height (LH) were measured in 107 lateral cephalometric x-rays of adult patients without prior orthodontic treatment. In addition, malocclusion type (Class I or III) and facial vertical skeletal pattern were considered. Through a principal component analysis (PCA) related variables were reduced. Simple regression equation and multivariate analyses of variance were also used. Incisor mandibular plane angle (P < .001) and extrusion (P  =  .03) values showed significant differences between the sagittal malocclusion groups. Variations in the mandibular plane have a negative correlation with LA (Class I P  =  .03 and Class III P  =  .01) and a positive correlation with LH (Class I P  =  .01 and Class III P  =  .02) in both groups. Within the Class III group, there was a negative correlation between the mandibular plane and LP (P  =  .02). PCA showed that the tendency toward a long face causes the symphysis to elongate and narrow. In Class III, alveolar narrowing is also found in normal faces. Vertical facial pattern is a significant factor in mandibular symphysis alveolar morphology and lower incisor positioning, both for Class I and Class III patients. Short-faced Class III patients have a widened alveolar bone. However, for long-faced and normal-faced Class III, natural compensation elongates the symphysis and influences lower incisor position.

  19. Arabidopsis Class I and Class II TCP Transcription Factors Regulate Jasmonic Acid Metabolism and Leaf Development Antagonistically1[C][W

    PubMed Central

    Danisman, Selahattin; van der Wal, Froukje; Dhondt, Stijn; Waites, Richard; de Folter, Stefan; Bimbo, Andrea; van Dijk, Aalt DJ; Muino, Jose M.; Cutri, Lucas; Dornelas, Marcelo C.; Angenent, Gerco C.; Immink, Richard G.H.

    2012-01-01

    TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1 (TCP) transcription factors control developmental processes in plants. The 24 TCP transcription factors encoded in the Arabidopsis (Arabidopsis thaliana) genome are divided into two classes, class I and class II TCPs, which are proposed to act antagonistically. We performed a detailed phenotypic analysis of the class I tcp20 mutant, showing an increase in leaf pavement cell sizes in 10-d-old seedlings. Subsequently, a glucocorticoid receptor induction assay was performed, aiming to identify potential target genes of the TCP20 protein during leaf development. The LIPOXYGENASE2 (LOX2) and class I TCP9 genes were identified as TCP20 targets, and binding of TCP20 to their regulatory sequences could be confirmed by chromatin immunoprecipitation analyses. LOX2 encodes for a jasmonate biosynthesis gene, which is also targeted by class II TCP proteins that are under the control of the microRNA JAGGED AND WAVY (JAW), although in an antagonistic manner. Mutation of TCP9, the second identified TCP20 target, resulted in increased pavement cell sizes during early leaf developmental stages. Analysis of senescence in the single tcp9 and tcp20 mutants and the tcp9tcp20 double mutants showed an earlier onset of this process in comparison with wild-type control plants in the double mutant only. Both the cell size and senescence phenotypes are opposite to the known class II TCP mutant phenotype in JAW plants. Altogether, these results point to an antagonistic function of class I and class II TCP proteins in the control of leaf development via the jasmonate signaling pathway. PMID:22718775

  20. Analysis of class II (hydrolytic) and class I (beta-lyase) apurinic/apyrimidinic endonucleases with a synthetic DNA substrate.

    PubMed Central

    Levin, J D; Demple, B

    1990-01-01

    We have developed simple and sensitive assays that distinguish the main classes of apurinic/apyrimidinic (AP) endonucleases: Class I enzymes that cleave on the 3' side of AP sites by beta-elimination, and Class II enzymes that cleave by hydrolysis on the 5' side. The distinction of the two types depends on the use of a synthetic DNA polymer that contains AP sites with 5'-[32P]phosphate residues. Using this approach, we now show directly that Escherichia coli endonuclease IV and human AP endonuclease are Class II enzymes, as inferred previously on the basis of indirect assays. The assay method does not exhibit significant interference by nonspecific nucleases or primary amines, which allows the ready determination of different AP endonuclease activities in crude cell extracts. In this way, we show that virtually all of the Class II AP endonuclease activity in E. coli can be accounted for by two enzymes: exonuclease III and endonuclease IV. In the yeast Saccharomyces cerevisiae, the Class II AP endonuclease activity is totally dependent on a single enzyme, the Apn1 protein, but there are probably multiple Class I enzymes. The versatility and ease of our approach should be useful for characterizing this important class of DNA repair enzymes in diverse systems. PMID:1698278

  1. Regulation of MHC class I expression by Foxp3 and its effect on Treg cell function

    PubMed Central

    Mu, Jie; Tai, Xuguang; Iyer, Shankar S.; Weissman, Jocelyn D.; Singer, Alfred; Singer, Dinah S.

    2014-01-01

    Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBFβ and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4+CD25+ T regulatory cells than in conventional CD4+CD25− T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell-type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IRE and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4+CD25+ T regulatory cells by enhancing immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function. PMID:24523508

  2. Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules

    PubMed Central

    1992-01-01

    T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin- 1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design. PMID:1316930

  3. Pedagogy of complex relationality exploring complexity theory, neuro-phenomenology, and attentiveness for education

    NASA Astrophysics Data System (ADS)

    Khattar, Randa

    What do the new sciences of complex relationality offer education? This work draws on complexity theory, neurological understandings of biology and phenomenology, and attentiveness to study what the new sciences might offer education and the possibilities of a pedagogical understanding of embodied knowing. Complexity theory provides understandings of local-global relationality, self-organization, far-from-equilibrium conditions, and emergent dynamics that are important for describing pedagogical relationality. In itself, however, complexity theory is lacking an attention to issues of embodiment that respond directly to an ethical understanding of relationality. Phenomenology provides important views on the human experience of perception, for example, Merleau-Ponty's, whose research opens up possibilities for embodiment and attentiveness. At the level of pedagogical practice, I will pose, following biologists Humberto Maturana and Francisco Varela's autopoietic self-making understanding of life, that attentiveness perspectives, which have been largely absent from western pedagogical theory and practice, are crucial to promoting embodied knowing for education. Maturana and Varela's autopoietic perspective offers an embodied understanding of living---and therefore education---which opens up necessary attentive spaces to listen to one another in non judgmental awareness in the present moment of experience. I offer insights into a relationally complex conception of education drawing on this biological and autopoietically-grounded framework. These insights are framed in the context of five clusters of relations: (1) emergence, far-from-equilibrium, and local-global relationality; (2) autopoietic autonomy, structural determination and sensory-motor coupling; (3) triggering perturbations, structural plasticity, and autopoietic organization; (4) knowing as adequate action, domains of interaction, and blind spots; and (5) attentiveness and responsive relationality. Four

  4. MHC class I–specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice

    PubMed Central

    Strait, Richard T.; Hicks, Wyenona; Barasa, Nathaniel; Mahler, Ashley; Khodoun, Marat; Köhl, Jörg; Stringer, Keith; Witte, David; Van Rooijen, Nico; Susskind, Brian M.

    2011-01-01

    Transfusion-related acute lung injury (TRALI), a form of noncardiogenic pulmonary edema that develops during or within 6 h after a blood transfusion, is the most frequent cause of transfusion-associated death in the United States. Because development of TRALI is associated with donor antibodies (Abs) reactive with recipient major histocompatibility complex (MHC), a mouse model has been studied in which TRALI-like disease is caused by injecting mice with anti–MHC class I monoclonal Ab (mAb). Previous publications with this model have concluded that disease is caused by FcR-dependent activation of neutrophils and platelets, with production of reactive oxygen species that damage pulmonary vascular endothelium. In this study, we confirm the role of reactive oxygen species in the pathogenesis of this mouse model of TRALI and show ultrastructural evidence of pulmonary vascular injury within 5 min of anti–MHC class I mAb injection. However, we demonstrate that disease induction in this model involves macrophages rather than neutrophils or platelets, activation of complement and production of C5a rather than activation of FcγRI, FcγRIII, or FcγRIV, and binding of anti–MHC class I mAb to non-BM–derived cells such as pulmonary vascular endothelium. These observations have important implications for the prevention and treatment of TRALI. PMID:22025304

  5. Automated benchmarking of peptide-MHC class I binding predictions.

    PubMed

    Trolle, Thomas; Metushi, Imir G; Greenbaum, Jason A; Kim, Yohan; Sidney, John; Lund, Ole; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

    2015-07-01

    Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto_bench/mhci/join. mniel@cbs.dtu.dk or bpeters@liai.org Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Automated benchmarking of peptide-MHC class I binding predictions

    PubMed Central

    Trolle, Thomas; Metushi, Imir G.; Greenbaum, Jason A.; Kim, Yohan; Sidney, John; Lund, Ole; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

    2015-01-01

    Motivation: Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. Results: The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Availability and implementation: Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto_bench/mhci/join. Contact: mniel@cbs.dtu.dk or bpeters@liai.org Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25717196

  7. Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.

    PubMed

    Tassaneeyakul, Wichittra; Prabmeechai, Napat; Sukasem, Chonlaphat; Kongpan, Thachanan; Konyoung, Parinya; Chumworathayi, Pansu; Tiamkao, Somsak; Khunarkornsiri, Usanee; Kulkantrakorn, Kongkiat; Saksit, Niwat; Nakkam, Nontaya; Satapornpong, Patompong; Vannaprasaht, Suda; Sangviroon, Alisara; Mahasirimongkol, Surakameth; Wichukchinda, Nuanjun; Rerkpattanapipat, Ticha; Tassaneeyakul, Wongwiwat

    2016-05-01

    Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.

  8. 40 CFR 82.12 - Transfers of allowances for class I controlled substances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... § 82.12 Transfers of allowances for class I controlled substances. (a) Inter-company transfers. (1) Until January 1, 1996, for all class I controlled substances, except for Group VI, and until January 1... amount of the transferor's consumption allowances or production allowances, and effective January 1, 1995...

  9. Haemophilus ducreyi Cutaneous Ulcer Strains Are Nearly Identical to Class I Genital Ulcer Strains

    PubMed Central

    Gangaiah, Dharanesh; Webb, Kristen M.; Humphreys, Tricia L.; Fortney, Kate R.; Toh, Evelyn; Tai, Albert; Katz, Samantha S.; Pillay, Allan; Chen, Cheng-Yen; Roberts, Sally A.; Munson, Robert S.; Spinola, Stanley M.

    2015-01-01

    Background Although cutaneous ulcers (CU) in the tropics is frequently attributed to Treponema pallidum subspecies pertenue, the causative agent of yaws, Haemophilus ducreyi has emerged as a major cause of CU in yaws-endemic regions of the South Pacific islands and Africa. H. ducreyi is generally susceptible to macrolides, but CU strains persist after mass drug administration of azithromycin for yaws or trachoma. H. ducreyi also causes genital ulcers (GU) and was thought to be exclusively transmitted by microabrasions that occur during sex. In human volunteers, the GU strain 35000HP does not infect intact skin; wounds are required to initiate infection. These data led to several questions: Are CU strains a new variant of H. ducreyi or did they evolve from GU strains? Do CU strains contain additional genes that could allow them to infect intact skin? Are CU strains susceptible to azithromycin? Methodology/Principal Findings To address these questions, we performed whole-genome sequencing and antibiotic susceptibility testing of 5 CU strains obtained from Samoa and Vanuatu and 9 archived class I and class II GU strains. Except for single nucleotide polymorphisms, the CU strains were genetically almost identical to the class I strain 35000HP and had no additional genetic content. Phylogenetic analysis showed that class I and class II strains formed two separate clusters and CU strains evolved from class I strains. Class I strains diverged from class II strains ~1.95 million years ago (mya) and CU strains diverged from the class I strain 35000HP ~0.18 mya. CU and GU strains evolved under similar selection pressures. Like 35000HP, the CU strains were highly susceptible to antibiotics, including azithromycin. Conclusions/Significance These data suggest that CU strains are derivatives of class I strains that were not recognized until recently. These findings require confirmation by analysis of CU strains from other regions. PMID:26147869

  10. The syntactic complexity of Russian relative clauses

    PubMed Central

    Fedorenko, Evelina; Gibson, Edward

    2012-01-01

    Although syntactic complexity has been investigated across dozens of studies, the available data still greatly underdetermine relevant theories of processing difficulty. Memory-based and expectation-based theories make opposite predictions regarding fine-grained time course of processing difficulty in syntactically constrained contexts, and each class of theory receives support from results on some constructions in some languages. Here we report four self-paced reading experiments on the online comprehension of Russian relative clauses together with related corpus studies, taking advantage of Russian’s flexible word order to disentangle predictions of competing theories. We find support for key predictions of memory-based theories in reading times at RC verbs, and for key predictions of expectation-based theories in processing difficulty at RC-initial accusative noun phrase (NP) objects, which corpus data suggest should be highly unexpected. These results suggest that a complete theory of syntactic complexity must integrate insights from both expectation-based and memory-based theories. PMID:24711687

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

    PubMed

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

    2015-11-01

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

  12. Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.

    PubMed

    Djajadiningrat, Rosa S; Horenblas, Simon; Heideman, Daniëlle A M; Sanders, Joyce; de Jong, Jeroen; Jordanova, Ekaterina S

    2015-04-01

    Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome. We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models. Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival. To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  13. Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch

    PubMed Central

    Blees, Andreas; Reichel, Katrin; Trowitzsch, Simon; Fisette, Olivier; Bock, Christoph; Abele, Rupert; Hummer, Gerhard; Schäfer, Lars V.; Tampé, Robert

    2015-01-01

    Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I. We demonstrate that a single salt bridge in the membrane between the transporter associated with antigen processing TAP and the MHC I-specific chaperone tapasin is essential for the assembly of the PLC and for efficient MHC I antigen presentation. Molecular modeling and all-atom molecular dynamics simulations suggest an ionic lock-switch mechanism for the binding of TAP to tapasin, in which an unfavorable uncompensated charge in the ER-membrane is prevented through complex formation. Our findings not only deepen the understanding of the interaction network within the PLC, but also provide evidence for a general interaction principle of dynamic multiprotein membrane complexes in immunity. PMID:26611325

  14. Frontal Changes in the Lower Face After Clockwise Rotation of the Maxillomandibular Complex Without Perisurgical Orthodontic Treatment in Angle Class I and Skeletal Class III Women.

    PubMed

    Lee, Sang Woo; Cho, Jeongmok; Kim, Kikap; Ahn, Seung Hyun

    2017-06-01

    Orthognathic surgery has become more popular to slenderize a wide lower face and to improve facial esthetics in Asian patients with normal occlusion. Clockwise rotation (CR) of the maxillomandibular complex (MMC) steepens the mandibular plane. This study performed a quantitative analysis on the influence of CR on slenderness of the lower face from the frontal view. This retrospective study included 36 female patients with Angle Class I occlusion and skeletal Class III pattern. The subjects underwent CR of the MMC without perioperative orthodontic treatment and change in the occlusion only for the purpose of esthetic improvement. Linear and angular variables were measured on a cephalogram and three-dimensional computed tomography (3D CT) obtained before and at least 6 months after surgery. Data were analyzed using paired t tests and Spearman correlations. Univariate regression analysis was used to predict the postoperative change according to the amount of posterior impaction. The mean posterior impaction was 3.81 mm. All mandibular plane angle (MPA) measurements were increased (ranged from 5.69° to 13.12°, p < 0.001), exhibiting a significant correlation with the amount of posterior impaction. Bigonial width measurements were decreased after surgery (ranged from 4.97 to 5.51 mm, p < 0.001). Among the MPAs derived from the 3D CT, the coronal projection from the frontal view exhibited a discrepancy between right and left side. The changes in linear and angular measurements in this study indicate that the lower face becomes narrower and more slender as the MMC rotates in a clockwise direction. Orthognathic surgery with CR has the advantage of increasing the MPAs and obtaining natural soft tissue contouring while minimizing the amount of bone resection. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions

  15. Structure and function of three novel MHC class I antigens derived from a C3H ultraviolet-induced fibrosarcoma

    PubMed Central

    1986-01-01

    The UV-induced, C3H fibrosarcoma, 1591, expresses at least three unique MHC class I antigens not found on normal C3H tissue. Here we report the complete DNA sequence of the three novel class I genes encoding these molecules, and describe in detail the recognition of the individual products by tumor-reactive and allospecific CTL. Remarkably, although C3H does not appear to express H-2L locus information, this C3H tumor expresses two distinct antigens, termed A149 and A166, which are extremely homologous to each other and to the H-2Ld antigen from BALB/c. The gene encoding the third novel class I antigen from 1591, A216, is quite homologous to H-2Kk) throughout its 3' end. Since all three of these genes account for polymorphic restriction fragments not found in C3H, it is likely that they were derived by recombination from the endogenous class I genes of C3H. The DNA sequence homology of A149, A166, and H-2Ld is especially significant given the functional conservation observed between the products of these genes. Limited sequence substitutions appear to correlate with some of the discrete serological differences observed between these molecules. In addition, both A149 and A166 crossreact, but to differing extents, with H-2Ld at the level of T cell recognition. Our results are consistent with the view that CTL recognize complex conformational determinants on class I molecules, but extend previous observations by comparing a set of antigens with discrete and overlapping structural and functional differences. PMID:3489061

  16. Adaptive control for a class of nonlinear complex dynamical systems with uncertain complex parameters and perturbations.

    PubMed

    Liu, Jian; Liu, Kexin; Liu, Shutang

    2017-01-01

    In this paper, adaptive control is extended from real space to complex space, resulting in a new control scheme for a class of n-dimensional time-dependent strict-feedback complex-variable chaotic (hyperchaotic) systems (CVCSs) in the presence of uncertain complex parameters and perturbations, which has not been previously reported in the literature. In detail, we have developed a unified framework for designing the adaptive complex scalar controller to ensure this type of CVCSs asymptotically stable and for selecting complex update laws to estimate unknown complex parameters. In particular, combining Lyapunov functions dependent on complex-valued vectors and back-stepping technique, sufficient criteria on stabilization of CVCSs are derived in the sense of Wirtinger calculus in complex space. Finally, numerical simulation is presented to validate our theoretical results.

  17. Adaptive control for a class of nonlinear complex dynamical systems with uncertain complex parameters and perturbations

    PubMed Central

    Liu, Jian; Liu, Kexin; Liu, Shutang

    2017-01-01

    In this paper, adaptive control is extended from real space to complex space, resulting in a new control scheme for a class of n-dimensional time-dependent strict-feedback complex-variable chaotic (hyperchaotic) systems (CVCSs) in the presence of uncertain complex parameters and perturbations, which has not been previously reported in the literature. In detail, we have developed a unified framework for designing the adaptive complex scalar controller to ensure this type of CVCSs asymptotically stable and for selecting complex update laws to estimate unknown complex parameters. In particular, combining Lyapunov functions dependent on complex-valued vectors and back-stepping technique, sufficient criteria on stabilization of CVCSs are derived in the sense of Wirtinger calculus in complex space. Finally, numerical simulation is presented to validate our theoretical results. PMID:28467431

  18. Complex I deficiency related to T10158C mutation ND3 gene: A further definition of the clinical spectrum.

    PubMed

    Grosso, Salvatore; Carluccio, Maria Alessandra; Cardaioli, Elena; Cerase, Alfonso; Malandrini, Alessandro; Romano, Chiara; Federico, Antonio; Dotti, Maria Teresa

    2017-03-01

    Complex I deficiency is the most common energy generation disorder which may clinically present at any age with a wide spectrum of symptoms and signs. The T10158C mutation ND3 gene is rare and occurs in patients showing an early rapid neurological deterioration invariably leading to death after a few months. We report a 9year-old boy with a mtDNA T10158C mutation showing a mild MELAS-like phenotype and brain MRI features congruent with both MELAS and Leigh syndrome. Epilepsia partialis continua also occurred in the clinical course and related to a mild cortical atrophy of the left perisylvian area. The present case confirms that the clinical spectrum of Complex I deficiency related to T10158C mutation ND3 gene is wider than previously described. Our observation further suggests that testing mutation in the MT-ND3 gene should be included in the diagnostic work-up of patients presenting with epilepsia partialis continua accompanied by suspicion of mitochondrial disorder. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  19. Cattle NK Cell Heterogeneity and the Influence of MHC Class I

    PubMed Central

    Allan, Alasdair J.; Sanderson, Nicholas D.; Gubbins, Simon; Ellis, Shirley A.

    2015-01-01

    Primate and rodent NK cells form highly heterogeneous lymphocyte populations owing to the differential expression of germline-encoded receptors. Many of these receptors are polymorphic and recognize equally polymorphic determinants of MHC class I. This diversity can lead to individuals carrying NK cells with different specificities. Cattle have an unusually diverse repertoire of NK cell receptor genes predicted to encode receptors that recognize MHC class I. To begin to examine whether this genetic diversity leads to a diverse NK cell population, we isolated peripheral NK cells from cattle with different MHC homozygous genotypes. Cytokine stimulation differentially influenced the transcription of five receptors at the cell population level. Using dilution cultures, we found that a further seven receptors were differentially transcribed, including five predicted to recognize MHC class I. Moreover, there was a statistically significant reduction in killer cell lectin-like receptor mRNA expression between cultures with different CD2 phenotypes and from animals with different MHC class I haplotypes. This finding confirms that cattle NK cells are a heterogeneous population and reveals that the receptors creating this diversity are influenced by the MHC. The importance of this heterogeneity will become clear as we learn more about the role of NK cells in cattle disease resistance and vaccination. PMID:26216890

  20. Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples1

    PubMed Central

    Tang, Jianming; Shao, Wenshuo; Yoo, Yun Joo; Brill, Ilene; Mulenga, Joseph; Allen, Susan; Hunter, Eric; Kaslow, Richard A.

    2008-01-01

    Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to cytotoxic T-lymphocytes. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplotype) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized co-factors of infection, including age and genital ulcer/inflammation. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission. {This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publishers of The JI, holds the copyright to this manuscript. This manuscript has not been copyedited or subjected to editorial proofreading by The JI; hence it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the United States National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org}. PMID:18684953

  1. Hexanuclear gold(I) phosphide complexes as platforms for multiple redox-active ferrocenyl units.

    PubMed

    Lee, Terence Kwok-Ming; Cheng, Eddie Chung-Chin; Zhu, Nianyong; Yam, Vivian Wing-Wah

    2014-01-03

    The synthesis, X-ray crystal structures, electrochemical, and spectroscopic studies of a series of hexanuclear gold(I) μ(3)-ferrocenylmethylphosphido complexes stabilized by bridging phosphine ligands, [Au(6)(P-P)(n)(Fc-CH(2)-P)(2)][PF(6)](2) (n=3, P-P=dppm (bis(diphenylphosphino)methane) (1), dppe (1,2-bis(diphenylphosphino)ethane) (2), dppp (1,3-bis(diphenylphosphino)propane) (3), Ph(2)PN(C(3)H(7))-PPh(2) (4), Ph(2)PN(Ph-CH(3)-p)PPh(2) (5), dppf (1,1′-bis(diphenylphosphino)ferrocene) (6); n=2, P-P=dpepp (bis(2-diphenylphosphinoethyl)phenylphosphine) (7)), as platforms for multiple redox-active ferrocenyl units, are reported. The investigation of the structural changes of the clusters has been probed by introducing different bridging phosphine ligands. This class of gold(I) μ(3)-ferrocenylmethylphosphido complexes has been found to exhibit one reversible oxidation couple, suggestive of the absence of electronic communication between the ferrocene units through the Au(6)P(2) cluster core, providing an understanding of the electronic properties of the hexanuclear Au(I) cluster linkage. The present complexes also serve as an ideal system for the design of multi-electron reservoir and molecular battery systems.

  2. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... sell one (1) kilogram of class I, Group VI controlled substances from inventory produced or imported... for pre-plant uses means the privilege granted by this subpart to produce or import one (1) kilogram... substance at a destruction efficiency of 98 percent or greater, using one of the destruction technologies...

  3. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... sell one (1) kilogram of class I, Group VI controlled substances from inventory produced or imported... for pre-plant uses means the privilege granted by this subpart to produce or import one (1) kilogram... substance at a destruction efficiency of 98 percent or greater, using one of the destruction technologies...

  4. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... sell one (1) kilogram of class I, Group VI controlled substances from inventory produced or imported... for pre-plant uses means the privilege granted by this subpart to produce or import one (1) kilogram... substance at a destruction efficiency of 98 percent or greater, using one of the destruction technologies...

  5. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... sell one (1) kilogram of class I, Group VI controlled substances from inventory produced or imported... for pre-plant uses means the privilege granted by this subpart to produce or import one (1) kilogram... substance at a destruction efficiency of 98 percent or greater, using one of the destruction technologies...

  6. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... sell one (1) kilogram of class I, Group VI controlled substances from inventory produced or imported... for pre-plant uses means the privilege granted by this subpart to produce or import one (1) kilogram... substance at a destruction efficiency of 98 percent or greater, using one of the destruction technologies...

  7. Immunodetection of human topoisomerase I-DNA covalent complexes

    PubMed Central

    Patel, Anand G.; Flatten, Karen S.; Peterson, Kevin L.; Beito, Thomas G.; Schneider, Paula A.; Perkins, Angela L.; Harki, Daniel A.; Kaufmann, Scott H.

    2016-01-01

    A number of established and investigational anticancer drugs slow the religation step of DNA topoisomerase I (topo I). These agents induce cytotoxicity by stabilizing topo I-DNA covalent complexes, which in turn interact with advancing replication forks or transcription complexes to generate lethal lesions. Despite the importance of topo I-DNA covalent complexes, it has been difficult to detect these lesions within intact cells and tumors. Here, we report development of a monoclonal antibody that specifically recognizes covalent topo I-DNA complexes, but not free topo I or DNA, by immunoblotting, immunofluorescence or flow cytometry. Utilizing this antibody, we demonstrate readily detectable topo I-DNA covalent complexes after treatment with camptothecins, indenoisoquinolines and cisplatin but not nucleoside analogues. Topotecan-induced topo I-DNA complexes peak at 15–30 min after drug addition and then decrease, whereas indotecan-induced complexes persist for at least 4 h. Interestingly, simultaneous staining for covalent topo I-DNA complexes, phospho-H2AX and Rad51 suggests that topotecan-induced DNA double-strand breaks occur at sites distinct from stabilized topo I-DNA covalent complexes. These studies not only provide new insight into the action of topo I-directed agents, but also illustrate a strategy that can be applied to study additional topoisomerases and their inhibitors in vitro and in vivo. PMID:26917015

  8. MHC Class I Chain-Related Gene A Polymorphisms and Linkage Disequilibrium with HLA-B and HLA-C Alleles in Ocular Toxoplasmosis.

    PubMed

    Ayo, Christiane Maria; Camargo, Ana Vitória da Silveira; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Previato, Mariana; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; Barbosa, Amanda Pires; Brandão de Mattos, Cinara de Cássia; de Mattos, Luiz Carlos

    2015-01-01

    This study investigated whether polymorphisms of the MICA (major histocompatibility complex class I chain-related gene A) gene are associated with eye lesions due to Toxoplasma gondii infection in a group of immunocompetent patients from southeastern Brazil. The study enrolled 297 patients with serological diagnosis of toxoplasmosis. Participants were classified into two distinct groups after conducting fundoscopic exams according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of the ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping of the MICA and HLA alleles was performed by the polymerase chain reaction-sequence specific oligonucleotide technique (PCR-SSO; One Lambda®) and the MICA-129 polymorphism (rs1051792) was identified by nested polymerase chain reaction (PCR-RFLP). Significant associations involving MICA polymorphisms were not found. Although the MICA*002~HLA-B*35 haplotype was associated with increased risk of developing ocular toxoplasmosis (P-value = 0.04; OR = 2.20; 95% CI = 1.05-4.60), and the MICA*008~HLA-C*07 haplotype was associated with protection against the development of manifestations of ocular toxoplasmosis (P-value = 0.009; OR: 0.44; 95% CI: 0.22-0.76), these associations were not statistically significant after adjusting for multiple comparisons. MICA polymorphisms do not appear to influence the development of ocular lesions in patients diagnosed with toxoplasmosis in this study population.

  9. Misfolding of major histocompatibility complex class I molecules in activated T cells allows cis-interactions with receptors and signaling molecules and is associated with tyrosine phosphorylation.

    PubMed

    Santos, Susana G; Powis, Simon J; Arosa, Fernando A

    2004-12-17

    Knowledge of the origin and biochemical status of beta(2)-microglobulin-free or misfolded major histocompatibility complex (MHC)-I molecules is essential for understanding their pleiotropic properties. Here we show that in normal human T cells, misfolding of MHC-I molecules is turned on upon activation and cell division and is proportional to the level of proliferation. Immunoprecipitation showed that a number of proteins are associated with MHC-I heavy chains at the surface of activated T cells, including the CD8alphabeta receptor and the chaperone tandem calreticulin/ERp57, associations that rely upon the existence of a pool of HC-10-reactive molecules. Biochemical analysis showed that misfolded MHC-I molecules present at the cell surface are fully glycosylated mature molecules. Importantly, misfolded MHC-I molecules are tyrosine phosphorylated and are associated with kinase activity. In vitro kinase assays followed by reprecipitation indicated that tyrosine phosphorylation of the class I heavy chain is probably mediated by a Src tyrosine kinase because Lck was found associated with HC-10 immunocomplexes. Finally, we show that inhibition of tyrosine phosphorylation by using the Src-family tyrosine kinase inhibitor PP2 resulted in enhanced release of MHC-I heavy chains from the cell surface of activated T cells and a slight down-regulation of cell surface W6/32-reactive molecules. This study provides new insights into the biology of MHC-I molecules and suggests that tyrosine phosphorylation may be involved in the regulation of MHC-I misfolding and expression.

  10. A common minimal motif for the ligands of HLA-B*27 class I molecules.

    PubMed

    Barriga, Alejandro; Lorente, Elena; Johnstone, Carolina; Mir, Carmen; del Val, Margarita; López, Daniel

    2014-01-01

    CD8(+) T cells identify and kill infected cells through the specific recognition of short viral antigens bound to human major histocompatibility complex (HLA) class I molecules. The colossal number of polymorphisms in HLA molecules makes it essential to characterize the antigen-presenting properties common to large HLA families or supertypes. In this context, the HLA-B*27 family comprising at least 100 different alleles, some of them widely distributed in the human population, is involved in the cellular immune response against pathogens and also associated to autoimmune spondyloarthritis being thus a relevant target of study. To this end, HLA binding assays performed using nine HLA-B*2705-restricted ligands endogenously processed and presented in virus-infected cells revealed a common minimal peptide motif for efficient binding to the HLA-B*27 family. The motif was independently confirmed using four unrelated peptides. This experimental approach, which could be easily transferred to other HLA class I families and supertypes, has implications for the validation of new bioinformatics tools in the functional clustering of HLA molecules, for the identification of antiviral cytotoxic T lymphocyte responses, and for future vaccine development.

  11. Glass-ionomer-silver-cermet interim Class I restorations for permanent teeth.

    PubMed

    Croll, T P; Killian, C M

    1992-11-01

    Glass-ionomer-silver-cermet cement has proved to be a worthy alternative to silver amalgam for restoring certain Class I lesions in primary teeth. Such restorations are now known to last up to 8 years without need for repair or replacement. Cermet cement has also been used for interim restoration of permanent teeth in special cases, with ideal results. The procedure for placing a glass-ionomer-silver-cermet cement Class I restoration is described.

  12. Class, Identity, and Teacher Education

    ERIC Educational Resources Information Center

    Van Galen, Jane A.

    2010-01-01

    This paper explores the possibilities of working with White, working-class teacher education students to explore the "complex social trajectory" (Reay in Women's Stud Int Forum 20(2):225-233, 1997a, p. 19) of class border crossing as they progress through college. Through analysis of a course that I have developed, "Education and the American…

  13. Finishing occlusion in Class II or Class III molar relation: therapeutic Class II and III.

    PubMed

    Nangia, A; Darendeliler, M A

    2001-11-01

    The most frequent extraction regime consists of the removal of upper and lower premolars. Depending on anchorage requirements, camouflage treatment options, surgical intervention, or the absence of teeth in only one arch, it may become necessary to finalize the occlusion with a one-dental-unit discrepancy between the upper and lower dental arches. Guidelines are presented for finishing occlusions in Class II or Class III molar relation.

  14. The life of plant mitochondrial complex I.

    PubMed

    Braun, Hans-Peter; Binder, Stefan; Brennicke, Axel; Eubel, Holger; Fernie, Alisdair R; Finkemeier, Iris; Klodmann, Jennifer; König, Ann-Christine; Kühn, Kristina; Meyer, Etienne; Obata, Toshihiro; Schwarzländer, Markus; Takenaka, Mizuki; Zehrmann, Anja

    2014-11-01

    The mitochondrial NADH dehydrogenase complex (complex I) of the respiratory chain has several remarkable features in plants: (i) particularly many of its subunits are encoded by the mitochondrial genome, (ii) its mitochondrial transcripts undergo extensive maturation processes (e.g. RNA editing, trans-splicing), (iii) its assembly follows unique routes, (iv) it includes an additional functional domain which contains carbonic anhydrases and (v) it is, indirectly, involved in photosynthesis. Comprising about 50 distinct protein subunits, complex I of plants is very large. However, an even larger number of proteins are required to synthesize these subunits and assemble the enzyme complex. This review aims to follow the complete "life cycle" of plant complex I from various molecular perspectives. We provide arguments that complex I represents an ideal model system for studying the interplay of respiration and photosynthesis, the cooperation of mitochondria and the nucleus during organelle biogenesis and the evolution of the mitochondrial oxidative phosphorylation system. Copyright © 2014 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  15. Random oligonucleotide mutagenesis: application to a large protein coding sequence of a major histocompatibility complex class I gene, H-2DP.

    PubMed Central

    Murray, R; Pederson, K; Prosser, H; Muller, D; Hutchison, C A; Frelinger, J A

    1988-01-01

    We have used random oligonucleotide mutagenesis (or saturation mutagenesis) to create a library of point mutations in the alpha 1 protein domain of a Major Histocompatibility Complex (MHC) molecule. This protein domain is critical for T cell and B cell recognition. We altered the MHC class I H-2DP gene sequence such that synthetic mutant alpha 1 exons (270 bp of coding sequence), which contain mutations identified by sequence analysis, can replace the wild type alpha 1 exon. The synthetic exons were constructed from twelve overlapping oligonucleotides which contained an average of 1.3 random point mutations per intact exon. DNA sequence analysis of mutant alpha 1 exons has shown a point mutant distribution that fits a Poisson distribution, and thus emphasizes the utility of this mutagenesis technique to "scan" a large protein sequence for important mutations. We report our use of saturation mutagenesis to scan an entire exon of the H-2DP gene, a cassette strategy to replace the wild type alpha 1 exon with individual mutant alpha 1 exons, and analysis of mutant molecules expressed on the surface of transfected mouse L cells. Images PMID:2903482

  16. Docosahexaenoic acid modifies the clustering and size of lipid rafts and the lateral organization and surface expression of MHC class I of EL4 cells.

    PubMed

    Shaikh, Saame Raza; Rockett, Benjamin Drew; Salameh, Muhammad; Carraway, Kristen

    2009-09-01

    An emerging molecular mechanism by which docosahexaenoic acid (DHA) exerts its effects is modification of lipid raft organization. The biophysical model, based on studies with liposomes, shows that DHA avoids lipid rafts because of steric incompatibility between DHA and cholesterol. The model predicts that DHA does not directly modify rafts; rather, it incorporates into nonrafts to modify the lateral organization and/or conformation of membrane proteins, such as the major histocompatibility complex (MHC) class I. Here, we tested predictions of the model at a cellular level by incorporating oleic acid, eicosapentaenoic acid (EPA), and DHA, compared with a bovine serum albumin (BSA) control, into the membranes of EL4 cells. Quantitative microscopy showed that DHA, but not EPA, treatment, relative to the BSA control diminished lipid raft clustering and increased their size. Approximately 30% of DHA was incorporated directly into rafts without changing the distribution of cholesterol between rafts and nonrafts. Quantification of fluorescence colocalization images showed that DHA selectively altered MHC class I lateral organization by increasing the fraction of the nonraft protein into rafts compared with BSA. Both DHA and EPA treatments increased antibody binding to MHC class I compared with BSA. Antibody titration showed that DHA and EPA did not change MHC I conformation but increased total surface levels relative to BSA. Taken together, our findings are not in agreement with the biophysical model. Therefore, we propose a model that reconciles contradictory viewpoints from biophysical and cellular studies to explain how DHA modifies lipid rafts on several length scales. Our study supports the notion that rafts are an important target of DHA's mode of action.

  17. 48 CFR 211.271 - Elimination of use of class I ozone-depleting substances.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... class I ozone-depleting substances. 211.271 Section 211.271 Federal Acquisition Regulations System... Using and Maintaining Requirements Documents 211.271 Elimination of use of class I ozone-depleting substances. See subpart 223.8 for restrictions on contracting for ozone-depleting substances. [70 FR 73150...

  18. 48 CFR 211.271 - Elimination of use of class I ozone-depleting substances.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... class I ozone-depleting substances. 211.271 Section 211.271 Federal Acquisition Regulations System... Using and Maintaining Requirements Documents 211.271 Elimination of use of class I ozone-depleting substances. See subpart 223.8 for restrictions on contracting for ozone-depleting substances. [70 FR 73150...

  19. 48 CFR 211.271 - Elimination of use of class I ozone-depleting substances.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... class I ozone-depleting substances. 211.271 Section 211.271 Federal Acquisition Regulations System... Using and Maintaining Requirements Documents 211.271 Elimination of use of class I ozone-depleting substances. See subpart 223.8 for restrictions on contracting for ozone-depleting substances. [70 FR 73150...

  20. 48 CFR 211.271 - Elimination of use of class I ozone-depleting substances.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... class I ozone-depleting substances. 211.271 Section 211.271 Federal Acquisition Regulations System... Using and Maintaining Requirements Documents 211.271 Elimination of use of class I ozone-depleting substances. See subpart 223.8 for restrictions on contracting for ozone-depleting substances. [70 FR 73150...

  1. 48 CFR 211.271 - Elimination of use of class I ozone-depleting substances.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... class I ozone-depleting substances. 211.271 Section 211.271 Federal Acquisition Regulations System... Using and Maintaining Requirements Documents 211.271 Elimination of use of class I ozone-depleting substances. See subpart 223.8 for restrictions on contracting for ozone-depleting substances. [70 FR 73150...

  2. Evaluation of cervical posture of children in skeletal class I, II, and III.

    PubMed

    D'Attilio, Michele; Caputi, Sergio; Epifania, Ettore; Festa, Felice; Tecco, Simona

    2005-07-01

    Previous studies on the relationship between morphological structure of the face and cervical posture have predominantly focused on vertical dimensions of the face. The aim of this study was to investigate whether there are significant differences in cervical posture in subjects with a different sagittal morphology of the face, i.e., a different skeletal class. One hundred twenty (120) children (60 males and 60 females, average age 9.5 yrs., SD+/-0.5) were admitted for orthodontic treatment. Selection criteria was: European ethnic origin, date of birth, considerable skeletal growth potential remaining and an absence of temporomandibular joint dysfunction (TMD). Lateral skull radiographs were taken in mirror position. Subjects were divided into three groups based on their skeletal class. The cephalometric tracings included postural variables. The most interesting findings were: 1. children in skeletal class III showed a significantly lower cervical lordosis angle (p<0.001) than the children in skeletal class I and skeletal class II; 2. children in skeletal class II showed a significantly higher extension of the head upon the spinal column compared to children in skeletal class I and skeletal class III (p<0.001 and p<0.01, respectively). This is probably because the lower part of their spinal column was straighter than those of subjects in skeletal class I and II (p<0.01 and p<0.001, respectively). Significant differences among the three groups were also observed in the inclination of maxillary and mandibular bases to the spinal column. The posture of the neck seems to be strongly associated with the sagittal as well as the vertical structure of the face.

  3. Different Functions of Phylogenetically Distinct Bacterial Complex I Isozymes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spero, Melanie A.; Brickner, Joshua R.; Mollet, Jordan T.

    NADH:quinone oxidoreductase (complex I) is a bioenergetic enzyme that transfers electrons from NADH to quinone, conserving the energy of this reaction by contributing to the proton motive force. While the importance of NADH oxidation to mitochondrial aerobic respiration is well documented, the contribution of complex I to bacterial electron transport chains has been tested in only a few species. Here, we analyze the function of two phylogenetically distinct complex I isozymes in Rhodobacter sphaeroides, an alphaproteobacterium that contains well-characterized electron transport chains. We found that R. sphaeroides complex I activity is important for aerobic respiration and required for anaerobic dimethylmore » sulfoxide (DMSO) respiration (in the absence of light), photoautotrophic growth, and photoheterotrophic growth (in the absence of an external electron acceptor). Our data also provide insight into the functions of the phylogenetically distinct R. sphaeroides complex I enzymes (complex I A and complex I E) in maintaining a cellular redox state during photoheterotrophic growth. We propose that the function of each isozyme during photoheterotrophic growth is either NADH synthesis (complex I A) or NADH oxidation (complex I E). The canonical alphaproteobacterial complex I isozyme (complex I A) was also shown to be important for routing electrons to nitrogenase-mediated H 2 production, while the horizontally acquired enzyme (complex I E) was dispensable in this process. Unlike the singular role of complex I in mitochondria, we predict that the phylogenetically distinct complex I enzymes found across bacterial species have evolved to enhance the functions of their respective electron transport chains. Cells use a proton motive force (PMF), NADH, and ATP to support numerous processes. In mitochondria, complex I uses NADH oxidation to generate a PMF, which can drive ATP synthesis. This study analyzed the function of complex I in bacteria, which contain more

  4. Different Functions of Phylogenetically Distinct Bacterial Complex I Isozymes

    DOE PAGES

    Spero, Melanie A.; Brickner, Joshua R.; Mollet, Jordan T.; ...

    2016-02-01

    NADH:quinone oxidoreductase (complex I) is a bioenergetic enzyme that transfers electrons from NADH to quinone, conserving the energy of this reaction by contributing to the proton motive force. While the importance of NADH oxidation to mitochondrial aerobic respiration is well documented, the contribution of complex I to bacterial electron transport chains has been tested in only a few species. Here, we analyze the function of two phylogenetically distinct complex I isozymes in Rhodobacter sphaeroides, an alphaproteobacterium that contains well-characterized electron transport chains. We found that R. sphaeroides complex I activity is important for aerobic respiration and required for anaerobic dimethylmore » sulfoxide (DMSO) respiration (in the absence of light), photoautotrophic growth, and photoheterotrophic growth (in the absence of an external electron acceptor). Our data also provide insight into the functions of the phylogenetically distinct R. sphaeroides complex I enzymes (complex I A and complex I E) in maintaining a cellular redox state during photoheterotrophic growth. We propose that the function of each isozyme during photoheterotrophic growth is either NADH synthesis (complex I A) or NADH oxidation (complex I E). The canonical alphaproteobacterial complex I isozyme (complex I A) was also shown to be important for routing electrons to nitrogenase-mediated H 2 production, while the horizontally acquired enzyme (complex I E) was dispensable in this process. Unlike the singular role of complex I in mitochondria, we predict that the phylogenetically distinct complex I enzymes found across bacterial species have evolved to enhance the functions of their respective electron transport chains. Cells use a proton motive force (PMF), NADH, and ATP to support numerous processes. In mitochondria, complex I uses NADH oxidation to generate a PMF, which can drive ATP synthesis. This study analyzed the function of complex I in bacteria, which contain more

  5. Subunit mass fingerprinting of mitochondrial complex I.

    PubMed

    Morgner, Nina; Zickermann, Volker; Kerscher, Stefan; Wittig, Ilka; Abdrakhmanova, Albina; Barth, Hans-Dieter; Brutschy, Bernhard; Brandt, Ulrich

    2008-10-01

    We have employed laser induced liquid bead ion desorption (LILBID) mass spectrometry to determine the total mass and to study the subunit composition of respiratory chain complex I from Yarrowia lipolytica. Using 5-10 pmol of purified complex I, we could assign all 40 known subunits of this membrane bound multiprotein complex to peaks in LILBID subunit fingerprint spectra by comparing predicted protein masses to observed ion masses. Notably, even the highly hydrophobic subunits encoded by the mitochondrial genome were easily detectable. Moreover, the LILBID approach allowed us to spot and correct several errors in the genome-derived protein sequences of complex I subunits. Typically, the masses of the individual subunits as determined by LILBID mass spectrometry were within 100 Da of the predicted values. For the first time, we demonstrate that LILBID spectrometry can be successfully applied to a complex I band eluted from a blue-native polyacrylamide gel, making small amounts of large multiprotein complexes accessible for subunit mass fingerprint analysis even if they are membrane bound. Thus, the LILBID subunit mass fingerprint method will be of great value for efficient proteomic analysis of complex I and its assembly intermediates, as well as of other water soluble and membrane bound multiprotein complexes.

  6. Structural and spectroscopic features of mixed valent Fe(II)Fe(I) complexes and factors related to the rotated configuration of diiron hydrogenase.

    PubMed

    Hsieh, Chung-Hung; Erdem, Ozlen F; Harman, Scott D; Singleton, Michael L; Reijerse, Edward; Lubitz, Wolfgang; Popescu, Codrina V; Reibenspies, Joseph H; Brothers, Scott M; Hall, Michael B; Darensbourg, Marcetta Y

    2012-08-08

    The compounds of this study have yielded to complementary structural, spectroscopic (Mössbauer, EPR/ENDOR, IR), and computational probes that illustrate the fine control of electronic and steric features that are involved in the two structural forms of (μ-SRS)[Fe(CO)2PMe3]2(0,+) complexes. The installation of bridgehead bulk in the -SCH2CR2CH2S- dithiolate (R = Me, Et) model complexes produces 6-membered FeS2C3 cyclohexane-type rings that produce substantial distortions in Fe(I)Fe(I) precursors. Both the innocent (Fc(+)) and the noninnocent or incipient (NO(+)/CO exchange) oxidations result in complexes with inequivalent iron centers in contrast to the Fe(I)Fe(I) derivatives. In the Fe(II)Fe(I) complexes of S = 1/2, there is complete inversion of one square pyramid relative to the other with strong super hyperfine coupling to one PMe3 and weak SHFC to the other. Remarkably, diamagnetic complexes deriving from isoelectronic replacement of CO by NO(+), {(μ-SRS)[Fe(CO)2PMe3] [Fe(CO)(NO)PMe3](+)}, are also rotated and exist in only one isomeric form with the -SCH2CR2CH2S- dithiolates, in contrast to R = H ( Olsen , M. T. ; Bruschi , M. ; De Gioia , L. ; Rauchfuss , T. B. ; Wilson , S. R. J. Am. Chem. Soc. 2008 , 130 , 12021 -12030 ). The results and redox levels determined from the extensive spectroscopic analyses have been corroborated by gas-phase DFT calculations, with the primary spin density either localized on the rotated iron in the case of the S = 1/2 compound, or delocalized over the {Fe(NO)} unit in the S = 0 complex. In the latter case, the nitrosyl has effectively shifted electron density from the Fe(I)Fe(I) bond, repositioning it onto the spin coupled Fe-N-O unit such that steric repulsion is sufficient to induce the rotated structure in the Fe(II)-{Fe(I)((•)NO)}(8) derivatives.

  7. 7 CFR 1001.52 - Adjusted Class I differentials.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Adjusted Class I differentials. 1001.52 Section 1001.52 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Milk), DEPARTMENT OF AGRICULTURE MILK IN THE NORTHEAST MARKETING AREA Order Regulating...

  8. Social Class and Mental Health: Testing Exploitation as a Relational Determinant of Depression

    PubMed Central

    Muntaner, Carles; Ng, Edwin; Prins, Seth J.; Bones-Rocha, Katia; Espelt, Albert; Chung, Haejoo

    2016-01-01

    This study tests whether social class exploitation operates as a relational mechanism that generates mental health inequalities in the nursing home industry. We ask, does social class exploitation (i.e., the acquisition of economic benefits from the labor of those who are dominated) have a systematic and predictable impact on depression among nursing assistants? Using cross-sectional data from 868 nursing assistants employed in 50 nursing homes in three U.S. states, we measure social class exploitation as “ownership type” (private for-profit, private not-for-profit, and public) and “managerial domination” (labor relations violations, perceptions of labor-management conflict). Depression is assessed using the original and revised versions of the Center for Epidemiologic Studies Depression Scale (CES-D and CESD-R). Using two-level logistic regressions, we find that private for-profit ownership and higher managerial domination are predictive of depression among nursing assistants even after adjustment for potential confounders and mediators. Our findings confirm the theoretical and empirical value of applying a social class approach to understanding how mental health inequalities are generated through exploitative mechanisms. Ownership type and managerial domination appear to affect depression through social relations that generate mental health inequalities through the process of acquiring profits, controlling production, supervising and monitoring labor, and enforcing disciplinary sanctions. PMID:25813501

  9. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.

    2007-12-01

    The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8more » α-I (EGSFQPSQE), respectively, are reported.« less

  10. Purification of Ovine Respiratory Complex I Results in a Highly Active and Stable Preparation*

    PubMed Central

    Letts, James A.; Degliesposti, Gianluca; Fiedorczuk, Karol; Skehel, Mark; Sazanov, Leonid A.

    2016-01-01

    NADH-ubiquinone oxidoreductase (complex I) is the largest (∼1 MDa) and the least characterized complex of the mitochondrial electron transport chain. Because of the ease of sample availability, previous work has focused almost exclusively on bovine complex I. However, only medium resolution structural analyses of this complex have been reported. Working with other mammalian complex I homologues is a potential approach for overcoming these limitations. Due to the inherent difficulty of expressing large membrane protein complexes, screening of complex I homologues is limited to large mammals reared for human consumption. The high sequence identity among these available sources may preclude the benefits of screening. Here, we report the characterization of complex I purified from Ovis aries (ovine) heart mitochondria. All 44 unique subunits of the intact complex were identified by mass spectrometry. We identified differences in the subunit composition of subcomplexes of ovine complex I as compared with bovine, suggesting differential stability of inter-subunit interactions within the complex. Furthermore, the 42-kDa subunit, which is easily lost from the bovine enzyme, remains tightly bound to ovine complex I. Additionally, we developed a novel purification protocol for highly active and stable mitochondrial complex I using the branched-chain detergent lauryl maltose neopentyl glycol. Our data demonstrate that, although closely related, significant differences exist between the biochemical properties of complex I prepared from ovine and bovine mitochondria and that ovine complex I represents a suitable alternative target for further structural studies. PMID:27672209

  11. 33 CFR 326.6 - Class I administrative penalties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    .... 326.6 Section 326.6 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE ENFORCEMENT § 326.6 Class I administrative penalties. (a) Introduction. (1) This... giving public notice and providing the opportunity for public comment are contained in § 326.6(c). (4) At...

  12. Characterization of 47 MHC class I sequences in Filipino cynomolgus macaques

    PubMed Central

    Campbell, Kevin J.; Detmer, Ann M.; Karl, Julie A.; Wiseman, Roger W.; Blasky, Alex J.; Hughes, Austin L.; Bimber, Benjamin N.; O’Connor, Shelby L.; O’Connor, David H.

    2009-01-01

    Cynomolgus macaques (Macaca fascicularis) provide increasingly common models for infectious disease research. Several geographically distinct populations of these macaques from Southeast Asia and the Indian Ocean island of Mauritius are available for pathogenesis studies. Though host genetics may profoundly impact results of such studies, similarities and differences between populations are often overlooked. In this study we identified 47 full-length MHC class I nucleotide sequences in 16 cynomolgus macaques of Filipino origin. The majority of MHC class I sequences characterized (39 of 47) were unique to this regional population. However, we discovered eight sequences with perfect identity and six sequences with close similarity to previously defined MHC class I sequences from other macaque populations. We identified two ancestral MHC haplotypes that appear to be shared between Filipino and Mauritian cynomolgus macaques, notably a Mafa-B haplotype that has previously been shown to protect Mauritian cynomolgus macaques against challenge with a simian/human immunodeficiency virus, SHIV89.6P. We also identified a Filipino cynomolgus macaque MHC class I sequence for which the predicted protein sequence differs from Mamu-B*17 by a single amino acid. This is important because Mamu-B*17 is strongly associated with protection against simian immunodeficiency virus (SIV) challenge in Indian rhesus macaques. These findings have implications for the evolutionary history of Filipino cynomolgus macaques as well as for the use of this model in SIV/SHIV research protocols. PMID:19107381

  13. Self-esteem in adolescents with Angle Class I, II and III malocclusion in a Peruvian sample.

    PubMed

    Florián-Vargas, Karla; Honores, Marcos J Carruitero; Bernabé, Eduardo; Flores-Mir, Carlos

    2016-01-01

    To compare self-esteem scores in 12 to 16-year-old adolescents with different Angle malocclusion types in a Peruvian sample. A cross-sectional study was conducted in a sample of 276 adolescents (159, 52 and 65 with Angle Class I, II and III malocclusions, respectively) from Trujillo, Peru. Participants were asked to complete the Rosenberg Self-Esteem Scale (RSES) and were also clinically examined, so as to have Angle malocclusion classification determined. Analysis of covariance (ANCOVA) was used to compare RSES scores among adolescents with Class I, II and III malocclusions, with participants' demographic factors being controlled. Mean RSES scores for adolescents with Class I, II and III malocclusions were 20.47 ± 3.96, 21.96 ± 3.27 and 21.26 ± 4.81, respectively. The ANCOVA test showed that adolescents with Class II malocclusion had a significantly higher RSES score than those with Class I malocclusion, but there were no differences between other malocclusion groups. Supplemental analysis suggested that only those with Class II, Division 2 malocclusion might have greater self-esteem when compared to adolescents with Class I malocclusion. This study shows that, in general, self-esteem did not vary according to adolescents' malocclusion in the sample studied. Surprisingly, only adolescents with Class II malocclusion, particularly Class II, Division 2, reported better self-esteem than those with Class I malocclusion. A more detailed analysis assessing the impact of anterior occlusal features should be conducted.

  14. Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes

    PubMed Central

    Blakeslee, Weston W.; Lin, Ying-Hsi; Stratton, Matthew S.; Tatman, Philip D.; Hu, Tianjing; Ferguson, Bradley S.; McKinsey, Timothy A.

    2018-01-01

    Class I histone deacetylase (HDAC) inhibitors block hypertrophy and fibrosis of the heart by suppressing pathological signaling and gene expression programs in cardiac myocytes and fibroblasts. The impact of HDAC inhibition in unstressed cardiac cells remains poorly understood. Here, we demonstrate that treatment of cultured cardiomyocytes with small molecule HDAC inhibitors leads to dramatic induction of c-Jun amino-terminal kinase (JNK)-interacting protein-1 (JIP1) mRNA and protein expression. In contrast to prior findings, elevated levels of endogenous JIP1 in cardiomyocytes failed to significantly alter JNK signaling or cardiomyocyte hypertrophy. Instead, HDAC inhibitor-mediated induction of JIP1 was required to stimulate expression of the kinesin heavy chain family member, KIF5A. We provide evidence for an HDAC-dependent regulatory circuit that promotes formation of JIP1:KIF5A:microtubule complexes that regulate intracellular transport of cargo such as autophagosomes. These findings define a novel role for class I HDACs in the control of the JIP1/kinesin axis in cardiomyocytes, and suggest that HDAC inhibitors could be used to alter microtubule transport in the heart. PMID:28886967

  15. Measuring case-mix complexity of tertiary care hospitals using DRGs.

    PubMed

    Park, Hayoung; Shin, Youngsoo

    2004-02-01

    The objectives of the study were to develop a model that measures and evaluates case-mix complexity of tertiary care hospitals, and to examine the characteristics of such a model. Physician panels defined three classes of case complexity and assigned disease categories represented by Adjacent Diagnosis Related Groups (ADRGs) to one of three case complexity classes. Three types of scores, indicating proportions of inpatients in each case complexity class standardized by the proportions at the national level, were defined to measure the case-mix complexity of a hospital. Discharge information for about 10% of inpatient episodes at 85 hospitals with bed size larger than 400 and their input structure and research and education activity were used to evaluate the case-mix complexity model. Results show its power to predict hospitals with the expected functions of tertiary care hospitals, i.e. resource intensive care, expensive input structure, and high levels of research and education activities.

  16. MHC Class I Chain-Related Gene A Polymorphisms and Linkage Disequilibrium with HLA-B and HLA-C Alleles in Ocular Toxoplasmosis

    PubMed Central

    Ayo, Christiane Maria; Camargo, Ana Vitória da Silveira; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Previato, Mariana; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; Barbosa, Amanda Pires; Brandão de Mattos, Cinara de Cássia; de Mattos, Luiz Carlos

    2015-01-01

    This study investigated whether polymorphisms of the MICA (major histocompatibility complex class I chain-related gene A) gene are associated with eye lesions due to Toxoplasma gondii infection in a group of immunocompetent patients from southeastern Brazil. The study enrolled 297 patients with serological diagnosis of toxoplasmosis. Participants were classified into two distinct groups after conducting fundoscopic exams according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of the ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping of the MICA and HLA alleles was performed by the polymerase chain reaction-sequence specific oligonucleotide technique (PCR-SSO; One Lambda®) and the MICA-129 polymorphism (rs1051792) was identified by nested polymerase chain reaction (PCR-RFLP). Significant associations involving MICA polymorphisms were not found. Although the MICA*002~HLA-B*35 haplotype was associated with increased risk of developing ocular toxoplasmosis (P-value = 0.04; OR = 2.20; 95% CI = 1.05–4.60), and the MICA*008~HLA-C*07 haplotype was associated with protection against the development of manifestations of ocular toxoplasmosis (P-value = 0.009; OR: 0.44; 95% CI: 0.22–0.76), these associations were not statistically significant after adjusting for multiple comparisons. MICA polymorphisms do not appear to influence the development of ocular lesions in patients diagnosed with toxoplasmosis in this study population. PMID:26672749

  17. Human Leukocyte Antigen Class I and Class II Polymorphisms and Serum Cytokine Profiles in Cervical Cancer.

    PubMed

    Bahls, Larissa; Yamakawa, Roger; Zanão, Karina; Alfieri, Daniela; Flauzino, Tamires; Delongui, Francieli; de Abreu, André; Souza, Raquel; Gimenes, Fabrícia; Reiche, Edna; Borelli, Sueli; Consolaro, Marcia

    2017-08-31

    Only a small proportion of women who are exposed to infection with high-risk human papillomavirus (HR-HPV) progress to persistent infection and develop cervical cancer (CC). The immune response and genetic background of the host may affect the risk of progression from a HR-HPV infection to lesions and cancer. However, to our knowledge, no studies has been conducted to evaluate the relationship between variability of human leukocyte antigens ( HLA ) genes and serum cytokine expression in this pathology. In the current study, we examined the associations of HLA alleles and haplotypes including Class I ( HLA-A , -B and -C ) and II ( HLA-DRB1 , -DQA1 and -DQB1 ) with serum levels of cytokines interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-10 and IL-17 as well as risks of HPV infections, lesions and CC among admixed Brazilian women. HLA polymorphisms were associated with an increased risk or protection from HPV, lesions and CC. Additionally, we demonstrated a potential association of a HLA class I haplotype ( HLA-B*14-C*08 ) with higher IL-10 cytokine serum levels in cervical disease, suggesting an association between HLA class I and specific cytokines in cervical carcinogenesis. However, larger studies with detailed HPV types coupled with genetic data are needed to further evaluate the effects of HLA and CC by HPV genotype.

  18. Human Leukocyte Antigen Class I and Class II Polymorphisms and Serum Cytokine Profiles in Cervical Cancer

    PubMed Central

    Bahls, Larissa; Yamakawa, Roger; Zanão, Karina; Alfieri, Daniela; Flauzino, Tamires; Delongui, Francieli; de Abreu, André; Souza, Raquel; Gimenes, Fabrícia; Reiche, Edna; Borelli, Sueli; Consolaro, Marcia

    2017-01-01

    Only a small proportion of women who are exposed to infection with high-risk human papillomavirus (HR-HPV) progress to persistent infection and develop cervical cancer (CC). The immune response and genetic background of the host may affect the risk of progression from a HR-HPV infection to lesions and cancer. However, to our knowledge, no studies has been conducted to evaluate the relationship between variability of human leukocyte antigens (HLA) genes and serum cytokine expression in this pathology. In the current study, we examined the associations of HLA alleles and haplotypes including Class I (HLA-A, -B and -C) and II (HLA-DRB1, -DQA1 and -DQB1) with serum levels of cytokines interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-10 and IL-17 as well as risks of HPV infections, lesions and CC among admixed Brazilian women. HLA polymorphisms were associated with an increased risk or protection from HPV, lesions and CC. Additionally, we demonstrated a potential association of a HLA class I haplotype (HLA-B*14-C*08) with higher IL-10 cytokine serum levels in cervical disease, suggesting an association between HLA class I and specific cytokines in cervical carcinogenesis. However, larger studies with detailed HPV types coupled with genetic data are needed to further evaluate the effects of HLA and CC by HPV genotype. PMID:28858203

  19. 46 CFR 108.173 - Class I, Division 2 locations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... locations. The following are Class I, Division 2 locations: (a) An enclosed space that has any open portion... mud pit. (b) A location in the weather that is— (1) Within the boundaries of the drilling derrick up...

  20. Purification of Ovine Respiratory Complex I Results in a Highly Active and Stable Preparation.

    PubMed

    Letts, James A; Degliesposti, Gianluca; Fiedorczuk, Karol; Skehel, Mark; Sazanov, Leonid A

    2016-11-18

    NADH-ubiquinone oxidoreductase (complex I) is the largest (∼1 MDa) and the least characterized complex of the mitochondrial electron transport chain. Because of the ease of sample availability, previous work has focused almost exclusively on bovine complex I. However, only medium resolution structural analyses of this complex have been reported. Working with other mammalian complex I homologues is a potential approach for overcoming these limitations. Due to the inherent difficulty of expressing large membrane protein complexes, screening of complex I homologues is limited to large mammals reared for human consumption. The high sequence identity among these available sources may preclude the benefits of screening. Here, we report the characterization of complex I purified from Ovis aries (ovine) heart mitochondria. All 44 unique subunits of the intact complex were identified by mass spectrometry. We identified differences in the subunit composition of subcomplexes of ovine complex I as compared with bovine, suggesting differential stability of inter-subunit interactions within the complex. Furthermore, the 42-kDa subunit, which is easily lost from the bovine enzyme, remains tightly bound to ovine complex I. Additionally, we developed a novel purification protocol for highly active and stable mitochondrial complex I using the branched-chain detergent lauryl maltose neopentyl glycol. Our data demonstrate that, although closely related, significant differences exist between the biochemical properties of complex I prepared from ovine and bovine mitochondria and that ovine complex I represents a suitable alternative target for further structural studies. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Oiso, Hiroshi; Furukawa, Noboru, E-mail: n-furu@gpo.kumamoto-u.ac.jp; Suefuji, Mihoshi

    2011-01-07

    Research highlights: {yields} A novel class I HDAC inhibitor decreased hepatic PEPCK mRNA and gluconeogenesis. {yields} Inhibition of HDAC decreased PEPCK by reducing HNF4{alpha} expression and FoxO1 activity. {yields} siRNA knockdown of HDAC1 in HepG2 cells reduced the expression of PEPCK and HNF4{alpha}. {yields} Inhibition of class I HDAC improves glucose homeostasis in HFD mice. -- Abstract: Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role ofmore » class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4{alpha} expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4{alpha} protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.« less

  2. The Gould's Belt Very Large Array Survey. I. The Ophiuchus Complex

    NASA Astrophysics Data System (ADS)

    Dzib, Sergio A.; Loinard, Laurent; Mioduszewski, Amy J.; Rodríguez, Luis F.; Ortiz-León, Gisela N.; Pech, Gerardo; Rivera, Juana L.; Torres, Rosa M.; Boden, Andrew F.; Hartmann, Lee; Evans, Neal J., II; Briceño, Cesar; Tobin, John

    2013-09-01

    We present large-scale (~2000 arcmin2), deep (~20 μJy), high-resolution (~1'') radio observations of the Ophiuchus star-forming complex obtained with the Karl G. Jansky Very Large Array at λ = 4 and 6 cm. In total, 189 sources were detected, 56 of them associated with known young stellar sources, and 4 with known extragalactic objects; the other 129 remain unclassified, but most of them are most probably background quasars. The vast majority of the young stars detected at radio wavelengths have spectral types K or M, although we also detect four objects of A/F/B types and two brown dwarf candidates. At least half of these young stars are non-thermal (gyrosynchrotron) sources, with active coronas characterized by high levels of variability, negative spectral indices, and (in some cases) significant circular polarization. As expected, there is a clear tendency for the fraction of non-thermal sources to increase from the younger (Class 0/I or flat spectrum) to the more evolved (Class III or weak line T Tauri) stars. The young stars detected both in X-rays and at radio wavelengths broadly follow a Güdel-Benz relation, but with a different normalization than the most radioactive types of stars. Finally, we detect a ~70 mJy compact extragalactic source near the center of the Ophiuchus core, which should be used as gain calibrator for any future radio observations of this region.

  3. Multiple Gaps in the Disk of the Class I Protostar GY 91

    NASA Astrophysics Data System (ADS)

    Sheehan, Patrick D.; Eisner, Josh A.

    2018-04-01

    We present the highest spatial resolution Atacama Large Millimeter/submillimeter Array (ALMA) observations to date of the Class I protostar GY 91 in the ρ Ophiuchus L1688 molecular cloud complex. Our 870 μm and 3 mm dust continuum maps show that the GY 91 disk has a radius of ∼80 au, and an inclination of ∼40°, but most interestingly that the disk has three dark lanes located at 10, 40, and 70 au. We model these features assuming they are gaps in the disk surface density profile and find that their widths are 7, 30, and 10 au. These gaps bear a striking resemblance to the gaps seen in the HL Tau disk, suggesting that there may be Saturn-mass planets hiding in the disk. To constrain the relative ages of GY 91 and HL Tau, we also model the disk and envelope of HL Tau and find that they are of similar ages, although GY 91 may be younger. Although snow lines and magnetic dead zones can also produce dark lanes, if planets are indeed carving these gaps then Saturn-mass planets must form within the first ∼0.5 Myr of the lifetime of protoplanetary disks.

  4. ROOT HAIR DEFECTIVE SIX-LIKE Class I Genes Promote Root Hair Development in the Grass Brachypodium distachyon

    PubMed Central

    Kim, Chul Min

    2016-01-01

    Genes encoding ROOT HAIR DEFECTIVE SIX-LIKE (RSL) class I basic helix loop helix proteins are expressed in future root hair cells of the Arabidopsis thaliana root meristem where they positively regulate root hair cell development. Here we show that there are three RSL class I protein coding genes in the Brachypodium distachyon genome, BdRSL1, BdRSL2 and BdRSL3, and each is expressed in developing root hair cells after the asymmetric cell division that forms root hair cells and hairless epidermal cells. Expression of BdRSL class I genes is sufficient for root hair cell development: ectopic overexpression of any of the three RSL class I genes induces the development of root hairs in every cell of the root epidermis. Expression of BdRSL class I genes in root hairless Arabidopsis thaliana root hair defective 6 (Atrhd6) Atrsl1 double mutants, devoid of RSL class I function, restores root hair development indicating that the function of these proteins has been conserved. However, neither AtRSL nor BdRSL class I genes is sufficient for root hair development in A. thaliana. These data demonstrate that the spatial pattern of class I RSL activity can account for the pattern of root hair cell differentiation in B. distachyon. However, the spatial pattern of class I RSL activity cannot account for the spatial pattern of root hair cells in A. thaliana. Taken together these data indicate that that the functions of RSL class I proteins have been conserved among most angiosperms—monocots and eudicots—despite the dramatically different patterns of root hair cell development. PMID:27494519

  5. Regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine.

    PubMed

    Fairstein, Moran; Swissa, Rotem; Dahan, Arik

    2013-04-01

    Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P(eff)) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F(abs)) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P(eff)-F(abs) correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P(eff) and F(abs) is involved in its absorption. Rather, it reflects the complexity behind P(eff) when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P(eff) that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

  6. Selective Downregulation of Rhesus Macaque and Sooty Mangabey Major Histocompatibility Complex Class I Molecules by Nef Alleles of Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 2▿

    PubMed Central

    DeGottardi, M. Quinn; Specht, Anke; Metcalf, Benjamin; Kaur, Amitinder; Kirchhoff, Frank; Evans, David T.

    2008-01-01

    Human immunodeficiency virus type 1 (HIV-1) Nef downregulates HLA-A and -B molecules, but not HLA-C or -E molecules, based on amino acid differences in their cytoplasmic domains to simultaneously evade cytotoxic T lymphocyte (CTL) and natural killer cell surveillance. Rhesus macaques and sooty mangabeys express orthologues of HLA-A, -B, and -E, but not HLA-C, and many of these molecules have unique amino acid differences in their cytoplasmic tails. We found that these differences also resulted in differential downregulation by primary simian immunodeficiency virus (SIV) SIVsmm/mac and HIV-2 Nef alleles. Thus, selective major histocompatibility complex class I downregulation is a conserved mechanism of immune evasion for pathogenic SIV infection of rhesus macaques and nonpathogenic SIV infection of sooty mangabeys. PMID:18199657

  7. MHC class I antigens and tumour-infiltrating leucocytes in laryngeal cancer: long-term follow-up.

    PubMed Central

    Esteban, F.; Redondo, M.; Delgado, M.; Garrido, F.; Ruiz-Cabello, F.

    1996-01-01

    Alteration in MHC class I expression may be used by cancer cells to avoid immune destruction. Much experimental evidence supports this idea, although survival studies are very scarce. To investigate whether the presence or absence of HLA-A, -B and -C antigens in laryngeal carcinoma influences survival, a series of 60 primary laryngeal tumours treated surgically and normal tissues were evaluated in frozen sections for the expression of MHC class I antigens and tumour-infiltrating leucocytes (CD3, CD4, CD8, CD11b, CD1, CD20 and CD16), using monoclonal antibodies and the APAAP, technique. Long-term follow-up from the patients is available, ranging from 6 to 10 years. Thirteen tumours presented total HLA-ABC loss, five selective losses of HLA-A antigens and one absence of HLA-B antigens. Total losses were statistically associated with several clinical and pathological parameters, but there were no differences regarding tumour-infiltrating leucocytes. After conducting a prospective study, only T and N staging and scoring according to Glanz's malignancy classification were found to be independently related to patients' outcome. From our data, we conclude that neither complete loss of HLA class I antigens nor tumour-infiltrating leucocytes appear to influence survival in squamous cell carcinoma of the larynx. PMID:8956796

  8. Cofactor specificity motifs and the induced fit mechanism in class I ketol-acid reductoisomerases.

    PubMed

    Cahn, Jackson K B; Brinkmann-Chen, Sabine; Spatzal, Thomas; Wiig, Jared A; Buller, Andrew R; Einsle, Oliver; Hu, Yilin; Ribbe, Markus W; Arnold, Frances H

    2015-06-15

    Although most sequenced members of the industrially important ketol-acid reductoisomerase (KARI) family are class I enzymes, structural studies to date have focused primarily on the class II KARIs, which arose through domain duplication. In the present study, we present five new crystal structures of class I KARIs. These include the first structure of a KARI with a six-residue β2αB (cofactor specificity determining) loop and an NADPH phosphate-binding geometry distinct from that of the seven- and 12-residue loops. We also present the first structures of naturally occurring KARIs that utilize NADH as cofactor. These results show insertions in the specificity loops that confounded previous attempts to classify them according to loop length. Lastly, we explore the conformational changes that occur in class I KARIs upon binding of cofactor and metal ions. The class I KARI structures indicate that the active sites close upon binding NAD(P)H, similar to what is observed in the class II KARIs of rice and spinach and different from the opening of the active site observed in the class II KARI of Escherichia coli. This conformational change involves a decrease in the bending of the helix that runs between the domains and a rearrangement of the nicotinamide-binding site. © The Authors Journal Compilation © 2015 Biochemical Society.

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

    PubMed Central

    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

  10. Handbook for Class I County School District Treasurers.

    ERIC Educational Resources Information Center

    Illinois State Board of Education, Springfield.

    This handbook is an updated edition provided by the Illinois State Board of Education for school district treasurers. Its intent is to assist Class I county treasurers in performing their duties efficiently and effectively. The handbook is divided into four sections, the first of which outlines custodial role, eligiblity, term of office, salary,…

  11. An Evaluation of Mandibular Dental and Basal Arch Dimensions in Class I and Class II Division 1 Adult Syrian Patients using Cone-beam Computed Tomography.

    PubMed

    Al-Hilal, Layal H; Sultan, Kinda; Hajeer, Mohammad Y; Mahmoud, Ghiath; Wanli, Abdulrahman A

    2018-04-01

    Aim: The aim of this study is (1) to inspect any difference in mandibular arch widths between males and females in class I and class II division 1 (class malocclusions using cone-beam computed tomography (CBCT), (2) to compare the mandibular dental and basal widths between the two groups, and (3) to investigate any possible correlation between dental and basal arch widths in both groups. Materials and methods: The CBCT images of 68 patients aged between 18 and 25 years consisted of 34 class I (17 males and 17 females) and 34 class (17 males and 17 females) who were recruited at the Department of Orthodontics, University of Damascus Dental School (Syria). Using on-demand three-dimensional (3D) on axial views, facial axis points for dental measurements and basal bone center (BBC) points for basal measurements were identified on lower canines and first molars. Dental and basal intercanine width (ICW) and intermolar width (IMW) were measured. Results: Independent t-test showed a statistically significant difference between males and females in several variables in both groups and a statistically significant difference between class I and class groups in the basal ICW for both genders and in the dental ICW for females only (p < 0.05). In class I group, Pearson's correlation coefficients between dental and basal measurements showed a strong correlation in the IMW for both genders (r > 0.73; p < 0.01) and a moderate correlation in females' ICW (r = 0.67; p < 0.01). In the class group, a moderate correlation in females' IMW (r = 0.67; p < 0.01) was found. Conclusion: Females compared with males had narrower dimensions. Class I patients had larger ICW than class II-1 patients in all measurements and had narrower IMW than class in most measurements for both genders. There were moderate-to-strong correlations between dental and basal dimensions. BBC points might be landmarks that accurately represent the basal bone arch. Clinical significance: CBCT-based assessments of dental

  12. Widespread dissemination of class 1 integron components in soils and related ecosystems as revealed by cultivation-independent analysis.

    PubMed

    Jechalke, Sven; Schreiter, Susanne; Wolters, Birgit; Dealtry, Simone; Heuer, Holger; Smalla, Kornelia

    2013-01-01

    Class 1 integrons contribute to the emerging problem of antibiotic resistance in human medicine by acquisition, exchange, and expression of resistance genes embedded within gene cassettes. Besides the clinical setting they were recently reported from environmental habitats and often located on plasmids and transposons, facilitating their transfer and spread within bacterial communities. In this study we aimed to provide insights into the occurrence of genes typically associated with the class 1 integrons in previously not studied environments with or without human impact and their association with IncP-1 plasmids. Total community DNA was extracted from manure-treated and untreated soils, lettuce and potato rhizosphere, digestates, and an on-farm biopurification system and screened by PCR with subsequent Southern blot hybridization for the presence of the class 1 integrase gene intI1 as well as qacE and qacEΔ 1 resistance genes. The results revealed a widespread dissemination of class 1 integrons in the environments analyzed, mainly related to the presence of qacEΔ 1 genes. All 28 IncP-1ε plasmids carrying class 1 integrons, which were captured exogenously in a recent study from piggery manure and soils treated with manure, carried qacEΔ 1 genes. Based on the strong hybridization signals in the rhizosphere of lettuce compared to the potato rhizosphere, the abundances of intI1, qacE/qacEΔ 1, and sul1 genes were quantified relative to the 16S rRNA gene abundance by real-time PCR in the rhizosphere of lettuce planted in three different soils and in the corresponding bulk soil. A significant enrichment of intI1 and qacE/qacEΔ 1 genes was confirmed in the rhizosphere of lettuce compared to bulk soil. Additionally, the relative abundance of korB genes specific for IncP-1 plasmids was enriched in the rhizosphere and correlated to the intI1 gene abundance indicating that IncP-1 plasmids might have contributed to the spread of class 1 integrons in the analyzed soils.

  13. Lack of MHC class I antigens and tumour aggressiveness of the squamous cell carcinoma of the larynx.

    PubMed Central

    Esteban, F.; Concha, A.; Delgado, M.; Pérez-Ayala, M.; Ruiz-Cabello, F.; Garrido, F.

    1990-01-01

    A series of 60 primary laryngeal and hypopharyngeal tumours, 24 lymph node metastases and normal tissue were evaluated in frozen sections for the expression of MHC class I antigens, using monoclonal antibodies and the APAAP technique. We found 13 tumours presenting total HLA-ABC loss, five with selective loss of HLA-A antigens and one with absence of HLA-B antigens. These losses were statistically associated with clinical and pathological parameters, such as T stage, degree of differentiation, scores according to the Jakobsson and Glanz grading systems and degree of leukocytic infiltration. Our results lead us to the following conclusions: (a) HLA class I losses were found in a group of tumours showing greater aggressiveness and worse prognosis; (b) these alterations in expression were not associated with an increased metastatic potential. Thus, the absence of HLA molecules in laryngeal tumours is related to greater local aggressiveness, and the loss of class I antigens seems to constitute an adaptive tumour mechanism to avoid the different anatomical and immunological barriers within the larynx. Images Figure 1 Figure 2 PMID:2257212

  14. Sequence analysis of MHC class I α2 from sockeye salmon (Oncorhynchus nerka).

    PubMed

    McClelland, Erin K; Ming, Tobi J; Tabata, Amy; Miller, Kristina M

    2011-09-01

    Most studies assessing adaptive MHC diversity in salmon populations have focused on the classical class II DAB or DAA loci, as these have been most amenable to single PCR amplifications due to their relatively low level of sequence divergence. Herein, we report the characterization of the classical class I UBA α2 locus based on collections taken throughout the species range of sockeye salmon (Oncorhynchus nerka). Through use of multiple lineage-specific primer sets, denaturing gradient gel electrophoresis and sequencing, we identified thirty-four alleles from three highly divergent lineages. Sequence identity between lineages ranged from 30.0% to 56.8% but was relatively high within lineages. Allelic identity within the antigen recognition site (ARS) was greater than for the longer sequence. Global positive selection on UBA was seen at the sequence level (dN:dS = 1.012) with four codons under positive selection and 12 codons under negative selection. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

  15. Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

    PubMed Central

    Haupt, V. Joachim; Schroeder, Michael; Labudde, Dirk

    2018-01-01

    The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes. Both classes differ significantly on a sequence and structural level, feature different reaction mechanisms, and occur in diverse oligomerization states. The one unifying aspect of both classes is their function of binding ATP. We identified Backbone Brackets and Arginine Tweezers as most compact ATP binding motifs characteristic for each Class. Geometric analysis shows a structural rearrangement of the Backbone Brackets upon ATP binding, indicating a general mechanism of all Class I structures. Regarding the origin of aaRS, the Rodin-Ohno hypothesis states that the peculiar nature of the two aaRS classes is the result of their primordial forms, called Protozymes, being encoded on opposite strands of the same gene. Backbone Brackets and Arginine Tweezers were traced back to the proposed Protozymes and their more efficient successors, the Urzymes. Both structural motifs can be observed as pairs of residues in contemporary structures and it seems that the time of their addition, indicated by their placement in the ancient aaRS, coincides with the evolutionary trace of Proto- and Urzymes. PMID:29659563

  16. Cytotoxicity of Triorganophosphinegold(I) Complexes of Thiobenzoate

    PubMed Central

    Vincent, Beverly R.; Clarke, David J.; Smyth, Douglas R.; de Vos, Dick

    2001-01-01

    The preparation and characterization of two triorganophosphinegold(I) complexes containing the anion derived from thiobenzoic acid are described. The cytotoxicity of these complexes has been investigated along with that of triphenylphosphinegold(I) mercaptopurinate, a known anti-tumor compound, against a variety of human cell lines. The complexes showed moderate to high cytotoxicity (ID50 250 – 2500 ng/ml). PMID:18475979

  17. Use of lichen fumigation studies to evaluate the effects of new emission sources on class I areas

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hart, R.; Webb, P.G.; Biggs, R.H.

    1988-02-01

    Allowable increments of SO/sub 2/ from new emission sources near Class I areas are severely limited by the PSD provisions of the Clean Air Act, unless the applicant can prove that the expected emissions will not adversely affect the air quality related values of Class I area. Lichens are considered to be the resource that is most sensitive to SO/sub 2/. If projected concentrations will not injure lichens, other resources should not be affected. Four lichen species native to two Class I area, Cape Romain National Wildlife Refuge and Everglades National Park, were fumigated in the laboratory with SO/sub 2/more » doses that simulated the frequencies, duration, and concentrations expected from potential new sources. Lichens from Cape Romain were fumigated with 240 ..mu..g/m/sup 3/, 400 ..mu..g/m/sup 3/, and ambient air 3 hours/week for 6 weeks. No differences in biomass gain, percent electrolyte leakage in solution (an indicator of membrane damage) or /sup 14/CO/sub 2/ assimilation were observed among treatments. Lichens from Everglades National Park were fumigated with 100 ..mu..g/m/sup 3/, 200 ..mu..g/m/sup 3/, 400 ..mu..g/m/sup 3/, and ambient air 6 hours/week for 10 weeks. Percent electrolyte leakage of Parmotrema tinctorum was greater at the two high concentrations, but there was no significant effect on biomass gain or /sup 14/CO/sub 2/ assimilation. Percent electrolyte leakage increased and biomass gain and /sup 14/CO/sub 2/ assimilation decreased in Ramalina denticulata at 400 ..mu..g/m/sup 3/ SO/sub 2/ in comparison with lower concentrations. Studies of fumigation effects on lichens are a useful technique for the evaluation of impacts of emission sources on air quality related values in Class I areas.« less

  18. Working-Class Women's Ways of Knowing: Effects of Gender, Race and Class.

    ERIC Educational Resources Information Center

    Luttrell, Wendy

    1989-01-01

    Analyzes the way black and white working-class women define and claim knowledge, challenging feminist analyses that have identified a single or universal mode of knowing for women. Contends that women speak to complex gender, racial, and class relations of power that shape how they think about learning and knowing. (Author/SLM)

  19. Human Relations Class. A Syllabus.

    ERIC Educational Resources Information Center

    Guillen, Mary A.

    A junior high level human relations class develops human interaction and oral communication skills. A week-by-week syllabus contains the following components: introduction of the students to each other and to the principles of body language, transactional analysis, and group interaction; behavior contracts; group dynamics topics and exercises;…

  20. Tailoring of EIA-649-1: Definition of Major (Class I) Engineering Change Proposal

    DTIC Science & Technology

    2015-05-15

    MISSILE SYSTEMS CENTER TAILORING TAILORING OF EIA -649-1: DEFINITION OF MAJOR (CLASS I) ENGINEERING CHANGE PROPOSAL APPROVED FOR...PUBLIC RELEASE; DISTRIBUTION IS UNLIMITED 1 Tailoring of EIA -649-1: Definition of Major (Class I) ECP. 1. Intent of this Tailoring Document...This tailoring document remedies a requirements gap in the industry consensus standard, EIA -649-1: 2015. Specifically, this tailoring provides a

  1. Gender, social class, and women's employment.

    PubMed

    McGinn, Kathleen L; Oh, Eunsil

    2017-12-01

    People in low-power positions, whether due to gender or class, tend to exhibit other-oriented rather than self-oriented behavior. Women's experiences at work and at home are shaped by social class, heightening identification with gender for relatively upper class women and identification with class for relatively lower class women, potentially mitigating, or even reversing, class-based differences documented in past research. Gender-class differences are reflected in women's employment beliefs and behaviors. Research integrating social class with gendered experiences in homes and workplaces deepens our understanding of the complex interplay between sources of power and status in society. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. z -classes of isometries of the hyperbolic space

    NASA Astrophysics Data System (ADS)

    Gongopadhyay, Krishnendu; Kulkarni, Ravi S.

    Let G be a group. Two elements x, y are said to be z -equivalent if their centralizers are conjugate in G . The class equation of G is the partition of G into conjugacy classes. Further decomposition of conjugacy classes into z -classes provides important information about the internal structure of the group; cf. J. Ramanujan Math. Soc. 22 (2007), 35-56, for the elaboration of this theme. Let I(H^n) denote the group of isometries of the hyperbolic n -space, and let I_o(H^n) be the identity component of I(H^n) . We show that the number of z -classes in I(H^n) is finite. We actually compute their number; cf. theorem 1.3. We interpret the finiteness of z -classes as accounting for the finiteness of ``dynamical types'' in I(H^n) . Along the way we also parametrize conjugacy classes. We mainly use the linear model of the hyperbolic space for this purpose. This description of parametrizing conjugacy classes appears to be new; cf. Academic Press, New York, 1974, 49-87 and Conformal geometry (Bonn, 1985/1986), 41-64, Aspects Math., E12, Vieweg, Braunschweig, 1988, for previous attempts. Ahlfors (Differential Geometry and Complex Analysis (Springer, 1985), 65-73) suggested the use of Clifford algebras to deal with higher dimensional hyperbolic geometry; cf. Ann. Acad. Sci. Fenn. Ser. A I Math. 10 (1985), 15-27, Quasiconformal Mappings and Analysis (Springer, 1998), 109-139, Complex Variables Theory Appl. 15 (1990), 125-133, and Adv. Math. 101 (1993), 87-113. These works may be compared to the approach suggested in this paper. In dimensions 2 and 3 , by remarkable Lie-theoretic isomorphisms, I_o(H2) and I_o(H3) can be lifted to GL_o(2, R) , and GL(2, C) respectively. For orientation-reversing isometries there are some modifications of these liftings. Using these liftings, in the appendix A, we have introduced a single numerical invariant c(A) , to classify the elements of I(H2) and I(H3) , and explained the classical terminology. Using the ``Iwasawa decomposition'' of I

  3. HLA Class I Sensitization in Islet Transplant Recipients – Report from the Collaborative Islet Transplant Registry

    PubMed Central

    Naziruddin, Bashoo; Wease, Steve; Stablein, Donald; Barton, Franca B.; Berney, Thierry; Rickels, Michael R.; Alejandro, Rodolfo

    2015-01-01

    Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and post-transplant human leukocyte antigen (HLA) class I sensitization rates in islet alone transplantation. Data came from 303 recipients transplanted with islet alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly post-transplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pre-transplant PRA was not predictive of islet graft failure. However, development of PRA ≥20% post-transplant was associated with 3.6 fold (p=.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions. PMID:22080832

  4. The overlooked "nonclassical" functions of major histocompatibility complex (MHC) class II antigens in immune and nonimmune cells.

    PubMed

    Altomonte, M; Pucillo, C; Maio, M

    1999-06-01

    Besides their "classical" antigenic peptide-presenting activity, major histocompatibility complex (MHC) class II antigens can activate different cellular functions in immune and nonimmune cells. However, this "nonclassical" role and its functional consequences are still substantially overlooked. In this review, we will focus on these alternative functional properties of MHC class II antigens, to reawaken attention to their present and foreseeable immunobiologic and pathogenetic implications. The main issues that will be addressed concern 1) the role of MHC class II molecules as basic components of exchangeable oligomeric protein complexes with intracellular signaling ability; 2) the nonclassical functions of MHC class II antigens in immune cells; 3) the pathogenetic role of MHC class II antigens in inflammatory/autoimmune and infectious disease; and 4) the functional role of MHC class II antigens in solid malignancies.

  5. SU-F-T-312: Identifying Distinct Radiation Therapy Plan Classes Through Multi-Dimensional Analysis of Plan Complexity Metrics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Desai, V; Labby, Z; Culberson, W

    Purpose: To determine whether body site-specific treatment plans form unique “plan class” clusters in a multi-dimensional analysis of plan complexity metrics such that a single beam quality correction determined for a representative plan could be universally applied within the “plan class”, thereby increasing the dosimetric accuracy of a detector’s response within a subset of similarly modulated nonstandard deliveries. Methods: We collected 95 clinical volumetric modulated arc therapy (VMAT) plans from four body sites (brain, lung, prostate, and spine). The lung data was further subdivided into SBRT and non-SBRT data for a total of five plan classes. For each control pointmore » in each plan, a variety of aperture-based complexity metrics were calculated and stored as unique characteristics of each patient plan. A multiple comparison of means analysis was performed such that every plan class was compared to every other plan class for every complexity metric in order to determine which groups could be considered different from one another. Statistical significance was assessed after correcting for multiple hypothesis testing. Results: Six out of a possible 10 pairwise plan class comparisons were uniquely distinguished based on at least nine out of 14 of the proposed metrics (Brain/Lung, Brain/SBRT lung, Lung/Prostate, Lung/SBRT Lung, Lung/Spine, Prostate/SBRT Lung). Eight out of 14 of the complexity metrics could distinguish at least six out of the possible 10 pairwise plan class comparisons. Conclusion: Aperture-based complexity metrics could prove to be useful tools to quantitatively describe a distinct class of treatment plans. Certain plan-averaged complexity metrics could be considered unique characteristics of a particular plan. A new approach to generating plan-class specific reference (pcsr) fields could be established through a targeted preservation of select complexity metrics or a clustering algorithm that identifies plans exhibiting similar

  6. Rotationally-supported disks around Class I sources in Taurus: disk formation constraints

    NASA Astrophysics Data System (ADS)

    Harsono, D.; Jørgensen, J. K.; van Dishoeck, E. F.; Hogerheijde, M. R.; Bruderer, S.; Persson, M. V.; Mottram, J. C.

    2014-02-01

    Context. Disks are observed around pre-main sequence stars, but how and when they form is still heavily debated. While disks around young stellar objects have been identified through thermal dust emission, spatially and spectrally resolved molecular line observations are needed to determine their nature. Only a handful of embedded rotationally supported disks have been identified to date. Aims: We identify and characterize rotationally supported disks near the end of the main accretion phase of low-mass protostars by comparing their gas and dust structures. Methods: Subarcsecond observations of dust and gas toward four Class I low-mass young stellar objects in Taurus are presented at significantly higher sensitivity than previous studies. The 13CO and C18O J = 2-1 transitions at 220 GHz were observed with the Plateau de Bure Interferometer at a spatial resolution of ≤0.8″ (56 AU radius at 140 pc) and analyzed using uv-space position velocity diagrams to determine the nature of their observed velocity gradient. Results: Rotationally supported disks (RSDs) are detected around 3 of the 4 Class I sources studied. The derived masses identify them as Stage I objects; i.e., their stellar mass is higher than their envelope and disk masses. The outer radii of the Keplerian disks toward our sample of Class I sources are ≤100 AU. The lack of on-source C18O emission for TMR1 puts an upper limit of 50 AU on its size. Flattened structures at radii >100 AU around these sources are dominated by infalling motion (υ ∝ r-1). A large-scale envelope model is required to estimate the basic parameters of the flattened structure from spatially resolved continuum data. Similarities and differences between the gas and dust disk are discussed. Combined with literature data, the sizes of the RSDs around Class I objects are best described with evolutionary models with an initial rotation of Ω = 10-14 Hz and slow sound speeds. Based on the comparison of gas and dust disk masses

  7. Amyloid Precursor-like Protein 2 Increases the Endocytosis, Instability, and Turnover of the H2-Kd MHC Class I Molecule1

    PubMed Central

    Tuli, Amit; Sharma, Mahak; McIlhaney, Mary M.; Talmadge, James E.; Naslavsky, Naava; Caplan, Steve; Solheim, Joyce C.

    2008-01-01

    The defense against the invasion of viruses and tumors relies on the presentation of viral and tumor-derived peptides to cytotoxic T lymphocytes by cell surface major histocompatibility complex (MHC) class I molecules. Previously, we showed that the ubiquitously expressed protein amyloid precursor-like protein 2 (APLP2) associates with the folded form of the MHC class I molecule Kd. In the current study, APLP2 was found to associate with folded Kd molecules following their endocytosis and to increase the amount of endocytosed Kd. In addition, increased expression of APLP2 was shown to decrease Kd surface expression and thermostability. Correspondingly, Kd thermostability and surface expression were increased by down-regulation of APLP2 expression. Overall, these data suggest that APLP2 modulates the stability and endocytosis of Kd molecules. PMID:18641335

  8. 49 CFR Schedule A to Subpart B of... - Class I Participating Carriers' Revenue Data

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... provide a data base for the continuing evaluation of the validity and usefulness of the “study carrier... 49 Transportation 8 2010-10-01 2010-10-01 false Class I Participating Carriers' Revenue Data A...—Class I Participating Carriers' Revenue Data [Dollars in thousands] Line No. and carrier annual report...

  9. 49 CFR Schedule A to Subpart B of... - Class I Participating Carriers' Revenue Data

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... provide a data base for the continuing evaluation of the validity and usefulness of the “study carrier... 49 Transportation 8 2012-10-01 2012-10-01 false Class I Participating Carriers' Revenue Data A...—Class I Participating Carriers' Revenue Data [Dollars in thousands] Line No. and carrier annual report...

  10. 49 CFR Schedule A to Subpart B of... - Class I Participating Carriers' Revenue Data

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... provide a data base for the continuing evaluation of the validity and usefulness of the “study carrier... 49 Transportation 8 2013-10-01 2013-10-01 false Class I Participating Carriers' Revenue Data A...—Class I Participating Carriers' Revenue Data [Dollars in thousands] Line No. and carrier annual report...

  11. 49 CFR Schedule A to Subpart B of... - Class I Participating Carriers' Revenue Data

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... provide a data base for the continuing evaluation of the validity and usefulness of the “study carrier... 49 Transportation 8 2014-10-01 2014-10-01 false Class I Participating Carriers' Revenue Data A...—Class I Participating Carriers' Revenue Data [Dollars in thousands] Line No. and carrier annual report...

  12. 49 CFR Schedule A to Subpart B of... - Class I Participating Carriers' Revenue Data

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... provide a data base for the continuing evaluation of the validity and usefulness of the “study carrier... 49 Transportation 8 2011-10-01 2011-10-01 false Class I Participating Carriers' Revenue Data A...—Class I Participating Carriers' Revenue Data [Dollars in thousands] Line No. and carrier annual report...

  13. Colonia Tovar: the history of a semi-isolated Venezuelan population of German ancestry described by HLA class I genes.

    PubMed

    Gendzekhadze, K; Montagnani, S; Ogando, V; Balbas, O; Mendez-Castellano, H; Layrisse, Z

    2003-11-01

    The history of Colonia Tovar is very complex, being the home of descendants of only a small fraction of immigrants arriving to the South American continent from a specific region of Germany, with a restricted number of founders, small population size and consanguineous mating, experiencing isolation for 100 years, with later migrations, a low rate of population growth and a high mean number of children per couple. How complex is its genetic structure? Do the highly polymorphic HLA genes reflect its history and confirm the story of this population described by other genes? Several studies have been made in this population, but we describe for the first time the HLA Class I variability in the population of Colonia Tovar using PCR-SSOP. Random genetic drift, founder effect and gene flow could explain the HLA allele and haplotype frequencies observed in this population but alleles at the class I loci were insufficient to identify the German origin of the community established through history. This agrees with findings obtained testing other genetic systems (ACP, AK, ESD, G6PD, GLO, PGM, PGD, ALB, CP, HP, TF), but the HLA-typing results indicate that the original gene pool has been diluted due to gene flow from the surrounding Mestizo population.

  14. Major histocompatibility complex class II molecule expression on muscle cells is regulated by differentiation: implications for the immunopathogenesis of muscle autoimmune diseases.

    PubMed

    Mantegazza, R; Gebbia, M; Mora, M; Barresi, R; Bernasconi, P; Baggi, F; Cornelio, F

    1996-08-01

    Major histocompatibility complex (MHC) class II molecules are expressed on myoblasts after interferon-gamma (IFN-gamma) treatment, suggesting a muscle cell involvement in antigen presentation in inflammatory myopathies. However, they were not observed on normal or pathological myofibers. This discrepancy might be related to different responsiveness of developmentally differentiated muscle cells to IFN-gamma. Myoblasts expressed class II transcripts and proteins after IFN-gamma, while myotubes and innervated contracting muscle cells did not show staining for class II molecules. At all cell stages no loss of IFN-gamma receptor was detected indicating that myofiber maturation blocks their capacity to express MHC class II molecules. This suggests that completely differentiated myofibers cannot participate in class II restricted immunological reactions.

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

    PubMed

    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.

  16. Sex-related and non-sex-related comorbidity subtypes of tic disorders: a latent class approach.

    PubMed

    Rodgers, S; Müller, M; Kawohl, W; Knöpfli, D; Rössler, W; Castelao, E; Preisig, M; Ajdacic-Gross, V

    2014-05-01

    Recent evidence suggests that there may be more than one Gilles de la Tourette syndrome (GTS)/tic disorder phenotype. However, little is known about the common patterns of these GTS/tic disorder-related comorbidities. In addition, sex-specific phenomenological data of GTS/tic disorder-affected adults are rare. Therefore, this community-based study used latent class analyses (LCA) to investigate sex-related and non-sex-related subtypes of GTS/tic disorders and their most common comorbidities. The data were drawn from the PsyCoLaus study (n = 3691), a population-based survey conducted in Lausanne, Switzerland. LCA were performed on the data of 80 subjects manifesting motor/vocal tics during their childhood/adolescence. Comorbid attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depressive, phobia and panic symptoms/syndromes comprised the selected indicators. The resultant classes were characterized by psychosocial correlates. In LCA, four latent classes provided the best fit to the data. We identified two male-related classes. The first class exhibited both ADHD and depression. The second class comprised males with only depression. Class three was a female-related class depicting obsessive thoughts/compulsive acts, phobias and panic attacks. This class manifested high psychosocial impairment. Class four had a balanced sex proportion and comorbid symptoms/syndromes such as phobias and panic attacks. The complementary occurrence of comorbid obsessive thoughts/compulsive acts and ADHD impulsivity was remarkable. To the best of our knowledge, this is the first study applying LCA to community data of GTS symptoms/tic disorder-affected persons. Our findings support the utility of differentiating GTS/tic disorder subphenotypes on the basis of comorbid syndromes. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  17. New results on Class I methanol masers in nearby low-mass star formation regions

    NASA Astrophysics Data System (ADS)

    Kalenskii, S. V.; Kurtz, S.; Hofner, P.

    We present the review of the properties of Class I methanol masers detected in low-mass star forming regions (LMSFRs). These masers, called further LMMIs, are associated with postshock gas in the lobes of chemically active outflows in LMSFRs NGC1333,NGC2023, HH25, and L1157. Flux densities of these masers are no higher than 18 Jy at 44 GHz and are lower in the other Class I lines, being much lower than those of strong Class I masers in the regions of high-mass star formation. However, LMMI luminosities at 44 GHz match the relation "maser luminosity-protostar luminosity" established for high- and intermediate-mass protostars. No variability of LMMIs has been found in 2004-2011. Radial velocities of most LMMIs are close to the systemic velocities of associated regions. The only known exception is the maser detected at 36 GHz toward the blue lobe of the extra-high-velocity outflow in NGC2023, whose radial velocity is 3.5 km s-1 lower than the systemic velocity. Four masers, NGC1333I2A, NGC1333I4A, HH25MMS, and L1157 have been observed at 44 GHz with the VLA in the D configuration with an angular resolution of about 1:500. All of them except NGC1333I2A have been later reobserved with the EVLA in the B configuration, which provides an angular resolution of about 0:200 at this frequency. The maser images consist of compact spots, unresolved or barely resolved even with the B configuration. The brightness temperatures of the strongest spots are hundreds of thousands Kelvins. Many spots consist of two spatial components and demonstrate double spectral lines. An interesting result is the detection of unresolved spots demonstrating broad(˜3-5 km s-1) spectral lines. Their fluxes correspond to brightness temperatures ˜1000 K. Thus, in spite of large linewidths, these objects could be weak masers. Probably, the broad lines, detected in some sources at 44 GHz and in other Class I lines as a result of single-dish observations, are also masers. We believe that turbulence plays

  18. Binding stability of peptides on major histocompatibility complex class I proteins: role of entropy and dynamics.

    PubMed

    Gul, Ahmet; Erman, Burak

    2018-01-16

    Prediction of peptide binding on specific human leukocyte antigens (HLA) has long been studied with successful results. We herein describe the effects of entropy and dynamics by investigating the binding stabilities of 10 nanopeptides on various HLA Class I alleles using a theoretical model based on molecular dynamics simulations. The fluctuational entropies of the peptides are estimated over a temperature range of 310-460 K. The estimated entropies correlate well with experimental binding affinities of the peptides: peptides that have higher binding affinities have lower entropies compared to non-binders, which have significantly larger entropies. The computation of the entropies is based on a simple model that requires short molecular dynamics trajectories and allows for approximate but rapid determination. The paper draws attention to the long neglected dynamic aspects of peptide binding, and provides a fast computation scheme that allows for rapid scanning of large numbers of peptides on selected HLA antigens, which may be useful in defining the right peptides for personal immunotherapy.

  19. Binding stability of peptides on major histocompatibility complex class I proteins: role of entropy and dynamics

    NASA Astrophysics Data System (ADS)

    Gul, Ahmet; Erman, Burak

    2018-03-01

    Prediction of peptide binding on specific human leukocyte antigens (HLA) has long been studied with successful results. We herein describe the effects of entropy and dynamics by investigating the binding stabilities of 10 nanopeptides on various HLA Class I alleles using a theoretical model based on molecular dynamics simulations. The fluctuational entropies of the peptides are estimated over a temperature range of 310-460 K. The estimated entropies correlate well with experimental binding affinities of the peptides: peptides that have higher binding affinities have lower entropies compared to non-binders, which have significantly larger entropies. The computation of the entropies is based on a simple model that requires short molecular dynamics trajectories and allows for approximate but rapid determination. The paper draws attention to the long neglected dynamic aspects of peptide binding, and provides a fast computation scheme that allows for rapid scanning of large numbers of peptides on selected HLA antigens, which may be useful in defining the right peptides for personal immunotherapy.

  20. Discrete structural features among interface residue-level classes.

    PubMed

    Sowmya, Gopichandran; Ranganathan, Shoba

    2015-01-01

    Protein-protein interaction (PPI) is essential for molecular functions in biological cells. Investigation on protein interfaces of known complexes is an important step towards deciphering the driving forces of PPIs. Each PPI complex is specific, sensitive and selective to binding. Therefore, we have estimated the relative difference in percentage of polar residues between surface and the interface for each complex in a non-redundant heterodimer dataset of 278 complexes to understand the predominant forces driving binding. Our analysis showed ~60% of protein complexes with surface polarity greater than interface polarity (designated as class A). However, a considerable number of complexes (~40%) have interface polarity greater than surface polarity, (designated as class B), with a significantly different p-value of 1.66E-45 from class A. Comprehensive analyses of protein complexes show that interface features such as interface area, interface polarity abundance, solvation free energy gain upon interface formation, binding energy and the percentage of interface charged residue abundance distinguish among class A and class B complexes, while electrostatic visualization maps also help differentiate interface classes among complexes. Class A complexes are classical with abundant non-polar interactions at the interface; however class B complexes have abundant polar interactions at the interface, similar to protein surface characteristics. Five physicochemical interface features analyzed from the protein heterodimer dataset are discriminatory among the interface residue-level classes. These novel observations find application in developing residue-level models for protein-protein binding prediction, protein-protein docking studies and interface inhibitor design as drugs.

  1. Discrete structural features among interface residue-level classes

    PubMed Central

    2015-01-01

    Background Protein-protein interaction (PPI) is essential for molecular functions in biological cells. Investigation on protein interfaces of known complexes is an important step towards deciphering the driving forces of PPIs. Each PPI complex is specific, sensitive and selective to binding. Therefore, we have estimated the relative difference in percentage of polar residues between surface and the interface for each complex in a non-redundant heterodimer dataset of 278 complexes to understand the predominant forces driving binding. Results Our analysis showed ~60% of protein complexes with surface polarity greater than interface polarity (designated as class A). However, a considerable number of complexes (~40%) have interface polarity greater than surface polarity, (designated as class B), with a significantly different p-value of 1.66E-45 from class A. Comprehensive analyses of protein complexes show that interface features such as interface area, interface polarity abundance, solvation free energy gain upon interface formation, binding energy and the percentage of interface charged residue abundance distinguish among class A and class B complexes, while electrostatic visualization maps also help differentiate interface classes among complexes. Conclusions Class A complexes are classical with abundant non-polar interactions at the interface; however class B complexes have abundant polar interactions at the interface, similar to protein surface characteristics. Five physicochemical interface features analyzed from the protein heterodimer dataset are discriminatory among the interface residue-level classes. These novel observations find application in developing residue-level models for protein-protein binding prediction, protein-protein docking studies and interface inhibitor design as drugs. PMID:26679043

  2. Disk Masses for Embedded Class I Protostars in the Taurus Molecular Cloud

    NASA Astrophysics Data System (ADS)

    Sheehan, Patrick D.; Eisner, Josh A.

    2017-12-01

    Class I protostars are thought to represent an early stage in the lifetime of protoplanetary disks, when they are still embedded in their natal envelope. Here we measure the disk masses of 10 Class I protostars in the Taurus Molecular Cloud to constrain the initial mass budget for forming planets in disks. We use radiative transfer modeling to produce synthetic protostar observations and fit the models to a multi-wavelength data set using a Markov Chain Monte Carlo fitting procedure. We fit these models simultaneously to our new Combined Array for Research in Millimeter-wave Astronomy 1.3 mm observations that are sensitive to the wide range of spatial scales that are expected from protostellar disks and envelopes so as to be able to distinguish each component, as well as broadband spectral energy distributions compiled from the literature. We find a median disk mass of 0.018 {M}ȯ on average, more massive than the Taurus Class II disks, which have median disk mass of ∼ 0.0025 {M}ȯ . This decrease in disk mass can be explained if dust grains have grown by a factor of 75 in grain size, indicating that by the Class II stage, at a few Myr, a significant amount of dust grain processing has occurred. However, there is evidence that significant dust processing has occurred even during the Class I stage, so it is likely that the initial mass budget is higher than the value quoted here.

  3. Comprehensive analysis of MHC class I genes from the U-, S-, and Z-lineages in Atlantic salmon.

    PubMed

    Lukacs, Morten F; Harstad, Håvard; Bakke, Hege G; Beetz-Sargent, Marianne; McKinnel, Linda; Lubieniecki, Krzysztof P; Koop, Ben F; Grimholt, Unni

    2010-03-05

    We have previously sequenced more than 500 kb of the duplicated MHC class I regions in Atlantic salmon. In the IA region we identified the loci for the MHC class I gene Sasa-UBA in addition to a soluble MHC class I molecule, Sasa-ULA. A pseudolocus for Sasa-UCA was identified in the nonclassical IB region. Both regions contained genes for antigen presentation, as wells as orthologues to other genes residing in the human MHC region. The genomic localisation of two MHC class I lineages (Z and S) has been resolved. 7 BACs were sequenced using a combination of standard Sanger and 454 sequencing. The new sequence data extended the IA region with 150 kb identifying the location of one Z-lineage locus, ZAA. The IB region was extended with 350 kb including three new Z-lineage loci, ZBA, ZCA and ZDA in addition to a UGA locus. An allelic version of the IB region contained a functional UDA locus in addition to the UCA pseudolocus. Additionally a BAC harbouring two MHC class I genes (UHA) was placed on linkage group 14, while a BAC containing the S-lineage locus SAA (previously known as UAA) was placed on LG10. Gene expression studies showed limited expression range for all class I genes with exception of UBA being dominantly expressed in gut, spleen and gills, and ZAA with high expression in blood. Here we describe the genomic organization of MHC class I loci from the U-, Z-, and S-lineages in Atlantic salmon. Nine of the described class I genes are located in the extension of the duplicated IA and IB regions, while three class I genes are found on two separate linkage groups. The gene organization of the two regions indicates that the IB region is evolving at a different pace than the IA region. Expression profiling, polymorphic content, peptide binding properties and phylogenetic relationship show that Atlantic salmon has only one MHC class Ia gene (UBA), in addition to a multitude of nonclassical MHC class I genes from the U-, S- and Z-lineages.

  4. Reactivity Study of Unsymmetrical β-Diketiminato Copper(I) Complexes: Effect of the Chelating Ring.

    PubMed

    Chuang, Wan-Jung; Hsu, Sung-Po; Chand, Kuldeep; Yu, Fu-Lun; Tsai, Cheng-Long; Tseng, Yu-Hsuan; Lu, Yuh-Hsiu; Kuo, Jen-Yu; Carey, James R; Chen, Hsuan-Ying; Chen, Hsing-Yin; Chiang, Michael Y; Hsu, Sodio C N

    2017-03-06

    β-Diketiminato copper(I) complexes play important roles in bioinspired catalytic chemistry and in applications to the materials industry. However, it has been observed that these complexes are very susceptible to disproportionation. Coordinating solvents or Lewis bases are typically used to prevent disproportionation and to block the coordination sites of the copper(I) center from further decomposition. Here, we incorporate this coordination protection directly into the molecule in order to increase the stability and reactivity of these complexes and to discover new copper(I) binding motifs. Here we describe the synthesis, structural characterization, and reactivity of a series of unsymmetrical N-aryl-N'-alkylpyridyl β-diketiminato copper(I) complexes and discuss the structures and reactivity of these complexes with respect to the length of the pyridyl arm. All of the aforementioned unsymmetrical ß-diketiminato copper(I) complexes bind CO reversibly and are stable to disproportionation. The binding ability of CO and the rate of pyridyl ligand decoordination of these copper(I) complexes are directly related to the competition between the degree of puckering of the chelate system and the steric demands of the N-aryl substituent.

  5. LINEAR POLARIZATION OF CLASS I METHANOL MASERS IN MASSIVE STAR-FORMING REGIONS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kang, Ji-hyun; Byun, Do-Young; Kim, Kee-Tae

    Class I methanol masers are found to be good tracers of the interaction between outflows from massive young stellar objects with their surrounding media. Although polarization observations of Class II methanol masers have been able to provide information about magnetic fields close to the central (proto)stars, polarization observations of Class I methanol masers are rare, especially at 44 and 95 GHz. We present the results of linear polarization observations of 39 Class I methanol maser sources at 44 and 95 GHz. These two lines are observed simultaneously with one of the 21 m Korean VLBI Network telescopes in single-dish mode.more » Approximately 60% of the observed sources have fractional polarizations of a few percent in at least one transition. This is the first reported detection of linear polarization of the 44 GHz methanol maser. The two maser transitions show similar polarization properties, indicating that they trace similar magnetic environments, although the fraction of the linear polarization is slightly higher at 95 GHz. We discuss the association between the directions of polarization angles and outflows. We also discuss some targets having different polarization properties at both lines, including DR21(OH) and G82.58+0.20, which show the 90° polarization angle flip at 44 GHz.« less

  6. Class I methanol masers in NGC 253: Alcohol at the end of the bar

    NASA Astrophysics Data System (ADS)

    Ellingsen, S. P.; Chen, X.; Breen, S. L.; Qiao, H.-H.

    2017-11-01

    We have used the Australia Telescope Compact Array to observe the 36.2-GHz class I methanol maser emission towards NGC 253 and find that it is located at the interface between the nuclear ring and both ends of the galactic bar. This is thought to be the location of the inner Linblad resonance and we suggest that the maser emission in this region is likely due to large-scale cloud-cloud collisions. We have detected the first extragalactic 44.1-GHz class I methanol maser and find that it is associated with the 36.2-GHz maser emission. In contrast to the class I methanol masers found in Galactic star formation regions, the 44.1-GHz emission in NGC 253 is two orders of magnitude weaker than the 36.2-GHz masers. Both the 36.2- and 44.1-GHz emission is orders of magnitude stronger than expected from typical high-mass star formation regions. This demonstrates that the luminous class I methanol masers observed in NGC 253 are significantly different from those associated with Galactic star formation.

  7. The dhnA gene of Escherichia coli encodes a class I fructose bisphosphate aldolase.

    PubMed Central

    Thomson, G J; Howlett, G J; Ashcroft, A E; Berry, A

    1998-01-01

    The gene encoding the Escherichia coli Class I fructose-1, 6-bisphosphate aldolase (FBP aldolase) has been cloned and the protein overproduced in high amounts. This gene sequence has previously been identified as encoding an E. coli dehydrin in the GenBanktrade mark database [gene dhnA; entry code U73760; Close and Choi (1996) Submission to GenBanktrade mark]. However, the purified protein overproduced from the dhnA gene shares all its properties with those known for the E. coli Class I FBP aldolase. The protein is an 8-10-mer with a native molecular mass of approx. 340 kDa, each subunit consisting of 349 amino acids. The Class I enzyme shows low sequence identity with other known FBP aldolases, both Class I and Class II (in the order of 20%), which may be reflected by some novel properties of this FBP aldolase. The active-site peptide has been isolated and the Schiff-base-forming lysine residue (Lys236) has been identified by a combination of site-directed mutagenesis, kinetics and electrospray-ionization MS. A second lysine residue (Lys238) has been implicated in substrate binding. The cloning of this gene and the high levels of overexpression obtained will facilitate future structure-function studies. PMID:9531482

  8. Universality classes of fluctuation dynamics in hierarchical complex systems

    NASA Astrophysics Data System (ADS)

    Macêdo, A. M. S.; González, Iván R. Roa; Salazar, D. S. P.; Vasconcelos, G. L.

    2017-03-01

    A unified approach is proposed to describe the statistics of the short-time dynamics of multiscale complex systems. The probability density function of the relevant time series (signal) is represented as a statistical superposition of a large time-scale distribution weighted by the distribution of certain internal variables that characterize the slowly changing background. The dynamics of the background is formulated as a hierarchical stochastic model whose form is derived from simple physical constraints, which in turn restrict the dynamics to only two possible classes. The probability distributions of both the signal and the background have simple representations in terms of Meijer G functions. The two universality classes for the background dynamics manifest themselves in the signal distribution as two types of tails: power law and stretched exponential, respectively. A detailed analysis of empirical data from classical turbulence and financial markets shows excellent agreement with the theory.

  9. The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

    PubMed Central

    Tang, Minzhong; Lautenberger, James A.; Gao, Xiaojiang; Sezgin, Efe; Hendrickson, Sher L.; Troyer, Jennifer L.; David, Victor A.; Guan, Li; Mcintosh, Carl E.; Guo, Xiuchan; Zheng, Yuming; Liao, Jian; Deng, Hong; Malasky, Michael; Kessing, Bailey; Winkler, Cheryl A.; Carrington, Mary; dé The, Guy; Zeng, Yi; O'Brien, Stephen J.

    2012-01-01

    Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China. PMID:23209447

  10. Methylation of class I translation termination factors: structural and functional aspects.

    PubMed

    Graille, Marc; Figaro, Sabine; Kervestin, Stéphanie; Buckingham, Richard H; Liger, Dominique; Heurgué-Hamard, Valérie

    2012-07-01

    During protein synthesis, release of polypeptide from the ribosome occurs when an in frame termination codon is encountered. Contrary to sense codons, which are decoded by tRNAs, stop codons present in the A-site are recognized by proteins named class I release factors, leading to the release of newly synthesized proteins. Structures of these factors bound to termination ribosomal complexes have recently been obtained, and lead to a better understanding of stop codon recognition and its coordination with peptidyl-tRNA hydrolysis in bacteria. Release factors contain a universally conserved GGQ motif which interacts with the peptidyl-transferase centre to allow peptide release. The Gln side chain from this motif is methylated, a feature conserved from bacteria to man, suggesting an important biological role. However, methylation is catalysed by completely unrelated enzymes. The function of this motif and its post-translational modification will be discussed in the context of recent structural and functional studies. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  11. MHC class I in dopaminergic neurons suppresses relapse to reward seeking

    PubMed Central

    Murakami, Gen; Edamura, Mitsuhiro; Furukawa, Tomonori; Kawasaki, Hideya; Kosugi, Isao; Fukuda, Atsuo; Iwashita, Toshihide; Nakahara, Daiichiro

    2018-01-01

    Major histocompatibility complex class I (MHCI) is an important immune protein that is expressed in various brain regions, with its deficiency leading to extensive synaptic transmission that results in learning and memory deficits. Although MHCI is highly expressed in dopaminergic neurons, its role in these neurons has not been examined. We show that MHCI expressed in dopaminergic neurons plays a key role in suppressing reward-seeking behavior. In wild-type mice, cocaine self-administration caused persistent reduction of MHCI specifically in dopaminergic neurons, which was accompanied by enhanced glutamatergic synaptic transmission and relapse to cocaine seeking. Functional MHCI knockout promoted this addictive phenotype for cocaine and a natural reward, namely, sucrose. In contrast, wild-type mice overexpressing a major MHCI gene (H2D) in dopaminergic neurons showed suppressed cocaine seeking. These results show that persistent cocaine-induced reduction of MHCI in dopaminergic neurons is necessary for relapse to cocaine seeking. PMID:29546241

  12. First Magnetic Field Detection on a Class I Protostar

    NASA Astrophysics Data System (ADS)

    Johns-Krull, Christopher M.; Greene, Thomas P.; Doppmann, Greg W.; Covey, Kevin R.

    2009-08-01

    Strong stellar magnetic fields are believed to truncate the inner accretion disks around young stars, redirecting the accreting material to the high latitude regions of the stellar surface. In the past few years, observations of strong stellar fields on T Tauri stars with field strengths in general agreement with the predictions of magnetospheric accretion theory have bolstered this picture. Currently, nothing is known about the magnetic field properties of younger, more embedded Class I young stellar objects. It is believed that protostars accrete much of their final mass during the Class I phase, but the physics governing this process remains poorly understood. Here, we use high-resolution near-infrared spectra obtained with NIRSPEC on Keck and with Phoenix on Gemini South to measure the magnetic field properties of the Class I protostar WL 17. We find clear signatures of a strong stellar magnetic field. Analysis of this data suggests a surface average field strength of 2.9 ± 0.43 kG on WL 17. We present our field measurements and discuss how they fit with the general model of magnetospheric accretion in young stars. Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the Science and Technology Facilities Council (United Kingdom), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council (Australia), Ministério da Ciência e Tecnologia (Brazil), and SECYT (Argentina). The Phoenix data were obtained under the program: GS-2006A-C-12.

  13. Effectiveness of laparoscopic Roux-en-Y gastric bypass on obese class I type 2 diabetes mellitus patients.

    PubMed

    Xu, Lu; Yin, Jun; Mikami, Dean J; Portenier, Dana D; Zhou, Xiaojun; Mao, Zhongqi

    2015-01-01

    Laparoscopic Roux-en-Y gastric bypass (LRYGB) can dramatically improve type 2 diabetes mellitus (T2D) in obese class II and III patients. There is increasing evidence that shows bariatric surgery can also ameliorate T2D in patients with BMI between 30 kg/m(2) and 35 kg/m(2) (obese class I). To compare the effectiveness of LRYGB on T2D in obese class I patients with that of obese class II and III T2D patients. University Hospital, China A prospective study was performed in the authors' center from March 2010 to July 2011. Forty-two consecutive obese patients were included in the study. Anthropometric and metabolism parameters were compared between obese class II and III patients and obese class I patients before and after LRYGB. No patients were lost to follow up. After 36 months, metabolic parameters significantly improved in both groups. Partial remission rates between the 2 groups at each time point (12 months, 24 months, and 36 months) were comparable. Obese class II and III patients had higher complete remission rates at 12 months and 24 months, but no difference was observed at 36 months. Both obese class II and III patients and obese class I T2D patients showed significant improvement in multiple parameters after LRYGB. Obese class II and III patients had a higher complete remission rate than obese class I patients. Standardized remission criteria are needed to make outcomes form different centers comparable. Large prospective studies are needed and long-term outcomes have to be observed to better evaluate effectiveness of LRYGB on obese class I T2D patients. Copyright © 2015 American Society for Bariatric Surgery. All rights reserved.

  14. 40 CFR 147.2200 - State-administered program-Class I, III, IV, and V wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... the in situ combustion of coal are regulated by the Rail Road Commission of Texas under a separate UIC... program for Class I, III, IV, and V wells in the State of Texas, except for those wells on Indian lands... (SDWA). Notice of the original approval for Class I, III, IV, and V wells was published in the Federal...

  15. 40 CFR 147.2200 - State-administered program-Class I, III, IV, and V wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... the in situ combustion of coal are regulated by the Rail Road Commission of Texas under a separate UIC... program for Class I, III, IV, and V wells in the State of Texas, except for those wells on Indian lands... (SDWA). Notice of the original approval for Class I, III, IV, and V wells was published in the Federal...

  16. A complex ligase ribozyme evolved in vitro from a group I ribozyme domain

    NASA Technical Reports Server (NTRS)

    Jaeger, L.; Wright, M. C.; Joyce, G. F.; Bada, J. L. (Principal Investigator)

    1999-01-01

    Like most proteins, complex RNA molecules often are modular objects made up of distinct structural and functional domains. The component domains of a protein can associate in alternative combinations to form molecules with different functions. These observations raise the possibility that complex RNAs also can be assembled from preexisting structural and functional domains. To test this hypothesis, an in vitro evolution procedure was used to isolate a previously undescribed class of complex ligase ribozymes, starting from a pool of 10(16) different RNA molecules that contained a constant region derived from a large structural domain that occurs within self-splicing group I ribozymes. Attached to this constant region were three hypervariable regions, totaling 85 nucleotides, that gave rise to the catalytic motif within the evolved catalysts. The ligase ribozymes catalyze formation of a 3',5'-phosphodiester linkage between adjacent template-bound oligonucleotides, one bearing a 3' hydroxyl and the other a 5' triphosphate. Ligation occurs in the context of a Watson-Crick duplex, with a catalytic rate of 0.26 min(-1) under optimal conditions. The constant region is essential for catalytic activity and appears to retain the tertiary structure of the group I ribozyme. This work demonstrates that complex RNA molecules, like their protein counterparts, can share common structural domains while exhibiting distinct catalytic functions.

  17. Redox modulation of plant developmental regulators from the class I TCP transcription factor family.

    PubMed

    Viola, Ivana L; Güttlein, Leandro N; Gonzalez, Daniel H

    2013-07-01

    TEOSINTE BRANCHED1-CYCLOIDEA-PROLIFERATING CELL FACTOR1 (TCP) transcription factors participate in plant developmental processes associated with cell proliferation and growth. Most members of class I, one of the two classes that compose the family, have a conserved cysteine at position 20 (Cys-20) of the TCP DNA-binding and dimerization domain. We show that Arabidopsis (Arabidopsis thaliana) class I proteins with Cys-20 are sensitive to redox conditions, since their DNA-binding activity is inhibited after incubation with the oxidants diamide, oxidized glutathione, or hydrogen peroxide or with nitric oxide-producing agents. Inhibition can be reversed by treatment with the reductants dithiothreitol or reduced glutathione or by incubation with the thioredoxin/thioredoxin reductase system. Mutation of Cys-20 in the class I protein TCP15 abolished its redox sensitivity. Under oxidizing conditions, covalently linked dimers were formed, suggesting that inactivation is associated with the formation of intermolecular disulfide bonds. Inhibition of class I TCP protein activity was also observed in vivo, in yeast (Saccharomyces cerevisiae) cells expressing TCP proteins and in plants after treatment with redox agents. This inhibition was correlated with modifications in the expression of the downstream CUC1 gene in plants. Modeling studies indicated that Cys-20 is located at the dimer interface near the DNA-binding surface. This places this residue in the correct orientation for intermolecular disulfide bond formation and explains the sensitivity of DNA binding to the oxidation of Cys-20. The redox properties of Cys-20 and the observed effects of cellular redox agents both in vitro and in vivo suggest that class I TCP protein action is under redox control in plants.

  18. Structural analysis of DNA binding by C.Csp231I, a member of a novel class of R-M controller proteins regulating gene expression

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shevtsov, M. B.; Streeter, S. D.; Thresh, S.-J.

    2015-02-01

    The structure of the new class of controller proteins (exemplified by C.Csp231I) in complex with its 21 bp DNA-recognition sequence is presented, and the molecular basis of sequence recognition in this class of proteins is discussed. An unusual extended spacer between the dimer binding sites suggests a novel interaction between the two C-protein dimers. In a wide variety of bacterial restriction–modification systems, a regulatory ‘controller’ protein (or C-protein) is required for effective transcription of its own gene and for transcription of the endonuclease gene found on the same operon. We have recently turned our attention to a new class ofmore » controller proteins (exemplified by C.Csp231I) that have quite novel features, including a much larger DNA-binding site with an 18 bp (∼60 Å) spacer between the two palindromic DNA-binding sequences and a very different recognition sequence from the canonical GACT/AGTC. Using X-ray crystallography, the structure of the protein in complex with its 21 bp DNA-recognition sequence was solved to 1.8 Å resolution, and the molecular basis of sequence recognition in this class of proteins was elucidated. An unusual aspect of the promoter sequence is the extended spacer between the dimer binding sites, suggesting a novel interaction between the two C-protein dimers when bound to both recognition sites correctly spaced on the DNA. A U-bend model is proposed for this tetrameric complex, based on the results of gel-mobility assays, hydrodynamic analysis and the observation of key contacts at the interface between dimers in the crystal.« less

  19. Effect of monoclonal antibodies (MoAb) to class I and class II HLA antigens on lectin- and MoAb OKT3-induced lymphocyte proliferation.

    PubMed

    Akiyama, Y; Zicht, R; Ferrone, S; Bonnard, G D; Herberman, R B

    1985-04-01

    We have examined the effect of several monoclonal antibodies (MoAb) to monomorphic determinants of class II HLA antigens, and MoAb to monomorphic determinants of class I HLA antigens and to beta-2-microglobulin (beta 2-mu) on lectin- and MoAb OKT3-induced proliferation of human peripheral blood mononuclear cells (PBMNC) and cultured T cells (CTC). Some, but not all, anti-class II HLA MoAb inhibited the proliferative response of PBMNC to MoAb OKT3 and pokeweed mitogen (PWM). The degree of inhibitory effect varied considerably. This effect was not limited to anti-class II HLA MoAb since anti-class I HLA MoAb and anti-beta 2-mu MoAb also inhibited MoAb OKT3- or PWM-induced proliferative responses. In contrast, the response of PBMNC to phytohemagglutinin (PHA) and concanavalin A (Con A) was not blocked by any anti-class II HLA MoAb. However, some anti-class II HLA MoAb also inhibited the proliferative response of CTC plus allogeneic peripheral blood adherent accessory cells (AC) to PHA or Con A as well as to MoAb OKT3 or PWM. This may be attributable to the substantially greater class II HLA antigen expression by CTC than by fresh lymphocytes. Pretreatment of either CTC or AC with anti-class II HLA MoAb inhibited OKT3-induced proliferation. In contrast, pretreatment of CTC, but not AC, with anti-class I HLA MoAb inhibited the proliferative response of CTC to OKT3. Pretreatment of CTC with anti-class I HLA MoAb inhibited PHA-, Con A and PWM-induced proliferation, to a greater degree than the anti-class II HLA MoAb. It appears as if lymphocyte activation by different mitogens exhibits variable requirements for the presence of cells expressing major histocompatibility determinants. Binding of Ab to membrane markers may interfere with lymphocyte-AC cooperation, perhaps by inhibiting binding of mitogens to their receptors or by interfering with lymphocyte and AC function. We also have examined the role of class II HLA antigens on CTC by depleting class II HLA-positive cells

  20. Sequence-Based Genotyping of Expressed Swine Leukocyte Antigen Class I Alleles by Next-Generation Sequencing Reveal Novel Swine Leukocyte Antigen Class I Haplotypes and Alleles in Belgian, Danish, and Kenyan Fattening Pigs and Göttingen Minipigs.

    PubMed

    Sørensen, Maria Rathmann; Ilsøe, Mette; Strube, Mikael Lenz; Bishop, Richard; Erbs, Gitte; Hartmann, Sofie Bruun; Jungersen, Gregers

    2017-01-01

    The need for typing of the swine leukocyte antigen (SLA) is increasing with the expanded use of pigs as models for human diseases and organ-transplantation experiments, their use in infection studies, and for design of veterinary vaccines. Knowledge of SLA sequences is furthermore a prerequisite for the prediction of epitope binding in pigs. The low number of known SLA class I alleles and the limited knowledge of their prevalence in different pig breeds emphasizes the need for efficient SLA typing methods. This study utilizes an SLA class I-typing method based on next-generation sequencing of barcoded PCR amplicons. The amplicons were generated with universal primers and predicted to resolve 68-88% of all known SLA class I alleles dependent on amplicon size. We analyzed the SLA profiles of 72 pigs from four different pig populations; Göttingen minipigs and Belgian, Kenyan, and Danish fattening pigs. We identified 67 alleles, nine previously described haplotypes and 15 novel haplotypes. The highest variation in SLA class I profiles was observed in the Danish pigs and the lowest among the Göttingen minipig population, which also have the highest percentage of homozygote individuals. Highlighting the fact that there are still numerous unknown SLA class I alleles to be discovered, a total of 12 novel SLA class I alleles were identified. Overall, we present new information about known and novel alleles and haplotypes and their prevalence in the tested pig populations.

  1. A stable Fe{sup III}-Fe{sup IV} replacement of tyrosyl radical in a class I ribonucleotide reductase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Voevodskaya, N.; Lendzian, F.; Graeslund, A.

    2005-05-20

    Ribonucleotide reductase (RNR) of Chlamydia trachomatis is a class I RNR enzyme composed of two homodimeric components, proteins R1 and R2. In class I RNR, R1 has the substrate binding site, whereas R2 has a diferric site and normally in its active form a stable tyrosyl free radical. C. trachomatis RNR is unusual, because its R2 component has a phenylalanine in the place of the radical carrier tyrosine. Replacing the tyrosyl radical, a paramagnetic Fe{sup III}-Fe{sup IV} species (species X, normally a transient intermediate in the process leading to radical formation) may provide the oxidation equivalent needed to start themore » catalytic process via long range electron transfer from the active site in R1. Here EPR spectroscopy shows that in C. trachomatis RNR, species X can become essentially stable when formed in a complete RNR (R1/R2/substrate) complex, adding further weight to the possible role of this species X in the catalytic reaction.« less

  2. Energy-Complexity Relations by Structural Complexity Methods

    NASA Astrophysics Data System (ADS)

    Ricca, Renzo L.

    2011-09-01

    In this paper we shall review some of the most recent developments and results on work on energy-complexity relations and, if time will allow it, we shall provide an analytical proof of eq. (3) below, a fundamental relation between energy and complexity established by numerical experiments.

  3. Structure and spectroscopic properties of the dimeric copper(I) N-heterocyclic carbene complex [Cu₂(CNC(t-Bu))₂](PF₆)₂.

    PubMed

    Riener, Korbinian; Pöthig, Alexander; Cokoja, Mirza; Herrmann, Wolfgang A; Kühn, Fritz E

    2015-08-01

    In recent years, the use of copper N-heterocyclic carbene (NHC) complexes has expanded to fields besides catalysis, namely medicinal chemistry and luminescence applications. In the latter case, multinuclear copper NHC compounds have attracted interest, however, the number of these complexes in the literature is still quite limited. Bis[μ-1,3-bis(3-tert-butylimidazolin-2-yliden-1-yl)pyridine]-1κ(4)C(2),N:N,C(2');2κ(4)C(2),N:N,C(2')-dicopper(I) bis(hexafluoridophosphate), [Cu2(C19H25N5)2](PF6)2, is a dimeric copper(I) complex bridged by two CNC, i.e. bis(N-heterocyclic carbene)pyridine, ligands. Each Cu(I) atom is almost linearly coordinated by two NHC ligands and interactions are observed between the pyridine N atoms and the metal centres, while no cuprophilic interactions were observed. Very strong absorption bands are evident in the UV-Vis spectrum at 236 and 274 nm, and an emission band is observed at 450 nm. The reported complex is a new example of a multinuclear copper NHC complex and a member of a compound class which has only rarely been reported.

  4. Multipotent adult germ-line stem cells, like other pluripotent stem cells, can be killed by cytotoxic T lymphocytes despite low expression of major histocompatibility complex class I molecules

    PubMed Central

    Dressel, Ralf; Guan, Kaomei; Nolte, Jessica; Elsner, Leslie; Monecke, Sebastian; Nayernia, Karim; Hasenfuss, Gerd; Engel, Wolfgang

    2009-01-01

    Background Multipotent adult germ-line stem cells (maGSCs) represent a new pluripotent cell type that can be derived without genetic manipulation from spermatogonial stem cells (SSCs) present in adult testis. Similarly to induced pluripotent stem cells (iPSCs), they could provide a source of cellular grafts for new transplantation therapies of a broad variety of diseases. To test whether these stem cells can be rejected by the recipients, we have analyzed whether maGSCs and iPSCs can become targets for cytotoxic T lymphocytes (CTL) or whether they are protected, as previously proposed for embryonic stem cells (ESCs). Results We have observed that maGSCs can be maintained in prolonged culture with or without leukemia inhibitory factor and/or feeder cells and still retain the capacity to form teratomas in immunodeficient recipients. They were, however, rejected in immunocompetent allogeneic recipients, and the immune response controlled teratoma growth. We analyzed the susceptibility of three maGSC lines to CTL in comparison to ESCs, iPSCs, and F9 teratocarcinoma cells. Major histocompatibility complex (MHC) class I molecules were not detectable by flow cytometry on these stem cell lines, apart from low levels on one maGSC line (maGSC Stra8 SSC5). However, using a quantitative real time PCR analysis H2K and B2m transcripts were detected in all pluripotent stem cell lines. All pluripotent stem cell lines were killed in a peptide-dependent manner by activated CTLs derived from T cell receptor transgenic OT-I mice after pulsing of the targets with the SIINFEKL peptide. Conclusion Pluripotent stem cells, including maGSCs, ESCs, and iPSCs can become targets for CTLs, even if the expression level of MHC class I molecules is below the detection limit of flow cytometry. Thus they are not protected against CTL-mediated cytotoxicity. Therefore, pluripotent cells might be rejected after transplantation by this mechanism if specific antigens are presented and if specific

  5. Patterns of selection and allele diversity of class I and class II major histocompatibility loci across the species range of sockeye salmon (Oncorhynchus nerka).

    PubMed

    McClelland, Erin K; Ming, Tobi J; Tabata, Amy; Kaukinen, Karia H; Beacham, Terry D; Withler, Ruth E; Miller, Kristina M

    2013-09-01

    The major histocompatibility complex (MHC), an important component of the vertebrate immune system, provides an important suite of genes to examine the role of genetic diversity at non-neutral loci for population persistence. We contrasted patterns of diversity at the two classical MHC loci in sockeye salmon (Oncorhynchus nerka), MHC class I (UBA) and MHC class II (DAB), and neutral microsatellite loci across 70 populations spanning the species range from Washington State to Japan. There was no correlation in allelic richness or heterozygosity between MHC loci or between MHC loci and microsatellites. The two unlinked MHC loci may be responding to different selective pressures; the distribution of FST values for the two loci was uncorrelated, and evidence for both balancing and directional selection on alleles and lineages of DAB and UBA was observed in populations throughout the species range but rarely on both loci within a population. These results suggest that fluctuating selection has resulted in the divergence of MHC loci in contemporary populations. © 2013 John Wiley & Sons Ltd.

  6. A porphyrin complex of Gold(I): (Phosphine)gold(I) azides as cation precursors

    PubMed Central

    Partyka, David V.; Robilotto, Thomas J.; Zeller, Matthias; Hunter, Allen D.; Gray, Thomas G.

    2008-01-01

    A silver- and Brönsted acid-free protocol for generating the (tricyclohexylphosphine)gold(I) cation from the corresponding azide complexes is disclosed. The gold(I) cations so liberated are trapped by complexation with octaethylporphyrin. The first structurally authenticated gold(I) porphyrin complex crystallizes with formula C72H112Au2F12N4P2Sb2, space group C2/c, a = 21.388 (4), b = 19.679 (4), c = 19.231 (3) Å; β = 111.030 (3)°. Solution spectroscopic studies indicate that the di-gold complex fragments on dissolution in organic solvents. Approximate density-functional theory calculations find an electrostatic origin for the binding of two gold(I) centers to the unprotonated nitrogen atoms, despite greater orbital density on the porphyrin meso carbons. PMID:18780788

  7. Reevaluation of the major histocompatibility complex genes of the NOD-progenitor CTS/Shi strain.

    PubMed

    Mathews, C E; Graser, R T; Serreze, D V; Leiter, E H

    2000-01-01

    The common Kd and/or Db alleles of NOD mice contribute to the development of autoimmune diabetes, but their respective contributions are unresolved. The major histocompatibility complex (MHC) of the CTS/Shi mouse, originally designated as H2ct, shares MHC class II region identity with the H2g7 haplotype of NOD mice. However, CTS mice were reported to express distinct but undefined MHC class I gene products. Because diabetes frequency was reduced 56% in females of a NOD stock congenic for H2ct, this partial resistance may have derived from the MHC class I allelic differences. In the present report, we use a combination of serologic analysis and sequencing of MHC class I cDNAs to establish that NOD/Lt and CTS/Shi share a common H2-Kd allele but differ at the H2-D end of the MHC complex. The H2-D allele of CTS/Shi was identified as the rare H2-Ddx recently described in ALR/Lt, another NOD-related strain. These results in mouse model systems show that multiple MHC genes confer diabetes resistance and suggest that at least one of the protective MHC or MHC-linked genes in CTS mice may be at the H2-D end of the complex.

  8. HLA class Ib in pregnancy and pregnancy-related disorders.

    PubMed

    Persson, Gry; Melsted, Wenna Nascimento; Nilsson, Line Lynge; Hviid, Thomas Vauvert F

    2017-08-01

    The HLA class Ib genes, HLA-E, HLA-F, and HLA-G, were discovered long after the classical HLA class Ia genes. The elucidation of their functions had a modest beginning. However, their basic functions and involvement in pathophysiology and a range of diseases are now emerging. Although results from a range of studies support the functional roles for the HLA class Ib molecules in adult life, especially HLA-G and HLA-F have most intensively been, and were also primarily, studied in relation to reproduction and pregnancy. The expression of HLA class Ib proteins at the feto-maternal interface in the placenta seems to be important for the maternal acceptance of the semi-allogenic fetus. In contrast to the functions of HLA class Ia, HLA-G possesses immune-modulatory and tolerogenic functions. Here, we review an accumulating amount of data describing the functions of HLA class Ib molecules in relation to fertility, reproduction, and pregnancy, and a possible role for these molecules in certain pregnancy complications, such as implantation failure, recurrent spontaneous abortions, and pre-eclampsia. The results from different kinds of studies point toward a role for HLA class Ib, especially HLA-G, throughout the reproductive cycle from conception to the birth weight of the child.

  9. [A new human leukocyte antigen class I allele, HLA- B*52:11].

    PubMed

    Li, Xiao-feng; Zhang, Xu; Zhang, Kun-lian; Chen, Yang; Liu, Xian-zhi; Li, Jian-ping

    2011-12-01

    To identify and confirm a novel HLA allele. A new human leukocyte antigen class I allele was found during routine HLA genotyping by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) and sequencing-based typing (SBT). The novel HLA-B*52 allele was identical to B*52:01:01 with an exception of one base substitution at position 583 of exon 3 where a C was changed to T resulting in codon 195 changed from CAC(H) to TAC(Y). A new HLA class I allele, B*52:11, is identified, and is named officially by the WHO Nomenclature Committee.

  10. Applications of Functional Amyloids from Fungi: Surface Modification by Class I Hydrophobins.

    PubMed

    Piscitelli, Alessandra; Cicatiello, Paola; Gravagnuolo, Alfredo Maria; Sorrentino, Ilaria; Pezzella, Cinzia; Giardina, Paola

    2017-06-26

    Class I hydrophobins produced from fungi are amongst the first proteins recognized as functional amyloids. They are amphiphilic proteins involved in the formation of aerial structures such as spores or fruiting bodies. They form chemically robust layers which can only be dissolved in strong acids. These layers adhere to different surfaces, changing their wettability, and allow the binding of other proteins. Herein, the modification of diverse types of surfaces with Class I hydrophobins is reported, highlighting the applications of the coated surfaces. Indeed, these coatings can be exploited in several fields, spanning from biomedical to industrial applications, which include biosensing and textile manufacturing.

  11. Murine Ia-associated invariant chain's processing to complex oligosaccharide forms and its dissociation from the I-Ak complex.

    PubMed

    Holt, G D; Swiedler, S J; Freed, J H; Hart, G W

    1985-07-01

    The processing of murine invariant chain (Ii) to a cell surface form bearing complex N-linked oligosaccharides has been demonstrated in the B cell lymphoma, AKTB-1b. In addition, the rate of processing of pulse-labeled Ii has been determined relative to its rate of dissociation from the alpha/beta complex of I-Ak. Ii, alpha-, and beta-chains were immunoprecipitated with anti-I-Ak or anti-Ii monoclonal antibodies. The heretofore uncharacterized complex oligosaccharide form of Ii (Ii-c) was identified in gel-purified immunoprecipitates by peptide mapping with reverse-phase HPLC. Ii-c is resistant to deglycosylation by Endo H, which is specific for high-mannose N-linkages, but can be digested with Endo F, a glycosidase capable of cleaving both complex and high-mannose N-linked oligosaccharides. Immunoprecipitation of surface iodinated cells indicates that Ii-c is expressed on the plasma membrane. Pulse-chase metabolic labeling data show that the processing of Ii to Ii-c occurs with a t1/2 of about 120 min. In contrast, the processing of both alpha- and beta-chains of I-Ak to complex forms occurs with a t1/2 of 15 to 20 min. Our data show that Ii-hm begins to dissociate rapidly from the I-Ak complex after 100 to 120 min of chase. Only a small amount (less than 5% on a per mole basis) of Ii-c was found associated with the I-Ak complexes after 300 min of continuous metabolic labeling. These results are consistent with Ii serving as a carrier for Ia antigens as they are transported to the cell surface. In addition, they suggest that the processing of Ii to Ii-c, or a late processing event of the alpha- and beta-chains, such as their sialylation, may be a possible mechanism for inducing the dissociation of Ii from the I-Ak complex.

  12. 49 CFR 1150.45 - Procedures and relevant dates-transactions under section 10902 that involve creation of Class I...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Procedures and relevant dates-transactions under section 10902 that involve creation of Class I or Class II rail carriers. 1150.45 Section 1150.45... dates—transactions under section 10902 that involve creation of Class I or Class II rail carriers. (a...

  13. 49 CFR 1150.45 - Procedures and relevant dates-transactions under section 10902 that involve creation of Class I...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Procedures and relevant dates-transactions under section 10902 that involve creation of Class I or Class II rail carriers. 1150.45 Section 1150.45... dates—transactions under section 10902 that involve creation of Class I or Class II rail carriers. (a...

  14. 49 CFR 1150.45 - Procedures and relevant dates-transactions under section 10902 that involve creation of Class I...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Procedures and relevant dates-transactions under section 10902 that involve creation of Class I or Class II rail carriers. 1150.45 Section 1150.45... dates—transactions under section 10902 that involve creation of Class I or Class II rail carriers. (a...

  15. 49 CFR 1150.45 - Procedures and relevant dates-transactions under section 10902 that involve creation of Class I...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Procedures and relevant dates-transactions under section 10902 that involve creation of Class I or Class II rail carriers. 1150.45 Section 1150.45... dates—transactions under section 10902 that involve creation of Class I or Class II rail carriers. (a...

  16. 49 CFR 1150.45 - Procedures and relevant dates-transactions under section 10902 that involve creation of Class I...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Procedures and relevant dates-transactions under section 10902 that involve creation of Class I or Class II rail carriers. 1150.45 Section 1150.45... dates—transactions under section 10902 that involve creation of Class I or Class II rail carriers. (a...

  17. 46 CFR 108.171 - Class I, Division 1 locations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... locations. The following are Class I, Division 1 locations: (a) An enclosed space that contains any part of the mud circulating system that has an opening into the space and is between the well and final... possible source of gas release. (c) An enclosed space that is on the drill floor, and is not separated by a...

  18. 46 CFR 108.171 - Class I, Division 1 locations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... locations. The following are Class I, Division 1 locations: (a) An enclosed space that contains any part of the mud circulating system that has an opening into the space and is between the well and final... possible source of gas release. (c) An enclosed space that is on the drill floor, and is not separated by a...

  19. 46 CFR 108.171 - Class I, Division 1 locations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... locations. The following are Class I, Division 1 locations: (a) An enclosed space that contains any part of the mud circulating system that has an opening into the space and is between the well and final... possible source of gas release. (c) An enclosed space that is on the drill floor, and is not separated by a...

  20. 46 CFR 108.171 - Class I, Division 1 locations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... locations. The following are Class I, Division 1 locations: (a) An enclosed space that contains any part of the mud circulating system that has an opening into the space and is between the well and final... possible source of gas release. (c) An enclosed space that is on the drill floor, and is not separated by a...

  1. 46 CFR 108.171 - Class I, Division 1 locations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... locations. The following are Class I, Division 1 locations: (a) An enclosed space that contains any part of the mud circulating system that has an opening into the space and is between the well and final... possible source of gas release. (c) An enclosed space that is on the drill floor, and is not separated by a...

  2. The Magnetic Field of the Class I Protostar WL 17

    NASA Astrophysics Data System (ADS)

    Johns-Krull, Christopher M.; Greene, T. P.; Doppmann, G.; Covey, K. R.

    2007-12-01

    Strong stellar magnetic fields are believed to truncate the inner accretion disks around young stars, redirecting the accreting material to the high latitude regions of the stellar surface. In the past few years, observations of strong stellar fields on Classical T Tauri stars [class II young stellar objects (YSOs)] with field strengths in general agreement with the predictions of magnetopsheric accretion theory have bolstered this picture. Currently, nothing is known about the magnetic field properties of younger, more embedded class I YSOs. It is during this protostellar evolutionary phase that stars accrete most of their final mass, but the physics governing this process remains poorly understood. Here, we use high resolution near infrared spectra obtained with NIRSPEC on Keck and with PHOENIX on Gemini South to measure the magnetic field properties of the class I protostar WL 17. We find clear signatures of a strong stellar magnetic field. Initial analysis of this data suggests a surface average field strength of 3.6 kG on the surface of WL 17. This is the highest mean surface field detected to date on any YSO. We present our field measurements and discuss how they fit with the general model of magnetospheric accretion in young stars.

  3. An Ontology for Modeling Complex Inter-relational Organizations

    NASA Astrophysics Data System (ADS)

    Wautelet, Yves; Neysen, Nicolas; Kolp, Manuel

    This paper presents an ontology for organizational modeling through multiple complementary aspects. The primary goal of the ontology is to dispose of an adequate set of related concepts for studying complex organizations involved in a lot of relationships at the same time. In this paper, we define complex organizations as networked organizations involved in a market eco-system that are playing several roles simultaneously. In such a context, traditional approaches focus on the macro analytic level of transactions; this is supplemented here with a micro analytic study of the actors' rationale. At first, the paper overviews enterprise ontologies literature to position our proposal and exposes its contributions and limitations. The ontology is then brought to an advanced level of formalization: a meta-model in the form of a UML class diagram allows to overview the ontology concepts and their relationships which are formally defined. Finally, the paper presents the case study on which the ontology has been validated.

  4. Coding of Class I and II aminoacyl-tRNA synthetases

    PubMed Central

    Carter, Charles W.

    2018-01-01

    SUMMARY The aminoacyl-tRNA synthetases and their cognate transfer RNAs translate the universal genetic code. The twenty canonical amino acids are sufficiently diverse to create a selective advantage for dividing amino acid activation between two distinct, apparently unrelated superfamilies of synthetases, Class I amino acids being generally larger and less polar, Class II amino acids smaller and more polar. Biochemical, bioinformatic, and protein engineering experiments support the hypothesis that the two Classes descended from opposite strands of the same ancestral gene. Parallel experimental deconstructions of Class I and II synthetases reveal parallel losses in catalytic proficiency at two novel modular levels—protozymes and Urzymes—associated with the evolution of catalytic activity. Bi-directional coding supports an important unification of the proteome; affords a genetic relatedness metric—middle base-pairing frequencies in sense/antisense alignments—that probes more deeply into the evolutionary history of translation than do single multiple sequence alignments; and has facilitated the analysis of hitherto unknown coding relationships in tRNA sequences. Reconstruction of native synthetases by modular thermodynamic cycles facilitated by domain engineering emphasizes the subtlety associated with achieving high specificity, shedding new light on allosteric relationships in contemporary synthetases. Synthetase Urzyme structural biology suggests that they are catalytically active molten globules, broadening the potential manifold of polypeptide catalysts accessible to primitive genetic coding and motivating revisions of the origins of catalysis. Finally, bi-directional genetic coding of some of the oldest genes in the proteome places major limitations on the likelihood that any RNA World preceded the origins of coded proteins. PMID:28828732

  5. Duration of the peak of adolescent growth spurt in class i and ii malocclusion subjects using a cervical vertebrae maturation analysis.

    PubMed

    Salazar-Lazo, Rodrigo; Arriola-Guillén, Luis E; Flores-Mir, Carlos

    2014-01-01

    The aim of the present work was to determine the duration of the adolescent peak growth spurt using cervical vertebral maturation analysis in class I and II malocclusion subjects. The study was conducted on a sample which consisted of 154 lateral cephalograms of children and adolescents aged 9-15 years (84 females and 70 males). The evaluation of skeletal maturation stage was performed using a visual morphological analysis of CS3 and CS4 cervical vertebrae. The sagittal skeletal relation was evaluated according to Steiner analysis. Descriptive statistics were used to summarize chronological age in each malocclusion group and for each CS3 and CS4 skeletal maturation stage. Due to a lack of normal distribution, comparisons of CS3 and CS4 age intervals on class I and II subjects were compared using the Mann-Whitney U test for independent samples. The results show that the mean duration of the adolescent peak growth spurt was 10 months between CS3 and CS4 stages in class I malocclusion subjects, whereas in class II malocclusion patients the duration was 6 months. This difference of 4 months was statistically significant (p<0.001). Finally, a clinically significant difference of 4 months in the duration of the adolescent peak growth spurt for class I and II malocclusion subjects was identified.

  6. Guidelines for evaluating air pollution impacts on class I wilderness areas in the Pacific Northwest.

    Treesearch

    Janice Peterson; Daniel L. Schmoldt; David Peterson; Joseph Eilers; Richard Fisher; Robert Bachman

    1992-01-01

    Forest Service air resource managers in the Pacific Northwest are responsible for protecting class I wilderness areas from air pollution. To do this, they need scientifically defensible information to determine critical concentrations of air pollution having the potential to impact class I wilderness values. This report documents the results of a workshop where current...

  7. Single locus typing of MHC class I and class II B loci in a population of red jungle fowl.

    PubMed

    Worley, K; Gillingham, M; Jensen, P; Kennedy, L J; Pizzari, T; Kaufman, J; Richardson, D S

    2008-05-01

    In species with duplicated major histocompatibility complex (MHC) genes, estimates of genetic variation often rely on multilocus measures of diversity. It is possible that such measures might not always detect more detailed patterns of selection at individual loci. Here, we describe a method that allows us to investigate classical MHC diversity in red jungle fowl (Gallus gallus), the wild ancestor of the domestic chicken, using a single locus approach. This is possible due to the well-characterised gene organisation of the 'minimal essential' MHC (BF/BL region) of the domestic chicken, which comprises two differentially expressed duplicated class I (BF) and two class II B (BLB) genes. Using a combination of reference strand-mediated conformation analysis, cloning and sequencing, we identify nine BF and ten BLB alleles in a captive population of jungle fowl. We show that six BF and five BLB alleles are from the more highly expressed locus of each gene, BF2 and BLB2, respectively. An excess of non-synonymous substitutions across the jungle fowl BF/BL region suggests that diversifying selection has acted on this population. Importantly, single locus screening reveals that the strength of selection is greatest on the highly expressed BF2 locus. This is the first time that a population of red jungle fowl has been typed at the MHC region, laying the basis for further research into the underlying processes acting to maintain MHC diversity in this and other species.

  8. Recombinant modified vaccinia virus Ankara–simian immunodeficiency virus gag pol elicits cytotoxic T lymphocytes in rhesus monkeys detected by a major histocompatibility complex class I/peptide tetramer

    PubMed Central

    Seth, Aruna; Ourmanov, Ilnour; Kuroda, Marcelo J.; Schmitz, Jörn E.; Carroll, Miles W.; Wyatt, Linda S.; Moss, Bernard; Forman, Meryl A.; Hirsch, Vanessa M.; Letvin, Norman L.

    1998-01-01

    The utility of modified vaccinia virus Ankara (MVA) as a vector for eliciting AIDS virus-specific cytotoxic T lymphocytes (CTL) was explored in the simian immunodeficiency virus (SIV)/rhesus monkey model. After two intramuscular immunizations with recombinant MVA-SIVSM gag pol, the monkeys developed a Gag epitope-specific CTL response readily detected in peripheral blood lymphocytes by using a functional killing assay. Moreover, those immunizations also elicited a population of CD8+ T lymphocytes in the peripheral blood that bound a specific major histocompatibility complex class I/peptide tetramer. These Gag epitope-specific CD8+ T lymphocytes also were demonstrated by using both functional and tetramer-binding assays in lymph nodes of the immunized monkeys. These observations suggest that MVA may prove a useful vector for an HIV-1 vaccine. They also suggest that tetramer staining may be a useful technology for monitoring CTL generation in vaccine trials in nonhuman primates and in humans. PMID:9707609

  9. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

    PubMed

    Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

    1998-05-01

    In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes

  10. 40 CFR 147.650 - State-administrative program-Class I, II, III, IV, and V wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CONTROL PROGRAMS Idaho § 147.650 State-administrative program—Class I, II, III, IV, and V wells. The UIC program for Class I, II, III, IV, and V wells in the State of Idaho, other than those on Indian lands, is the program administered by the Idaho Department of Water Resources, approved by EPA pursuant to...

  11. The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer.

    PubMed

    Imai, Daisuke; Yoshizumi, Tomoharu; Okano, Shinji; Uchiyama, Hideaki; Ikegami, Toru; Harimoto, Norifumi; Itoh, Shinji; Soejima, Yuji; Aishima, Shinichi; Oda, Yoshinao; Maehara, Yoshihiko

    2017-07-01

    Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive tumor-microenvironment (TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 (PD-L1) and loss of human leukocyte antigen (HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD-L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLA-DR, PD-L1, PD-1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLA-DR, PD-L1 or PD-1 and the pattern of tumor infiltrating immune cells or the patients' prognosis were assessed. PD-L1 expression correlated with tumor infiltration by CD68 + and FoxP3 + cells. Low HLA class I expression was an only risk factor for poor survival. PD-L1 negative and HLA class I high-expressing PDA was significantly associated with higher numbers of infiltrating CD8 + T cells in the TME, and a better prognosis. Evaluation of both PD-L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD-1/PD-L1 immune checkpoint blockade therapies. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  12. Maxillary molar distalization with first class appliance

    PubMed Central

    Ramesh, Namitha; Palukunnu, Biswas; Ravindran, Nidhi; Nair, Preeti P

    2014-01-01

    Non-extraction treatment has gained popularity for corrections of mild-to-moderate class II malocclusion over the past few decades. The distalization of maxillary molars is of significant value for treatment of cases with minimal arch discrepancy and mild class II molar relation associated with a normal mandibular arch and acceptable profile. This paper describes our experience with a 16-year-old female patient who reported with irregularly placed upper front teeth and unpleasant smile. The patient was diagnosed to have angles class II malocclusion with moderate maxillary anterior crowding, deep bite of 4 mm on a skeletal class II base with an orthognathic maxilla and retrognathic mandible and normal growth pattern. She presented an ideal profile and so molar distalization was planned with the first-class appliance. Molars were distalised by 8 mm on the right and left quadrants and class I molar relation achieved within 4 months. The space gained was utilised effectively to align the arch and establish a class I molar and canine relation. PMID:24577171

  13. Deficiency of respiratory chain complex I in Hashimoto thyroiditis.

    PubMed

    Zimmermann, Franz A; Neureiter, Daniel; Feichtinger, René G; Trost, Andrea; Sperl, Wolfgang; Kofler, Barbara; Mayr, Johannes A

    2016-01-01

    Oncocytic cells (OCs) are characterized by an accumulation of mitochondria and their occurrence in the thyroid gland of patients with Hashimoto thyroiditis (HT) is well known. However, their properties and functional relevance are poorly understood. We investigated OC lesions (n=212) in the thyroid of 12 HT patients. Loss of complex I protein was observed in oncocytic lesions of each of the patients. In addition to isolated complex I deficiency, 25% of oncocytic lesions showed combined deficiency of complex I and IV. Thus, we demonstrate for the first time a defect of respiratory chain complex I in OCs of HT patients. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  14. 41 CFR 301-10.122 - What class of airline accommodations must I use?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false What class of airline accommodations must I use? 301-10.122 Section 301-10.122 Public Contracts and Property Management Federal Travel... Common Carrier Transportation Airline Accommodations § 301-10.122 What class of airline accommodations...

  15. Structure and function of complex I in animals and plants - a comparative view.

    PubMed

    Senkler, Jennifer; Senkler, Michael; Braun, Hans-Peter

    2017-09-01

    The mitochondrial NADH dehydrogenase complex (complex I) has a molecular mass of about 1000 kDa and includes 40-50 subunits in animals, fungi and plants. It is composed of a membrane arm and a peripheral arm and has a conserved L-like shape in all species investigated. However, in plants and possibly some protists it has a second peripheral domain which is attached to the membrane arm on its matrix exposed side at a central position. The extra domain includes proteins resembling prokaryotic gamma-type carbonic anhydrases. We here present a detailed comparison of complex I from mammals and flowering plants. Forty homologous subunits are present in complex I of both groups of species. In addition, five subunits are present in mammalian complex I, which are absent in plants, and eight to nine subunits are present in plant complex I which do not occur in mammals. Based on the atomic structure of mammalian complex I and biochemical insights into complex I architecture from plants we mapped the species-specific subunits. Interestingly, four of the five animal-specific and five of the eight to nine plant-specific subunits are localized at the inner surface of the membrane arm of complex I in close proximity. We propose that the inner surface of the membrane arm represents a workbench for attaching proteins to complex I, which are not directly related to respiratory electron transport, like nucleoside kinases, acyl-carrier proteins or carbonic anhydrases. We speculate that further enzyme activities might be bound to this micro-location in other groups of organisms. © 2017 Scandinavian Plant Physiology Society.

  16. Overexpression of the class I homeodomain transcription factor TaHDZipI-5 increases drought and frost tolerance in transgenic wheat.

    PubMed

    Yang, Yunfei; Luang, Sukanya; Harris, John; Riboni, Matteo; Li, Yuan; Bazanova, Natalia; Hrmova, Maria; Haefele, Stephan; Kovalchuk, Nataliya; Lopato, Sergiy

    2018-06-01

    Characterization of the function of stress-related genes helps to understand the mechanisms of plant responses to environmental conditions. The findings of this work defined the role of the wheat TaHDZipI-5 gene, encoding a stress-responsive homeodomain-leucine zipper class I (HD-Zip I) transcription factor, during the development of plant tolerance to frost and drought. Strong induction of TaHDZipI-5 expression by low temperatures, and the elevated TaHDZipI-5 levels of expression in flowers and early developing grains in the absence of stress, suggests that TaHDZipI-5 is involved in the regulation of frost tolerance at flowering. The TaHDZipI-5 protein behaved as an activator in a yeast transactivation assay, and the TaHDZipI-5 activation domain was localized to its C-terminus. The TaHDZipI-5 protein homo- and hetero-dimerizes with related TaHDZipI-3, and differences between DNA interactions in both dimers were specified at 3D molecular levels. The constitutive overexpression of TaHDZipI-5 in bread wheat significantly enhanced frost and drought tolerance of transgenic wheat lines with the appearance of undesired phenotypic features, which included a reduced plant size and biomass, delayed flowering and a grain yield decrease. An attempt to improve the phenotype of transgenic wheat by the application of stress-inducible promoters with contrasting properties did not lead to the elimination of undesired phenotype, apparently due to strict spatial requirements for TaHDZipI-5 overexpression. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  17. A first-principles study of carbon-related energy levels in GaN. I. Complexes formed by substitutional/interstitial carbons and gallium/nitrogen vacancies

    NASA Astrophysics Data System (ADS)

    Matsubara, Masahiko; Bellotti, Enrico

    2017-05-01

    Various forms of carbon based complexes in GaN are studied with first-principles calculations employing Heyd-Scuseria-Ernzerhof hybrid functionals within the framework of the density functional theory. We consider carbon complexes made of the combinations of single impurities, i.e., CN-CGa, CI-CN , and CI-CGa , where CN, CGa , and CI denote C substituting nitrogen, C substituting gallium, and interstitial C, respectively, and of neighboring gallium/nitrogen vacancies ( VGa / VN ), i.e., CN-VGa and CGa-VN . Formation energies are computed for all these configurations with different charge states after full geometry optimizations. From our calculated formation energies, thermodynamic transition levels are evaluated, which are related to the thermal activation energies observed in experimental techniques such as deep level transient spectroscopy. Furthermore, the lattice relaxation energies (Franck-Condon shift) are computed to obtain optical activation energies, which are observed in experimental techniques such as deep level optical spectroscopy. We compare our calculated values of activation energies with the energies of experimentally observed C-related trap levels and identify the physical origins of these traps, which were unknown before.

  18. [Spinal cord stimulation (SCS) as a treatment for the spread phenomenon related to complex regional pain syndrome type- I (CRPS-I )].

    PubMed

    Goto, Shinichi; Taira, Takaomi; Hori, Tomokatsu

    2009-09-01

    The authors describe an experience of spinal cord stimulation (SCS) in a 30-year-old woman who developed complex regional pain syndrome type-I (CRPS-I) with spread phenomenon. She had received lumbar SCS under a diagnosis of CRPS-I in her left leg for 8 years. She had refractory pain in her right arm for the recent two years. There was no new lesion explaining her refractory pain on physical or radiological examination. Thus, the pain in her right upper arm was considered as spread phenomenon of CRPS-I. Test stimulation with cervical epidural spinal electrode showed good results and the pulse generator was implanted. It is suggested that the symptom of CRPS-I involving spread phenomenon was possibly due to a cortical reorganization. But a certain effect of SCS may be contributing to the favorable results of test stimulation for the treatment of CRPS-I with spread phenomenon in this case.

  19. Role of Metalloproteases in Vaccinia Virus Epitope Processing for Transporter Associated with Antigen Processing (TAP)-independent Human Leukocyte Antigen (HLA)-B7 Class I Antigen Presentation*

    PubMed Central

    Lorente, Elena; García, Ruth; Mir, Carmen; Barriga, Alejandro; Lemonnier, François A.; Ramos, Manuel; López, Daniel

    2012-01-01

    The transporter associated with antigen processing (TAP) translocates the viral proteolytic peptides generated by the proteasome and other proteases in the cytosol to the endoplasmic reticulum lumen. There, they complex with nascent human leukocyte antigen (HLA) class I molecules, which are subsequently recognized by the CD8+ lymphocyte cellular response. However, individuals with nonfunctional TAP complexes or tumor or infected cells with blocked TAP molecules are able to present HLA class I ligands generated by TAP-independent processing pathways. Herein, using a TAP-independent polyclonal vaccinia virus-polyspecific CD8+ T cell line, two conserved vaccinia-derived TAP-independent HLA-B*0702 epitopes were identified. The presentation of these epitopes in normal cells occurs via complex antigen-processing pathways involving the proteasome and/or different subsets of metalloproteinases (amino-, carboxy-, and endoproteases), which were blocked in infected cells with specific chemical inhibitors. These data support the hypothesis that the abundant cellular proteolytic systems contribute to the supply of peptides recognized by the antiviral cellular immune response, thereby facilitating immunosurveillance. These data may explain why TAP-deficient individuals live normal life spans without any increased susceptibility to viral infections. PMID:22298786

  20. Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II

    PubMed Central

    Norman, Paul J.; Norberg, Steven J.; Guethlein, Lisbeth A.; Nemat-Gorgani, Neda; Royce, Thomas; Wroblewski, Emily E.; Dunn, Tamsen; Mann, Tobias; Alicata, Claudia; Hollenbach, Jill A.; Chang, Weihua; Shults Won, Melissa; Gunderson, Kevin L.; Abi-Rached, Laurent; Ronaghi, Mostafa; Parham, Peter

    2017-01-01

    The most polymorphic part of the human genome, the MHC, encodes over 160 proteins of diverse function. Half of them, including the HLA class I and II genes, are directly involved in immune responses. Consequently, the MHC region strongly associates with numerous diseases and clinical therapies. Notoriously, the MHC region has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-Mbp MHC region from genomic DNA. For 95 MHC homozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternative MHC reference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of the MHC region shows the approach accurately determines the sequences of the highly polymorphic HLA class I and HLA class II genes and the complex structural diversity of complement factor C4A/C4B. It has also uncovered extensive and unexpected diversity in other MHC genes; an example is MUC22, which encodes a lung mucin and exhibits more coding sequence alleles than any HLA class I or II gene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust reference MHC haplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome. PMID:28360230