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Sample records for va heavy chain

  1. Heavy Chain Diseases

    Science.gov (United States)

    ... heavy chain produced: Alpha Gamma Mu Alpha Heavy Chain Disease Alpha heavy chain disease (IgA heavy chain ... disease or lead to a remission. Gamma Heavy Chain Disease Gamma heavy chain disease (IgG heavy chain ...

  2. Heavy chain only antibodies

    DEFF Research Database (Denmark)

    Moghimi, Seyed Moein; Rahbarizadeh, Fatemeh; Ahmadvand, Davoud

    2013-01-01

    Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen...

  3. Two Cases of Heavy Chain MGUS

    Directory of Open Access Journals (Sweden)

    Jan Van Keer

    2016-01-01

    Full Text Available Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

  4. Transchromosomally derived Ig heavy chains

    Energy Technology Data Exchange (ETDEWEB)

    Knight, K.L.; Kingzette, M.; Crane, M.A. [Loyola Univ. Chicago, Maywood, IL (United States)] [and others

    1995-07-15

    During an immune response, activated B cells undergo isotype switching and begin to express isotypes other than IgM and IgD. Isotype switching occurs when downstream C{gamma}, C{alpha}, or C{epsilon} genes are rearranged into the S{mu} chromosomal region, resulting in the deletion of the region in between. These rearrangements usually occur in cis, i.e., intrachromosomally. In previous studies, we analyzed allotypic specificities of rabbit secretory IgA and identified a substantial number of IgA heavy chains with V{sub h} and C{alpha} allotypes that were encoded by V{sub h} and C{alpha} genes in trans. In those studies, however, we could not determine whether the trans association of V{sub H} and C{alpha} occurred during VDJ gene rearrangement or during isotype switching. Here, we cloned rabbit cDNA which encodes these trans IgA heavy chains and determined the chromosomal origin of the V{sub H}, J{sub H}, and C{alpha} regions. To determine whether the trans association occurred during VDJ gene rearrangement, we analyzed the nucleotide polymorphism of the J{sub H} region and the V{sub H} allotype encoded by the cDNA. We found that the V{sub H} and J{sub H} genes used in the VDJ gene rearrangements were from the same chromosome, indicating that the V{sub H}, D, and J{sub H} gene rearrangements occurred in cis. Furthermore, we analyzed the DNA polymorphisms of J{sub H} and C{alpha} and showed that the VDJ and C{alpha} genes encoding the trans IgA molecules were derived from different parental chromosomes. We suggest that the trans association occurred during isotype switching. This study shows that V{sub H} and C{sub H} can associate transchromosomally as part of a normal immune response. 34 refs., 5 figs.

  5. VA/Q distribution during heavy exercise and recovery in humans: implications for pulmonary edema

    Science.gov (United States)

    Schaffartzik, W.; Poole, D. C.; Derion, T.; Tsukimoto, K.; Hogan, M. C.; Arcos, J. P.; Bebout, D. E.; Wagner, P. D.

    1992-01-01

    Ventilation-perfusion (VA/Q) inequality has been shown to increase with exercise. Potential mechanisms for this increase include nonuniform pulmonary vasoconstriction, ventilatory time constant inequality, reduced large airway gas mixing, and development of interstitial pulmonary edema. We hypothesized that persistence of VA/Q mismatch after ventilation and cardiac output subside during recovery would be consistent with edema; however, rapid resolution would suggest mechanisms related to changes in ventilation and blood flow per se. Thirteen healthy males performed near-maximal cycle ergometry at an inspiratory PO2 of 91 Torr (because hypoxia accentuates VA/Q mismatch on exercise). Cardiorespiratory variables and inert gas elimination patterns were measured at rest, during exercise, and between 2 and 30 min of recovery. Two profiles of VA/Q distribution behavior emerged during heavy exercise: in group 1 an increase in VA/Q mismatch (log SDQ of 0.35 +/- 0.02 at rest and 0.44 +/- 0.02 at exercise; P less than 0.05, n = 7) and in group 2 no change in VA/Q mismatch (n = 6). There were no differences in anthropometric data, work rate, O2 uptake, or ventilation during heavy exercise between groups. Group 1 demonstrated significantly greater VA/Q inequality, lower vital capacity, and higher forced expiratory flow at 25-75% of forced vital capacity for the first 20 min during recovery than group 2. Cardiac index was higher in group 1 both during heavy exercise and 4 and 6 min postexercise. However, both ventilation and cardiac output returned toward baseline values more rapidly than did VA/Q relationships. Arterial pH was lower in group 1 during exercise and recovery. We conclude that greater VA/Q inequality in group 1 and its persistence during recovery are consistent with the hypothesis that edema occurs and contributes to the increase in VA/Q inequality during exercise. This is supported by observation of greater blood flows and acidosis and, presumably therefore

  6. Translocations affecting human immunoglobulin heavy chain locus

    Directory of Open Access Journals (Sweden)

    Sklyar I. V.

    2014-03-01

    Full Text Available Translocations involving human immunoglobulin heavy chain (IGH locus are implicated in different leukaemias and lymphomas, including multiple myeloma, mantle cell lymphoma, Burkitt’s lymphoma and diffuse large B cell lymphoma. We have analysed published data and identified eleven breakpoint cluster regions (bcr related to these cancers within the IgH locus. These ~1 kbp bcrs are specific for one or several types of blood cancer. Our findings could help devise PCR-based assays to detect cancer-related translocations, to identify the mechanisms of translocations and to help in the research of potential translocation partners of the immunoglobulin locus at different stages of B-cell differentiation.

  7. Diversity Analysis of the Immunoglobulin M Heavy Chain Gene in ...

    African Journals Online (AJOL)

    A full-length cDNA encoding the immunoglobulin (IgM) heavy chain gene of Nile tilapia was successfully cloned using the 5' and 3' RACE techniques. The complete cDNA of the Nile tilapia IgM heavy chain gene is 1,921 bp in length and has an open reading frame (ORF) of 1,740 bp, which corresponds to 580 amino acid ...

  8. Stability of llama heavy chain antibody fragments under extreme conditions

    NARCIS (Netherlands)

    Dolk, E.

    2004-01-01

    Camelids have next to their normal antibodies, a unique subset of antibodies lacking light chains. The resulting single binding domain, VHH, of these heavy chain antibodies consequently have unique properties. A high stability is one of these properties, which was investigated in this thesis. The

  9. Expression of heavy chain-only antibodies can support B-cell development in light chain knockout chickens.

    Science.gov (United States)

    Schusser, Benjamin; Collarini, Ellen J; Pedersen, Darlene; Yi, Henry; Ching, Kathryn; Izquierdo, Shelley; Thoma, Theresa; Lettmann, Sarah; Kaspers, Bernd; Etches, Robert J; van de Lavoir, Marie-Cecile; Harriman, William; Leighton, Philip A

    2016-09-01

    Since the discovery of antibody-producing B cells in chickens six decades ago, chickens have been a model for B-cell development in gut-associated lymphoid tissue species. Here we describe targeting of the immunoglobulin light chain locus by homologous recombination in chicken primordial germ cells (PGCs) and generation of VJCL knockout chickens. In contrast to immunoglobulin heavy chain knockout chickens, which completely lack mature B cells, homozygous light chain knockout (IgL(-/-) ) chickens have a small population of B lineage cells that develop in the bursa and migrate to the periphery. This population of B cells expresses the immunoglobulin heavy chain molecule on the cell surface. Soluble heavy-chain-only IgM and IgY proteins of reduced molecular weight were detectable in plasma in 4-week-old IgL(-/-) chickens, and antigen-specific IgM and IgY heavy chain proteins were produced in response to immunization. Circulating heavy-chain-only IgM showed a deletion of the CH1 domain of the constant region enabling the immunoglobulin heavy chain to be secreted in the absence of the light chain. Our data suggest that the heavy chain by itself is enough to support all the important steps in B-cell development in a gut-associated lymphoid tissue species. © 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Switch recombination and somatic hypermutation are controlled by the heavy chain 3' enhancer region.

    Science.gov (United States)

    Dunnick, Wesley A; Collins, John T; Shi, Jian; Westfield, Gerwin; Fontaine, Clinton; Hakimpour, Paul; Papavasiliou, F Nina

    2009-11-23

    Both class switch recombination (CSR) and somatic hypermutation (SHM) require transcription and the trans-acting factor activation-induced cytidine deaminase (AID), and must be up-regulated during antigen-dependent differentiation of B lymphocytes. To test the role of the heavy chain 3' enhancers in both CSR and SHM, we used a BAC transgene of the entire heavy chain constant region locus. Using Cre-loxP recombination to delete a 28-kb region that contains the four known 3' heavy chain enhancers, we isolated lines of BAC transgenic mice with an intact heavy chain locus and paired lines in the same chromosomal insertion site lacking the 3' enhancers. Intact heavy chain transgenes undergo CSR to all heavy chain genes and mutate their transgenic VDJ exon. In paired transgenes lacking the 3' enhancer region, CSR to most heavy chain genes is reduced to approximately 1% of the levels for intact heavy chain loci; SHM is also reduced. Finally, we find that in B cells with a transgene lacking the 3' enhancers, interchromosomal recombination between the transgenic VDJ exon and the endogenous heavy chain C genes is more easily detected than CSR within the transgene.

  11. Switch recombination and somatic hypermutation are controlled by the heavy chain 3′ enhancer region

    Science.gov (United States)

    Collins, John T.; Shi, Jian; Westfield, Gerwin; Fontaine, Clinton; Hakimpour, Paul

    2009-01-01

    Both class switch recombination (CSR) and somatic hypermutation (SHM) require transcription and the trans-acting factor activation-induced cytidine deaminase (AID), and must be up-regulated during antigen-dependent differentiation of B lymphocytes. To test the role of the heavy chain 3′ enhancers in both CSR and SHM, we used a BAC transgene of the entire heavy chain constant region locus. Using Cre-loxP recombination to delete a 28-kb region that contains the four known 3′ heavy chain enhancers, we isolated lines of BAC transgenic mice with an intact heavy chain locus and paired lines in the same chromosomal insertion site lacking the 3′ enhancers. Intact heavy chain transgenes undergo CSR to all heavy chain genes and mutate their transgenic VDJ exon. In paired transgenes lacking the 3′ enhancer region, CSR to most heavy chain genes is reduced to ∼1% of the levels for intact heavy chain loci; SHM is also reduced. Finally, we find that in B cells with a transgene lacking the 3′ enhancers, interchromosomal recombination between the transgenic VDJ exon and the endogenous heavy chain C genes is more easily detected than CSR within the transgene. PMID:19887393

  12. Arginylation of Myosin Heavy Chain Regulates Skeletal Muscle Strength

    Directory of Open Access Journals (Sweden)

    Anabelle S. Cornachione

    2014-07-01

    Full Text Available Protein arginylation is a posttranslational modification with an emerging global role in the regulation of actin cytoskeleton. To test the role of arginylation in the skeletal muscle, we generated a mouse model with Ate1 deletion driven by the skeletal muscle-specific creatine kinase (Ckmm promoter. Ckmm-Ate1 mice were viable and outwardly normal; however, their skeletal muscle strength was significantly reduced in comparison to controls. Mass spectrometry of isolated skeletal myofibrils showed a limited set of proteins, including myosin heavy chain, arginylated on specific sites. Atomic force microscopy measurements of contractile strength in individual myofibrils and isolated myosin filaments from these mice showed a significant reduction of contractile forces, which, in the case of myosin filaments, could be fully rescued by rearginylation with purified Ate1. Our results demonstrate that arginylation regulates force production in muscle and exerts a direct effect on muscle strength through arginylation of myosin.

  13. Regional Myosin heavy chain distribution in selected paraspinal muscles.

    Science.gov (United States)

    Regev, Gilad J; Kim, Choll W; Thacker, Bryan E; Tomiya, Akihito; Garfin, Steven R; Ward, Samuel R; Lieber, Richard L

    2010-06-01

    Cross-sectional study with repeated measures design. To compare the myosin heavy-chain isoform distribution within and between paraspinal muscles and to test the theory that fiber-type gradients exist as a function of paraspinal muscle depth. There is still uncertainty regarding the fiber-type distributions within different paraspinal muscles. It has been previously proposed that deep fibers of the multifidus muscle may contain a higher ratio of type I to type II fibers, because, unlike superficial fibers, they primarily stabilize the spine, and may therefore have relatively higher endurance. Using a minimally invasive surgical approach, using tubular retractors that are placed within anatomic intermuscular planes, it was feasible to obtain biopsies from the multifidus, longissimus, iliocostalis, and psoas muscles at specific predefined depths. Under an institutional review board-approved protocol, muscle biopsies were obtained from 15 patients who underwent minimally invasive spinal surgery, using the posterior paramedian (Wiltse) approach or the minimally invasive lateral approach. Myosin heavy chain (MyHC) isoform distribution was analyzed using SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) electrophoresis. Because multiple biopsies were obtained from each patient, MyHC distribution was compared using both within- and between-muscle repeated measures analyses. The fiber-type distribution was similar among the posterior paraspinal muscles and was composed of relatively high percentage of type I (63%), compared to type IIA (19%) and type IIX (18%) fibers. In contrast, the psoas muscle was found to contain a lower percentage of type I fibers (42%) and a higher percentage of type IIA (33%) and IIX fibers (26%; Pmuscles. Fiber-type distribution between the posterior paraspinal muscles is consistent and is composed of relatively high percentage of type I fibers, consistent with a postural function. The psoas muscle, on the other hand, is

  14. Variable fragments of heavy chain antibodies (VHHs): a new magic bullet molecule of medicine?

    Science.gov (United States)

    Smolarek, Dorota; Bertrand, Olivier; Czerwinski, Marcin

    2012-06-14

     Serum of animals belonging to the Camelidae family (camels and llamas) contains fully active antibodies that are naturally devoid of light chains. Variable domains derived from heavy chain antibodies (hcAb) called VHHs or nanobodies™ can bind antigens as effectively as full-length antibodies and are easy to clone and express. Because of their potential, VHHs are being intensively studied as potential therapeutic, diagnostic and imaging tools. The paper reviews the molecular background of heavy chain antibodies and describes methods of obtaining recombinant fragments of heavy chain antibodies as well as their therapeutic, diagnostic and other applications.

  15.  Variable fragments of heavy chain antibodies (VHHs: a new magic bullet molecule of medicine?

    Directory of Open Access Journals (Sweden)

    Dorota Smolarek

    2012-06-01

    Full Text Available  Serum of animals belonging to the Camelidae family (camels and llamas contains fully active antibodies that are naturally devoid of light chains. Variable domains derived from heavy chain antibodies (hcAb called VHHs or nanobodies™ can bind antigens as effectively as full-length antibodies and are easy to clone and express. Because of their potential, VHHs are being intensively studied as potential therapeutic, diagnostic and imaging tools. The paper reviews the molecular background of heavy chain antibodies and describes methods of obtaining recombinant fragments of heavy chain antibodies as well as their therapeutic, diagnostic and other applications.

  16. Serial cerebrospinal fluid neurofilament heavy chain levels in severe Guillain-Barre syndrome

    NARCIS (Netherlands)

    Dujmovic, I.; Lunn, M.P.; Reilly, M.M.; Petzold, A.

    2013-01-01

    Introduction: Proximal axonotmesis results in the release of neurofilament (Nf) proteins into the cerebrospinal fluid (CSF) in patients with Guillain-Barré syndrome (GBS). High CSF levels of the phosphorylated form of Nf-heavy chain (NfH

  17. Sulfation of the bikunin chondroitin sulfate chain determines heavy chain·hyaluronan complex formation.

    Science.gov (United States)

    Lord, Megan S; Day, Anthony J; Youssef, Peter; Zhuo, Lisheng; Watanabe, Hideto; Caterson, Bruce; Whitelock, John M

    2013-08-09

    Inter-α-trypsin inhibitor (IαI) is a complex comprising two heavy chains (HCs) that are covalently bound by an ester bond to chondroitin sulfate (CS), which itself is attached to Ser-10 of bikunin. IαI is essential for the trans-esterification of HCs onto hyaluronan (HA). This process is important for the stabilization of HA-rich matrices during ovulation and some inflammatory processes. Bikunin has been isolated previously by anion exchange chromatography with a salt gradient up to 0.5 M NaCl and found to contain unsulfated and 4-sulfated CS disaccharides. In this study, bikunin-containing fractions in plasma and urine were separated by anion exchange chromatography with a salt gradient of 0.1-1.0 M NaCl, and fractions were analyzed for their reactivity with the 4-sulfated CS linkage region antibody (2B6). The fractions that reacted with the 2B6 antibody (0.5-0.8 M NaCl) were found to predominantly contain sulfated CS disaccharides, including disulfated disaccharides, whereas the fractions that did not react with this antibody (0.1-0.5 M NaCl) contained unsulfated and 4-sulfated CS disaccharides. IαI in the 0.5-0.8 M NaCl plasma fraction was able to promote the trans-esterification of HCs to HA in the presence of TSG-6, whereas the 0.1-0.5 M NaCl fraction had a much reduced ability to transfer HC proteins to HA, suggesting that the CS containing 4-sulfated linkage region structures and disulfated disaccharides are involved in the HC transfer. Furthermore, these data highlight that the structure of the CS attached to bikunin is important for the transfer of HC onto HA and emphasize a specific role of CS chain sulfation.

  18. Excessive amounts of mu heavy chain block B-cell development.

    Science.gov (United States)

    Zhu, Lingqiao; Chang, Cheong-Hee; Dunnick, Wesley

    2011-09-01

    Antigen-independent B-cell development occurs in several stages that depend on the expression of Ig heavy and light chain. We identified a line of mice that lacked mature B cells in the spleen. This mouse line carried approximately 11 copies of a transgene of the murine heavy chain constant region locus, and B-lineage cells expressed excessive amounts of the intracellular μ heavy chain. B-cell development failed in the bone marrow at the pro/pre B-cell transition, and examination of other lines with various copy numbers of the same transgene suggested that deficiencies in B-cell development increased with increased transgene copy number. Expression of a transgenic (Tg) light chain along with the Tg μ heavy chain led to minimal rescue of B-cell development in the bone marrow and B cells in the spleen. There are several potential mechanisms for the death of pro/pre B cells as a consequence of excess heavy chain expression.

  19. The association of heavy and light chain variable domains in antibodies: implications for antigen specificity.

    KAUST Repository

    Chailyan, Anna

    2011-06-28

    The antigen-binding site of immunoglobulins is formed by six regions, three from the light and three from the heavy chain variable domains, which, on association of the two chains, form the conventional antigen-binding site of the antibody. The mode of interaction between the heavy and light chain variable domains affects the relative position of the antigen-binding loops and therefore has an effect on the overall conformation of the binding site. In this article, we analyze the structure of the interface between the heavy and light chain variable domains and show that there are essentially two different modes for their interaction that can be identified by the presence of key amino acids in specific positions of the antibody sequences. We also show that the different packing modes are related to the type of recognized antigen.

  20. Heavy subgraph pairs for traceability of block-chains

    NARCIS (Netherlands)

    Li, Binlong; Li, Binlong; Broersma, Haitze J.; Zhang, Shenggui

    2014-01-01

    A graph is called traceable if it contains a Hamilton path, i.e., a path containing all its vertices. Let G be a graph on n vertices. We say that an induced subgraph of G is o-1-heavy if it contains two nonadjacent vertices which satisfy an Ore-type degree condition for traceability, i.e., with

  1. Heavy subgraph pairs for traceability of block-chains

    National Research Council Canada - National Science Library

    Li, Binlong; Broersma, Haitze J; Zhang, Shenggui

    2014-01-01

    ...., with degree sum at least n−1 in G. A block-chain is a graph whose block graph is a path, i.e., it is either a P1, P2, or a 2-connected graph, or a graph with at least one cut vertex and exactly two end-blocks...

  2. The catabolism of human γG immunoglobulins of different heavy chain subclasses. III. The catabolism of heavy chain disease proteins and of Fc fragments of myeloma proteins

    Science.gov (United States)

    Spiegelberg, H. L.; Fishkin, B. G.

    1972-01-01

    The catabolism of 131I and 125I paired labelled Fc fragments of myeloma proteins and of H chain disease proteins of different heavy chain subclasses was studied in men and monkeys. In contrast to the previously demonstrated catabolic heterogeneity of intact γG immunoglobulins, the Fc fragments and H chain disease proteins of all subclasses tested were catabolized at a similar rate. These data suggest that structures not present on the Fc fragments are responsible for the faster turnover rate of γG3 immunoglobulins and for the differences in half-lives of myeloma proteins within a given subclass. The catabolic features of the H chain disease proteins differed from those of intact γG. Although the whole body half-lives of the two proteins were similar, the fractional turnover rate of the H chain disease proteins was higher than that of γG, on the average 8% of the intravascular pool/day as compared to 4% for γG. One-half to 1% of the intravascular pool of the H chain disease protein and less than 0·1% of the γG was excreted into the urine. An average of 24% of the H chain disease proteins and 44% of the γG equilibrated into the intravascular compartment. PMID:4624553

  3. HEAVY-CHAIN DISEASES AND MYELOMA-ASSOCIATED FANCONI SYNDROME: AN UPDATE

    Directory of Open Access Journals (Sweden)

    Roberto Ria

    2018-01-01

    Full Text Available The heavy chain diseases (HCDs are rare B-cell malignancies characterized by the production of a monoclonal immunoglobulin heavy chain without an associated light chain. There are three types of HCD, defined by the class of immunoglobulin heavy chain produced: IgA (α-HCD, IgG (γ-HCD, and IgM (μ-HCD. Alpha-HCD is the most common and usually occurs as intestinal malabsorption in a young adult from a country of the Mediterranean area. Gamma- and μ-HCDs are more rare and associated to a B-cell non-Hodgkin lymphoma that produces an abnormal Ig heavy chain. These patients may occasionally be diagnosed with a monoclonal gammopathy of undetermined significance (MGUS. Fanconi syndrome, on the other hand, can be primary (inherited or secondary (acquired. The only exception to this rule is the idiopathic form. Adult acquired Fanconi syndrome can be a rare complication of a monoclonal gammopathy. At diagnosis, most patients have a MGUS or smoldering multiple myeloma, with renal failure and evidence of osteomalacia. During follow-up, patients can develop end-stage renal disease. Chemotherapy provides little benefit on renal function.

  4. Comparison of DSM-IV and DSM-5 criteria for alcohol use disorders in VA primary care patients with frequent heavy drinking enrolled in a trial.

    Science.gov (United States)

    Takahashi, Traci; Lapham, Gwen; Chavez, Laura J; Lee, Amy K; Williams, Emily C; Richards, Julie E; Greenberg, Diane; Rubinsky, Anna; Berger, Douglas; Hawkins, Eric J; Merrill, Joseph O; Bradley, Katharine A

    2017-07-18

    Criteria for alcohol use disorders (AUD) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) were intended to result in a similar prevalence of AUD as DSM-IV. We evaluated the prevalence of AUD using DSM-5 and DSM-IV criteria, and compared characteristics of patients who met criteria for: neither DSM-5 nor DSM-IV AUD, DSM-5 alone, DSM-IV alone, or both, among Veterans Administration (VA) outpatients in the Considering Healthier drinking Options In primary CarE (CHOICE) trial. VA primary care patients who reported frequent heavy drinking and enrolled in the CHOICE trial were interviewed at baseline using the DSM-IV Mini International Neuropsychiatric Interview for AUD, as well as questions about socio-demographics, mental health, alcohol craving, and substance use. We compared characteristics across 4 mutually exclusive groups based on DSM-5 and DSM-IV criteria. Of 304 participants, 13.8% met criteria for neither DSM-5 nor DSM-IV AUD; 12.8% met criteria for DSM-5 alone, and 73.0% met criteria for both DSM-IV and DSM-5. Only 1 patient (0.3%) met criteria for DSM-IV AUD alone. Patients meeting both DSM-5 and DSM-IV criteria had more negative drinking consequences, mental health symptoms and self-reported readiness to change compared with those meeting DSM-5 criteria alone or neither DSM-5 nor DSM-IV criteria. In this sample of primary care patients with frequent heavy drinking, DSM-5 identified 13% more patients with AUD than DSM-IV. This group had a lower mental health symptom burden and less self-reported readiness to change compared to those meeting criteria for both DSM-IV and DSM-5 AUD. Trial Registration ClinicalTrials.gov NCT01400581. 2011 February 17.

  5. Novel mutations in beta-myosin heavy chain, actin and troponin-I ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 88; Issue 3. Novel mutations in beta-myosin heavy chain, actin and troponin-I genes associated with dilated cardiomyopathy in Indian population. Ushasree Boda Shivani Vadapalli Narsimhan Calambur Pratibha Nallari. Research Note Volume 88 Issue 3 December 2009 pp ...

  6. Expression of porcine myosin heavy chain 1 gene in Berkshire loins ...

    African Journals Online (AJOL)

    Expression of porcine myosin heavy chain 1 gene in Berkshire loins with a high pH24 value. Jin Hun Kang, Woo Young Bang, Eun Jung Kwon, Yong Hwa Lee, Da Hye Park, Eun Seok Cho, Min Ji Kim, Jong-Soon Choi, Hwa Chun Park, Beom Young Park, Chul Wook Kim ...

  7. Improving properties of llama heavy chain antibodies using in silico analysis

    NARCIS (Netherlands)

    Lutje Hulsik, D.|info:eu-repo/dai/nl/311457517

    2009-01-01

    Microbicides offer a promising way to prevent HIV infection in developing countries. Llama heavy chain antibody fragments (VHHs) that neutralize HIV are an ideal candidate for usage as active microbicide component. A VHH is the smallest intact antigen binding domain which allows it to reach for

  8. Expression and production of llama variable heavy-chain antibody fragments (VHHs) by Aspergillus awamori

    NARCIS (Netherlands)

    Joosten, V.; Gouka, R.J.; Hondel, C.A.M.J.J. van den; Verrips, C.T.; Lokman, B.C.

    2005-01-01

    We report the expression and production of llama variable heavy-chain antibody fragments (VHHs) by Aspergillus awamori. Fragments encoding VHHs were cloned in a suitable Aspergillus expression vector and transformants secreting VHH fragments were analysed for integrated gene copy-numbers, mRNA

  9. The motion planning problem and exponential stabilization of a heavy chain. Part II

    Directory of Open Access Journals (Sweden)

    Piotr Grabowski

    2008-01-01

    Full Text Available This is the second part of paper [P. Grabowski, The motion planning problem and exponential stabilization of a heavy chain. Part I, to appear in International Journal of Control], where a model of a heavy chain system with a punctual load (tip mass in the form of a system of partial differential equations was interpreted as an abstract semigroup system and then analysed on a Hilbert state space. In particular, in [P. Grabowski, The motion planning problem and exponential stabilization of a heavy chain. Part I, to appear in International Journal of Control] we have formulated the problem of exponential stabilizability of a heavy chain in a given position. It was also shown that the exponential stability can be achieved by applying a stabilizer of the colocated-type. The proof used the method of Lyapunov functionals. In the present paper, we give other two proofs of the exponential stability, which provides an additional intrinsic insight into the exponential stabilizability mechanism. The first proof makes use of some spectral properties of the system. In the second proof, we employ some relationships between exponential stability and exact observability.

  10. Myosin heavy chain composition of single fibres from m. biceps brachii of male body builders

    DEFF Research Database (Denmark)

    Klitgaard, H; Zhou, M.-Y.; Richter, Erik

    1990-01-01

    The myosin heavy chain (MHC) composition of single fibres from m. biceps brachii of young sedentary men (28 +/- 0.4 years, mean +/- SE, n = 4) and male body builders (25 +/- 2.0 years, n = 4) was analysed with a sensitive one-dimensional electrophoretic technique. Compared with sedentary men...

  11. Improved production and function of llama heavy chain antibody fragments by molecular evolution

    NARCIS (Netherlands)

    Linden, van der R.H.; Geus, de B.; Frenken, G.J.; Peters, H.; Verrips, C.T.

    2000-01-01

    The aim of this study was to improve production level of llama heavy chain antibody fragments (V (HH)) in Saccharomyces cerevisiae while retaining functional characteristics. For this purpose, the DNA shuffling technique was used on llama V (HH) fragments specific for the azo-dye reactive red-6. In

  12. Influence of VA-mycorrhiza on heavy metal uptake of oat (Avena sativa L.) from soils differing in heavy metal contamination; Einfluss der VA-Mykorrhiza auf die Schwermetallaufnahme von Hafer (Avena sativa L.) in Abhaengigkeit vom Kontaminationsgrad der Boeden

    Energy Technology Data Exchange (ETDEWEB)

    Loth, F.G. [Giessen Univ. (Germany). Inst. fuer Pflanzenernaehrung; Hoefner, W. [Giessen Univ. (Germany). Inst. fuer Pflanzenernaehrung

    1995-12-31

    The heavy metal uptake of mycorrhizal oat-plants (Avena sativa L.) was evaluated in pot experiments with two soils differing in heavy meatl accumulation. The effect of the fungal isolates on the uptake of the immobile metals Zn and Cu differed between the two soils: In the soil `Kleinlinden` mycorrhizal colonization increased heavy metal uptake by up to 37%. In the highly contaminated soil `Muenchen`, mycorrhizal infection lead to a higher uptake (max. 59%) in roots but to a reduced translocation to the aerial plant fractions. The higher uptake of Zn and Cu into the roots was related to the higher heavy metal concentrations in this soil. The Cd uptake showed no difference between the two soils, but was increased in the roots by VAM together with a lower translocation into the shoots. VAM-formation changed the root architecture by increacing the specific root length (m g{sup -1} root dry matter) and the total root length (km per pot). This increased absorbing surface of the roots was a major, but not the only cause for the differences in heavy metal uptake. (orig.) [Deutsch] Die Schwermetallaufnahme mykorrhizierter Hafer-Pflanzen (Avena sativa L.) wurde im Gefaessversuch mit zwei Boeden unterschiedlicher Belastung evaluiert. Der Einfluss der VAM-Pilzisolate auf die Aufnahme der relativ immobilen Metalle Zn und Cu war stark abhaengig vom eingesetzten Boden: Im Versuch mit dem gering belasteten Kleinlindener Boden wurde die Schwermetallaufnahme in den Spross bis zu 37% gesteigert. Die Beimpfung der Pflanzen auf dem hochkontaminierten Boden aus Muenchen fuehrte dagegen zu hoeheren Aufnahmeraten (bis zu 59%) in der Wurzel bei verringerter Translokation in die oberirdischen Pflanzenteile. Das mobile Schwermetall Cd wurde aus beiden Substraten verstaerkt in die infizierten Wurzeln aufgenommen und in vermindertem Mass in den Spross geleitet. Die mykorrhizainduzierte Vergroesserung der speziellen (m g{sup -1} Wurzel-TM) und der absoluten (km pro Gefaess) Wurzellaenge war in

  13. Llama heavy-chain V regions consist of at least four distinct subfamilies revealing novel sequence features

    NARCIS (Netherlands)

    Ruuls, R.C.; Nijman, I.J.; Niewold, T.A.; Frenken, L.G.J.; Geus, de B.

    2000-01-01

    In addition to conventional antibodies (Abs), camelids possess Abs consisting of only heavy chains. The variable domain of such a heavy-chain Ab (VHH) is fully capable of antigen (Ag) binding. Earlier analysis of 47 VHHs showed sequence features unique to VHH domains. These include the presence of

  14. Purification and quantification of heavy-chain antibodies from the milk of bactrian camels.

    Science.gov (United States)

    Yao, Hongqiang; Zhang, Min; Li, Yi; Yao, Jirimutu; Meng, He; Yu, Siriguleng

    2017-09-01

    Camel milk has a unique composition with naturally occurring heavy-chain antibodies (HCAbs), which exert rehabilitating potencies in infection and immunity. To characterize HCAb in camel milk, immunoglobulin G (IgG) was isolated from the milk of Camelus bactrianus by a combination of affinity chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis to purify and size-fractionate protein A and protein G, which were further identified by Western blotting, and were quantified by bicinchoninic acid (BCA) and ELISA. The results indicated that IgG1 fraction contains molecules of 50 kDa heavy chains and 36 kDa light chains. The HCAbs (IgG2 and IgG3 fractions) devoid of light chains, contain heavy chains of 45 kDa and 43 kDa, respectively, the amounts of which were significantly higher than that of the IgG1 in the milk of bactrian camels. Above all, we revealed the considerable amounts of HCAbs in the milk of bactrian camels, and developed a novel method for their purification and quantification. These findings provide the basis for developing potential effects of camel milk and its interface with the dairy industry, as well as future investigations of HCAb and its roles in human health and diseases. © 2017 Japanese Society of Animal Science.

  15. Heavy and Light chain amyloidosois presenting as complete heart block: A rare presentation of a rare disease

    Directory of Open Access Journals (Sweden)

    P S Priyamvada

    2015-01-01

    Full Text Available Amyloidosis is an uncommon disease characterized by deposition of proteinaceous material in the extracellular matrix, which results from abnormal protein folding. Even though more than 25 precursor proteins are identified, majority of systemic amyloidosis results from deposition of abnormal immunoglobulin (Ig light chains. In heavy chain amyloidosis (AH, deposits are derived from both heavy chain alone, whereas in heavy and light chain amyloidosis (AHL, the deposits are derived from Ig heavy chains and light chains. Both AH and AHL are extremely rare diseases. Here, we report an unusual presentation of IgG (lambda AHL amyloidosis in the background of multiple myeloma, where the initial clinical presentation was complete heart block, which preceded the definitive diagnosis by 18 months.

  16. Heavy and Light chain amyloidosois presenting as complete heart block: A rare presentation of a rare disease.

    Science.gov (United States)

    Priyamvada, P S; Morkhandikar, S; Srinivas, B H; Parameswaran, S

    2015-01-01

    Amyloidosis is an uncommon disease characterized by deposition of proteinaceous material in the extracellular matrix, which results from abnormal protein folding. Even though more than 25 precursor proteins are identified, majority of systemic amyloidosis results from deposition of abnormal immunoglobulin (Ig) light chains. In heavy chain amyloidosis (AH), deposits are derived from both heavy chain alone, whereas in heavy and light chain amyloidosis (AHL), the deposits are derived from Ig heavy chains and light chains. Both AH and AHL are extremely rare diseases. Here, we report an unusual presentation of IgG (lambda) AHL amyloidosis in the background of multiple myeloma, where the initial clinical presentation was complete heart block, which preceded the definitive diagnosis by 18 months.

  17. Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

    Directory of Open Access Journals (Sweden)

    Peter Bannas

    2017-11-01

    Full Text Available Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL. The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL. VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv. scFv modules in turn can be fused to one another, e.g., to generate a bispecific T-cell engager, or they can be fused in various orientations to antibody hinge and Fc domains to generate bi- and multispecific antibodies. However, the inherent hydrophobic interaction of VH and VL domains limits the stability and solubility of engineered antibodies, often causing aggregation and/or mispairing of V-domains. Nanobodies (15 kDa and nanobody-based human heavy chain antibodies (75 kDa can overcome these limitations. Camelids naturally produce antibodies composed only of heavy chains in which the target recognition module is composed of a single variable domain (VHH or Nb. Advantageous features of nanobodies include their small size, high solubility, high stability, and excellent tissue penetration in vivo. Nanobodies can readily be linked genetically to Fc-domains, other nanobodies, peptide tags, or toxins and can be conjugated chemically at a specific site to drugs, radionuclides, photosensitizers, and nanoparticles. These properties make them particularly suited for specific and efficient targeting of tumors in vivo. Chimeric nanobody-heavy chain antibodies combine advantageous features of nanobodies and human Fc domains in about half the size of a conventional antibody. In this review, we discuss recent developments and perspectives for applications of nanobodies and nanobody

  18. Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing

    Directory of Open Access Journals (Sweden)

    Pen Li

    2016-01-01

    Full Text Available When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT, a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT lymphoma. We describe a patient with a history of Sjögren’s syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP. However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.

  19. Clathrin heavy chain is important for viability, oviposition, embryogenesis and, possibly, systemic RNAi response in the predatory mite Metaseiulus occidentalis.

    Directory of Open Access Journals (Sweden)

    Ke Wu

    Full Text Available Clathrin heavy chain has been shown to be important for viability, embryogenesis, and RNA interference (RNAi in arthropods such as Drosophila melanogaster. However, the functional roles of clathrin heavy chain in chelicerate arthropods, such as the predatory mite Metaseiulus occidentalis, remain unknown. We previously showed that dsRNA ingestion, followed by feeding on spider mites, induced systemic and robust RNAi in M. occidentalis females. In the current study, we performed a loss-of-function analysis of the clathrin heavy chain gene in M. occidentalis using RNAi. We showed that ingestion of clathrin heavy chain dsRNA by M. occidentalis females resulted in gene knockdown and reduced longevity. In addition, clathrin heavy chain dsRNA treatment almost completely abolished oviposition by M. occidentalis females and the few eggs produced did not hatch. Finally, we demonstrated that clathrin heavy chain gene knockdown in M. occidentalis females significantly reduced a subsequent RNAi response induced by ingestion of cathepsin L dsRNA. The last finding suggests that clathrin heavy chain may be involved in systemic RNAi responses mediated by orally delivered dsRNAs in M. occidentalis.

  20. Coulomb explosion of polycyclic aromatic hydrocarbons induced by heavy cosmic rays: carbon chains production rates

    OpenAIRE

    Chabot, Marin; Béroff, Karine; Dartois, Emmanuel; Pino, Thomas; Godard, Marie

    2017-01-01

    Cosmic Rays (CR) process the matter of the Interstellar Medium. Such energetic processing not only modifies the interstellar matter but also injects chemical species in the gas phase. In this work, we study the effect of the CR on the astrophysical polycyclic aromatic hydrocarbons (PAH). For events in which many electrons are stripped out from the PAH by interaction with a heavy cosmic ray particle, coulomb explosion takes place and carbon chains are produced. The fragments production rates o...

  1. Differential susceptibility on myosin heavy chain isoform following eccentric-induced muscle damage

    OpenAIRE

    Choi, Seung Jun

    2014-01-01

    Based on myosin heavy chain (MHC) isoform, human skeletal muscle fibers can be categorized into three fiber types, type I, IIa, IIx fibers, and each fiber type has different characteristics. Typical characteristics are difference in force production, shortening velocity, and fatigue resistance. When the muscle is contract and stretched by a force that is greater than the force generated by the muscle, contraction-induced muscle damage frequently occurs. Several experimental models involving b...

  2. Broad phylogenetic expression of heavy-chain determinants detected by rabbit antisera to VHa allotypes.

    Science.gov (United States)

    Rosenshein, I L; Marchalonis, J J

    1985-10-01

    Immunoglobulin molecules from diverse vertebrate species were examined, using an enzyme-linked immunosorbent assay (ELISA), for the expression of determinants detectable by rabbit antisera to VHa allotypes. The data indicate that immunoglobulins of elasmobranchs, teleosts, amphibians and birds express determinants cross-reactive with those specified by the a1, a2 and a3 alleles in the domestic rabbit. We localize VHa cross-reactive specificity to the denatured heavy chain of a primitive vertebrate, the Galapagos shark (Carcharhinus galapagensis). Furthermore, the N-terminal amino acid sequence of the shark heavy chain shows significant homology with rabbit heavy chains of known VHa type at positions where allotype-correlated differences have been implicated. VHa-related determinants are shared by immunoglobulins of a wide range of vertebrates from sharks to man and thus seem to be epitopes which have been conserved during vertebrate evolution. The determinants detected on immunoglobulins of lower vertebrates by rabbit anti-VHa allotype sera most probably are VH-subgroup rather than allotypic markers. Their distribution demonstrates a strong phylogenetic conservation of VH-regions.

  3. Expression of heavy chain‐only antibodies can support B‐cell development in light chain knockout chickens

    Science.gov (United States)

    Schusser, Benjamin; Collarini, Ellen J.; Pedersen, Darlene; Yi, Henry; Ching, Kathryn; Izquierdo, Shelley; Thoma, Theresa; Lettmann, Sarah; Kaspers, Bernd; Etches, Robert J.; van de Lavoir, Marie‐Cecile; Harriman, William

    2016-01-01

    Since the discovery of antibody‐producing B cells in chickens six decades ago, chickens have been a model for B‐cell development in gut‐associated lymphoid tissue species. Here we describe targeting of the immunoglobulin light chain locus by homologous recombination in chicken primordial germ cells (PGCs) and generation of VJCL knockout chickens. In contrast to immunoglobulin heavy chain knockout chickens, which completely lack mature B cells, homozygous light chain knockout (IgL−/−) chickens have a small population of B lineage cells that develop in the bursa and migrate to the periphery. This population of B cells expresses the immunoglobulin heavy chain molecule on the cell surface. Soluble heavy‐chain‐only IgM and IgY proteins of reduced molecular weight were detectable in plasma in 4‐week‐old IgL−/− chickens, and antigen‐specific IgM and IgY heavy chain proteins were produced in response to immunization. Circulating heavy‐chain‐only IgM showed a deletion of the CH1 domain of the constant region enabling the immunoglobulin heavy chain to be secreted in the absence of the light chain. Our data suggest that the heavy chain by itself is enough to support all the important steps in B‐cell development in a gut‐associated lymphoid tissue species. PMID:27392810

  4. Optimization of heavy chain and light chain signal peptides for high level expression of therapeutic antibodies in CHO cells.

    Directory of Open Access Journals (Sweden)

    Ryan Haryadi

    Full Text Available Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is a critical step in protein secretion. The aim of this work was to develop a platform technology to optimize the signal peptides for high level production of therapeutic antibodies in CHO cells. A database of signal peptides from a large number of human immunoglobulin (Ig heavy chain (HC and kappa light chain (LC was generated. Most of the HC signal peptides contain 19 amino acids which can be divided into three domains and the LC signal peptides contain 22 amino acids. The signal peptides were then clustered according to sequence similarity. Based on the clustering, 8 HC and 2 LC signal peptides were analyzed for their impacts on the production of 5-top selling antibody therapeutics, namely, Herceptin, Avastin, Remicade, Rituxan, and Humira. The best HC and LC signal peptides for producing these 5 antibodies were identified. The optimized signal peptides for Rituxan is 2-fold better compared to its native signal peptides which are available in the public database. Substitution of a single amino acid in the optimized HC signal peptide for Avastin reduced its production significantly. Mass spectrometry analyses revealed that all optimized signal peptides are accurately removed in the mature antibodies. The results presented in this report are particularly important for the production of these 5 antibodies as biosimilar drugs. They also have the potential to be the best signal peptides for the production of new antibodies in CHO cells.

  5. A comprehensive analysis of immunoglobulin heavy chain genes in the Bactrian camel (Camelus bactrianus

    Directory of Open Access Journals (Sweden)

    Zuoxiang LIANG,Tao WANG,Yi SUN,Wenlong YANG,Zhihong LIU,Jing FEI,Ying GUO,Qingwei MA,Qingjie PAN,Liming REN

    2015-09-01

    Full Text Available Heavy chain only antibodies (HCAbs represent a rare type of antibody that is devoid of light chains and the CH1 domain that have been reported in cartilaginous fish and camelids. By analyzing transcript data and genome sequences, we conducted a comprehensive analysis of Bactrian camel immunoglobulin heavy chain genes. Based on the transcript data, one μ gene, five γ genes, one α gene and one ε gene were found. Additionally, the variable region of HCAbs (VHH and the conventional antibodies (VH sequences associated with the γ3, γ1a/b and μ genes were amplified. Based on these genome sequences, seven DH, six JH, μ, γ2a, γ2c, α, and ε genes and a portion of a γ3 gene were observed. Different Kozak sequences within different VH families were found in our analysis, and the variability index differed between the VHH3 and VH3 families. Phylogenetic analysis of the constant regions of the camelid immunoglobulin genes indicates that these genes appeared before the evolutionary divergence of Bactrian camels and dromedaries.

  6. Growth and Muscle Defects in Mice Lacking Adult Myosin Heavy Chain Genes

    OpenAIRE

    Acakpo-Satchivi, Leslie J.R.; Edelmann, Winfried; Sartorius, Carol; Lu, Brian D.; Wahr, Philip A.; Watkins, Simon C.; Metzger, Joseph M.; Leinwand, Leslie; Kucherlapati, Raju

    1997-01-01

    The three adult fast myosin heavy chains (MyHCs) constitute the vast majority of the myosin in adult skeletal musculature, and are >92% identical. We describe mice carrying null mutations in each of two predominant adult fast MyHC genes, IIb and IId/x. Both null strains exhibit growth and muscle defects, but the defects are different between the two strains and do not correlate with the abundance or distribution of each gene product. For example, despite the fact that MyHC-IIb accounts for >7...

  7. Antibody Heavy Chain Variable Domains of Different Germline Gene Origins Diversify through Different Paths

    Directory of Open Access Journals (Sweden)

    Ufuk Kirik

    2017-11-01

    Full Text Available B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes.

  8. High-resolution description of antibody heavy-chain repertoires in humans.

    Directory of Open Access Journals (Sweden)

    Ramy Arnaout

    Full Text Available Antibodies' protective, pathological, and therapeutic properties result from their considerable diversity. This diversity is almost limitless in potential, but actual diversity is still poorly understood. Here we use deep sequencing to characterize the diversity of the heavy-chain CDR3 region, the most important contributor to antibody binding specificity, and the constituent V, D, and J segments that comprise it. We find that, during the stepwise D-J and then V-DJ recombination events, the choice of D and J segments exert some bias on each other; however, we find the choice of the V segment is essentially independent of both. V, D, and J segments are utilized with different frequencies, resulting in a highly skewed representation of VDJ combinations in the repertoire. Nevertheless, the pattern of segment usage was almost identical between two different individuals. The pattern of V, D, and J segment usage and recombination was insufficient to explain overlap that was observed between the two individuals' CDR3 repertoires. Finally, we find that while there are a near-infinite number of heavy-chain CDR3s in principle, there are about 3-9 million in the blood of an adult human being.

  9. High-Resolution Description of Antibody Heavy-Chain Repertoires in Humans

    Science.gov (United States)

    Arnaout, Ramy; Lee, William; Cahill, Patrick; Honan, Tracey; Sparrow, Todd; Weiand, Michael; Nusbaum, Chad

    2011-01-01

    Antibodies' protective, pathological, and therapeutic properties result from their considerable diversity. This diversity is almost limitless in potential, but actual diversity is still poorly understood. Here we use deep sequencing to characterize the diversity of the heavy-chain CDR3 region, the most important contributor to antibody binding specificity, and the constituent V, D, and J segments that comprise it. We find that, during the stepwise D-J and then V-DJ recombination events, the choice of D and J segments exert some bias on each other; however, we find the choice of the V segment is essentially independent of both. V, D, and J segments are utilized with different frequencies, resulting in a highly skewed representation of VDJ combinations in the repertoire. Nevertheless, the pattern of segment usage was almost identical between two different individuals. The pattern of V, D, and J segment usage and recombination was insufficient to explain overlap that was observed between the two individuals' CDR3 repertoires. Finally, we find that while there are a near-infinite number of heavy-chain CDR3s in principle, there are about 3–9 million in the blood of an adult human being. PMID:21829618

  10. Expression cloning and production of Human Heavy Chain Only antibodies from murine transgenic plasma cells

    Directory of Open Access Journals (Sweden)

    Dubravka Drabek

    2016-12-01

    Full Text Available Several technologies have been developed to isolate human antibodies against different target antigens as a source of potential therapeutics, including hybridoma technology, phage and yeast display systems. For conventional antibodies this involves either random pairing of VH and VL domains in combinatorial display libraries, or isolation of cognate pairs of VH and VL domains from human B cells or from transgenic mice carrying human immunoglobulin loci followed by single cell sorting, single cell RT-PCR and bulk cloning of isolated natural VH-VL pairs. Heavy chain only antibodies (HCAbs that naturally occur in camelids require only heavy immunoglobulin chain cloning. Here, we present an automatable novel, high-throughput technology, for rapid direct cloning and production of fully human HCAbs from sorted population of transgenic mouse plasma cells carrying a human HCAb locus. Utility of the technique is demonstrated by isolation of diverse sets of sequence unique, soluble, high affinity influenza A strain X-31 hemagglutinin (HA specific HCAbs

  11. Antibody Heavy Chain Variable Domains of Different Germline Gene Origins Diversify through Different Paths

    Science.gov (United States)

    Kirik, Ufuk; Persson, Helena; Levander, Fredrik; Greiff, Lennart; Ohlin, Mats

    2017-01-01

    B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes. PMID:29180996

  12. Knockdown of embryonic myosin heavy chain reveals an essential role in the morphology and function of the developing heart

    Science.gov (United States)

    Rutland, Catrin Sian; Polo-Parada, Luis; Ehler, Elisabeth; Alibhai, Aziza; Thorpe, Aaran; Suren, Suganthi; Emes, Richard D.; Patel, Bhakti; Loughna, Siobhan

    2011-01-01

    The expression and function of embryonic myosin heavy chain (eMYH) has not been investigated within the early developing heart. This is despite the knowledge that other structural proteins, such as alpha and beta myosin heavy chains and cardiac alpha actin, play crucial roles in atrial septal development and cardiac function. Most cases of atrial septal defects and cardiomyopathy are not associated with a known causative gene, suggesting that further analysis into candidate genes is required. Expression studies localised eMYH in the developing chick heart. eMYH knockdown was achieved using morpholinos in a temporal manner and functional studies were carried out using electrical and calcium signalling methodologies. Knockdown in the early embryo led to abnormal atrial septal development and heart enlargement. Intriguingly, action potentials of the eMYH knockdown hearts were abnormal in comparison with the alpha and beta myosin heavy chain knockdowns and controls. Although myofibrillogenesis appeared normal, in knockdown hearts the tissue integrity was affected owing to apparent focal points of myocyte loss and an increase in cell death. An expression profile of human skeletal myosin heavy chain genes suggests that human myosin heavy chain 3 is the functional homologue of the chick eMYH gene. These data provide compelling evidence that eMYH plays a crucial role in important processes in the early developing heart and, hence, is a candidate causative gene for atrial septal defects and cardiomyopathy. PMID:21862559

  13. Directed evolution of human heavy chain variable domain (VH using in vivo protein fitness filter.

    Directory of Open Access Journals (Sweden)

    Dong-Sik Kim

    Full Text Available Human immunoglobulin heavy chain variable domains (VH are promising scaffolds for antigen binding. However, VH is an unstable and aggregation-prone protein, hindering its use for therapeutic purposes. To evolve the VH domain, we performed in vivo protein solubility selection that linked antibiotic resistance to the protein folding quality control mechanism of the twin-arginine translocation pathway of E. coli. After screening a human germ-line VH library, 95% of the VH proteins obtained were identified as VH3 family members; one VH protein, MG2x1, stood out among separate clones expressing individual VH variants. With further screening of combinatorial framework mutation library of MG2x1, we found a consistent bias toward substitution with tryptophan at the position of 50 and 58 in VH. Comparison of the crystal structures of the VH variants revealed that those substitutions with bulky side chain amino acids filled the cavity in the VH interface between heavy and light chains of the Fab arrangement along with the increased number of hydrogen bonds, decreased solvation energy, and increased negative charge. Accordingly, the engineered VH acquires an increased level of thermodynamic stability, reversible folding, and soluble expression. The library built with the VH variant as a scaffold was qualified as most of VH clones selected randomly were expressed as soluble form in E. coli regardless length of the combinatorial CDR. Furthermore, a non-aggregation feature of the selected VH conferred a free of humoral response in mice, even when administered together with adjuvant. As a result, this selection provides an alternative directed evolution pathway for unstable proteins, which are distinct from conventional methods based on the phage display.

  14. Bioaccumulative and conchological assessment of heavy metal transfer in a soil-plant-snail food chain

    Directory of Open Access Journals (Sweden)

    Nica Dragos V

    2012-06-01

    Full Text Available Abstract Background Copper (Cu, zinc (Zn, cadmium (Cd, and lead (Pb can pose serious threats to environmental health because they tend to bioaccumulate in terrestrial ecosystems. We investigated under field conditions the transfer of these heavy metals in a soil-plant-snail food chain in Banat area, Romania. The main goal of this paper was to assess the Roman snail (Helix pomatia usefulness in environmental monitoring as bioindicator of heavy metal accumulation. Eight sampling sites, selected by different history of heavy metal (HM exposure, were chosen to be sampled for soil, nettle leaves, and newly matured snails. This study also aimed to identify the putative effects of HM accumulation in the environment on phenotypic variability in selected shell features, which included shell height (SH, relative shell height (RSH, and whorl number (WN. Results Significantly higher amounts of HMs were accumulated in snail hepatopancreas and not in foot. Cu, Zn, and Cd have biomagnified in the snail body, particularly in the hepatopancreas. In contrast, Pb decreased when going up into the food chain. Zn, Cd, and Pb correlated highly with each other at all levels of the investigated food chain. Zn and Pb exhibited an effective soil–plant transfer, whereas in the snail body only foot Cu concentration was correlated with that in soil. There were significant differences among sampling sites for WN, SH, and RSH when compared with reference snails. WN was strongly correlated with Cd and Pb concentrations in nettle leaves but not with Cu and Zn. SH was independent of HM concentrations in soil, snail hepatopancreas, and foot. However, SH correlated negatively with nettle leaves concentrations for each HM except Cu. In contrast, RSH correlated significantly only with Pb concentration in hepatopancreas. Conclusions The snail hepatopancreas accumulates high amounts of HMs, and therefore, this organ can function as a reliable biomarker for tracking HM bioavailability

  15. Developmental expression and cardiac transcriptional regulation of Myh7b, a third myosin heavy chain in the vertebrate heart

    OpenAIRE

    Warkman, Andrew S.; Whitman, Samantha A; Miller, Melanie K.; Garriock, Robert J.; Schwach, Catherine M.; Gregorio, Carol C.; Krieg, Paul A.

    2012-01-01

    The mammalian heart expresses two myosin heavy chain genes (Myh6 and Myh7), which are major components of the thick filaments of the sarcomere. We have determined that a third myosin heavy chain, MYH7B, is also expressed in the myocardium. Developmental analysis shows Myh7b expression in cardiac and skeletal muscle of Xenopus, chick and mouse embryos, and in smooth muscle tissues during later stages of mouse embryogenesis. Myh7b is also expressed in the adult human heart. The promoter region ...

  16. Myosin heavy chain expression in rodent skeletal muscle: effects of exposure to zero gravity

    Science.gov (United States)

    Haddad, F.; Herrick, R. E.; Adams, G. R.; Baldwin, K. M.

    1993-01-01

    This study ascertained the effects of 9 days of zero gravity on the relative (percentage of total) and calculated absolute (mg/muscle) content of isomyosin expressed in both antigravity and locomotor skeletal muscle of ground control (CON) and flight-exposed (FL) rats. Results showed that although there were no differences in body weight between FL and CON animals, a significant reduction in muscle mass occurred in the vastus intermedius (VI) (P muscle protein and myofibril protein content were not different between the muscle regions examined in the FL and CON groups. In the VI, there were trends for reductions in the relative content of type I and IIa myosin heavy chains (MHCs) that were offset by increases in the relative content of both type IIb and possibly type IIx MHC protein (P > 0.05). mRNA levels were consistent with this pattern (P antigravity skeletal muscle during exposure to zero gravity that could affect muscle function.

  17. Myosin heavy chain isoforms in single fibres from m. vastus lateralis of sprinters: influence of training.

    Science.gov (United States)

    Andersen, J L; Klitgaard, H; Saltin, B

    1994-06-01

    The myosin heavy chain (MHC) composition of single fibres from m. vastus lateralis of a group of male sprint athletes (n = 6) was analysed, before and after a three months period of intensive strength- and interval-training, using a sensitive gel electrophoretic technique. Significant improvements were observed after training in almost all of a series of performance tests. After training the sprinters revealed a decrease in fibres containing only MHC isoform I (52.0 +/- 3.0% vs. 41.2 +/- 4.7% (mean +/- SE) (P training (12.9 +/- 5.0% vs. 5.1 +/- 3.1% (P sprinters seems therefore to contain both MHC isoforms IIA and IIB. Sprint-training appears to induce an increased expression of MHC isoform IIA in skeletal muscles. This seems related to a bi-directional transformation from both MHC isoforms I and IIB towards MHC isoform IIA.

  18. Trans-chromosomal recombination within the Ig heavy chain switch region in B lymphocytes

    Science.gov (United States)

    Kingzette, Mae; Spieker-Polet, Helga; Yam, Pi-Chen; Zhai, Shi-Kang; Knight, Katherine L.

    1998-01-01

    Somatic DNA rearrangements in B lymphocytes, including V(D)J gene rearrangements and isotype switching, generally occur in cis, i. e., intrachromosomally. We showed previously, however, that 3 to 7% of IgA heavy chains have the VH and Cα regions encoded in trans. To determine whether the trans-association of VH and Cα occurred by trans-chromosomal recombination, by trans-splicing, or by trans-chromosomal gene conversion, we generated and analyzed eight IgA-secreting rabbit hybridomas with trans-associated VH and Cα heavy chains. By ELISA and by nucleotide sequence analysis we found that the VH and Cα regions were encoded by genes that were in trans in the germline. We cloned the rearranged VDJ-Cα gene from a fosmid library of one hybridoma and found that the expressed VH and Cα genes were juxtaposed. Moreover, the juxtaposed VH and Cα genes originated from different IgH alleles. From the same hybridoma, we also identified a fosmid clone with the other expected product of a trans-chromosomal recombination. The recombination breakpoint occurred within the Sμ/Sα region, indicating that the trans-association of VH and Cα genes occurred by trans-chromosomal recombination during isotype switching. We conclude that trans-chromosomal recombination occurs at an unexpectedly high frequency (7%) within the IgH locus of B lymphocytes in normal animals, which may explain the high incidence of B-cell tumors that arise from oncogene translocation into the IgH locus. PMID:9751752

  19. Noninvasive Assessment of Skeletal Muscle Myosin Heavy Chain Expression in Trained and Untrained Men.

    Science.gov (United States)

    Fry, Andrew C; Housh, Terry J; Cramer, Joel B; Weir, Joseph P; Beck, Travis W; Schilling, Brian K; Miller, Jonathan D; Nicoll, Justin X

    2017-09-01

    Fry, AC, Housh, TJ, Cramer, JB, Weir, JP, Beck, TW, Schilling, BK, Miller, JD, and Nicoll, JX. Noninvasive assessment of skeletal muscle myosin heavy chain expression in trained and untrained men. J Strength Cond Res 31(9): 2355-2362, 2017-Numerous conditions and types of physical activity (e.g., exercise, aging, and muscle-related diseases) can influence muscle fiber types and the proteins expressed. To date, muscle fibers can only be characterized by actually obtaining a tissue sample using the invasive muscle biopsy procedure. Mechanomyography (MMG) is the assessment of the vibration properties of contracting skeletal muscle and has been proposed as a possible noninvasive method for muscle fiber analysis. Therefore, the purpose of this project was to examine the feasibility of using MMG and muscle performance measures to noninvasively assess muscle fiber characteristics. Fifteen men (5 endurance-trained, 5 weight-trained, and 5 sedentary) provided muscle samples from their vastus lateralis muscle. These samples were analyzed for relative myosin heavy chain (MHC) protein expression, which is highly correlated with % muscle fiber type areas. Additionally, each subject performed several muscle performance tests, and MMG of the quadriceps was assessed during a knee extension exercise. Multiple regression was used to develop prediction equations for determining relative muscle content of MHC types I, IIa, and IIx. A combination of MMG and knee extension performance variables estimated types I, IIa, and IIx MHCs with approximately 80% accuracy. Although preliminary, these data suggest that muscle performance tests in addition to MMG assessments during a simple muscle performance task (knee extension) can be used to estimate muscle fiber type composition in a healthy male population. Such methods could ultimately be used to noninvasively monitor muscle health and fitness.

  20. Protective Effects of Clenbuterol against Dexamethasone-Induced Masseter Muscle Atrophy and Myosin Heavy Chain Transition.

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    Daisuke Umeki

    Full Text Available Glucocorticoid has a direct catabolic effect on skeletal muscle, leading to muscle atrophy, but no effective pharmacotherapy is available. We reported that clenbuterol (CB induced masseter muscle hypertrophy and slow-to-fast myosin heavy chain (MHC isoform transition through direct muscle β2-adrenergic receptor stimulation. Thus, we hypothesized that CB would antagonize glucocorticoid (dexamethasone; DEX-induced muscle atrophy and fast-to-slow MHC isoform transition.We examined the effect of CB on DEX-induced masseter muscle atrophy by measuring masseter muscle weight, fiber diameter, cross-sectional area, and myosin heavy chain (MHC composition. To elucidate the mechanisms involved, we used immunoblotting to study the effects of CB on muscle hypertrophic signaling (insulin growth factor 1 (IGF1 expression, Akt/mammalian target of rapamycin (mTOR pathway, and calcineurin pathway and atrophic signaling (Akt/Forkhead box-O (FOXO pathway and myostatin expression in masseter muscle of rats treated with DEX and/or CB.Masseter muscle weight in the DEX-treated group was significantly lower than that in the Control group, as expected, but co-treatment with CB suppressed the DEX-induced masseter muscle atrophy, concomitantly with inhibition of fast-to-slow MHC isoforms transition. Activation of the Akt/mTOR pathway in masseter muscle of the DEX-treated group was significantly inhibited compared to that of the Control group, and CB suppressed this inhibition. DEX also suppressed expression of IGF1 (positive regulator of muscle growth, and CB attenuated this inhibition. Myostatin protein expression was unchanged. CB had no effect on activation of the Akt/FOXO pathway. These results indicate that CB antagonizes DEX-induced muscle atrophy and fast-to-slow MHC isoform transition via modulation of Akt/mTOR activity and IGF1 expression. CB might be a useful pharmacological agent for treatment of glucocorticoid-induced muscle atrophy.

  1. Aedes aegypti ferritin heavy chain homologue: feeding of iron or blood influences message levels, lengths and subunit abundance

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    Boris C. Dunkov

    2002-04-01

    Full Text Available Secreted ferritin in the mosquito, Aedes aegypti, has several subunits that are the products of at least two genes, one encoding a homologue of the vertebrate heavy chain (HCH and the other the light chain homologue (LCH. Here we report the developmental and organ specific pattern of expression of the ferritin HCH messages and of both subunit types in control sugar-fed mosquitoes, in those exposed to high levels of dietary iron, and after blood feeding.

  2. Lampreys Have a Single Gene Cluster for the Fast Skeletal Myosin Heavy Chain Gene Family

    Science.gov (United States)

    Ikeda, Daisuke; Ono, Yosuke; Hirano, Shigeki; Kan-no, Nobuhiro; Watabe, Shugo

    2013-01-01

    Muscle tissues contain the most classic sarcomeric myosin, called myosin II, which consists of 2 heavy chains (MYHs) and 4 light chains. In the case of humans (tetrapod), a total of 6 fast skeletal-type MYH genes (MYHs) are clustered on a single chromosome. In contrast, torafugu (teleost) contains at least 13 fast skeletal MYHs, which are distributed in 5 genomic regions; the MYHs are clustered in 3 of these regions. In the present study, the evolutionary relationship among fast skeletal MYHs is elucidated by comparing the MYHs of teleosts and tetrapods with those of cyclostome lampreys, one of two groups of extant jawless vertebrates (agnathans). We found that lampreys contain at least 3 fast skeletal MYHs, which are clustered in a head-to-tail manner in a single genomic region. Although there was apparent synteny in the corresponding MYH cluster regions between lampreys and tetrapods, phylogenetic analysis indicated that lamprey and tetrapod MYHs have independently duplicated and diversified. Subsequent transgenic approaches showed that the 5′-flanking sequences of Japanese lamprey fast skeletal MYHs function as a regulatory sequence to drive specific reporter gene expression in the fast skeletal muscle of zebrafish embryos. Although zebrafish MYH promoters showed apparent activity to direct reporter gene expression in myogenic cells derived from mice, promoters from Japanese lamprey MYHs had no activity. These results suggest that the muscle-specific regulatory mechanisms are partially conserved between teleosts and tetrapods but not between cyclostomes and tetrapods, despite the conserved synteny. PMID:24376886

  3. Lampreys have a single gene cluster for the fast skeletal myosin heavy chain gene family.

    Directory of Open Access Journals (Sweden)

    Daisuke Ikeda

    Full Text Available Muscle tissues contain the most classic sarcomeric myosin, called myosin II, which consists of 2 heavy chains (MYHs and 4 light chains. In the case of humans (tetrapod, a total of 6 fast skeletal-type MYH genes (MYHs are clustered on a single chromosome. In contrast, torafugu (teleost contains at least 13 fast skeletal MYHs, which are distributed in 5 genomic regions; the MYHs are clustered in 3 of these regions. In the present study, the evolutionary relationship among fast skeletal MYHs is elucidated by comparing the MYHs of teleosts and tetrapods with those of cyclostome lampreys, one of two groups of extant jawless vertebrates (agnathans. We found that lampreys contain at least 3 fast skeletal MYHs, which are clustered in a head-to-tail manner in a single genomic region. Although there was apparent synteny in the corresponding MYH cluster regions between lampreys and tetrapods, phylogenetic analysis indicated that lamprey and tetrapod MYHs have independently duplicated and diversified. Subsequent transgenic approaches showed that the 5'-flanking sequences of Japanese lamprey fast skeletal MYHs function as a regulatory sequence to drive specific reporter gene expression in the fast skeletal muscle of zebrafish embryos. Although zebrafish MYH promoters showed apparent activity to direct reporter gene expression in myogenic cells derived from mice, promoters from Japanese lamprey MYHs had no activity. These results suggest that the muscle-specific regulatory mechanisms are partially conserved between teleosts and tetrapods but not between cyclostomes and tetrapods, despite the conserved synteny.

  4. Alpaca (Lama pacos) as a convenient source of recombinant camelid heavy chain antibodies (VHHs)

    Science.gov (United States)

    Maass, David R.; Sepulveda, Jorge; Pernthaner, Anton; Shoemaker, Charles B.

    2007-01-01

    Recombinant single domain antibody fragments (VHHs) that derive from the unusual camelid heavy chain only IgG class (HCAbs) have many favourable properties compared with single-chain antibodies prepared from conventional IgG. As a result, VHHs have become widely used as binding reagents and are beginning to show potential as therapeutic agents. To date, the source of VHH genetic material has been camels and llamas despite their large size and limited availability. Here we demonstrate that the smaller, more tractable and widely available alpaca is an excellent source of VHH coding DNA. Alpaca sera IgG consists of about 50% HCAbs, mostly of the short-hinge variety. Sequencing of DNA encoding more than 50 random VHH and hinge domains permitted the design of PCR primers that will amplify virtually all alpaca VHH coding DNAs for phage display library construction. Alpacas were immunized with ovine tumour necrosis factor α (TNFα) and a VHH phage display library was prepared from a lymph node that drains the sites of immunizations and successfully employed in the isolation of VHHs that bind and neutralize ovine TNFα. PMID:17568607

  5. Biosynthesis and characterization of a non-repetitive polypeptide derived from silk fibroin heavy chain

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Gaoqiang; Wu, Mingyang; Yi, Honggen; Wang, Jiannan, E-mail: wangjn@suda.edu.cn

    2016-02-01

    Silk fibroin heavy chain is the major protein component of Bombyx mori silk fibroin and is composed of 12 repetitive and 11 non-repetitive regions, with the non-repetitive domain consisting of a hydrophilic polypeptide chain. In order to determine the biomedical function of the non-repetitive domain or potentially use it to modify hydrophobic biomaterials, high-purity isolation is necessary. Previously, we cloned and extended a gene motif (f(1)) encoding the non-repetitive domain. Here, this motif and its multimers are inserted into a glutathione S-transferase (GST)-tagged fusion-protein expression vector. Motif f(1) and multimers f(4) and f(8) were expressed in Escherichia coli BL21 cells following isopropyl β-D-1-thiogalactopyranoside induction, purified by GST-affinity chromatography, and single bands of purified fusion proteins GST-F(1), GST-F(4), and GST-F(8), were visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Target polypeptides F(1), F(4), and F(8), were cleaved clearly from the GST-fusion tag following thrombin digestion. Mass spectrometry results indicate that the molecular weights associated with fusion proteins GST-F(1), GST-F(4), and GST-F(8) are 31.5, 43.8, and 59.0 kDa, respectively, and with the cleaved polypeptides F(1), F(4), and F(8) are 4.8, 16.8, and 32.8 kDa, respectively. The F(1), F(4), and F(8) polypeptide chains are negatively charged with isoelectric points (pI) of 3.3, 3.2, and 3.0, respectively. The molecular weight and pI values of the polypeptide chains are consistent with the predicted values and the amino acid compositions similar to predicted sequences. FTIR and CD results show the molecular conformation of F(1) was mainly random coil, and more stable α-helix structure formed in longer molecular chain. - Highlights: • A non-repetitive domain and its multimers of silk fibroin were expressed by E. coli. • The corresponding target polypeptides F(1), F(4) and F(8) were cleaved clearly. • Their

  6. Immunoglobulin light and heavy chain amyloidosis AL/AH: renal pathology and differential diagnosis.

    Science.gov (United States)

    Picken, Maria M

    2007-01-01

    Among the varied and biochemically diverse group of protein folding disorders that are collectively known as the amyloidoses, AL-amyloidosis where deposits are derived from the immunoglobulin light chain fragments, is the most prevalent systemic form of the disease found in the western world. In contrast, AH-amyloidosis, resulting from the deposition of immunoglobulin heavy chains, is a rare disease with very few cases thus far reported. Both diseases primarily affect older individuals and are always associated with some form of plasma cell/B cell lymphoproliferative process. The overwhelming majority of monoclonal light chains are nephrotoxic leading to frequent renal involvement, although a wide variety of other organ systems may be involved. The most common clinical presentation is proteinuria and the disease is often diagnosed by renal biopsy. The kidneys are the most frequent site of amyloid fibril deposition in AL and light microscopic examination of Congo red stained sections is the prime means of detection. Electron microscopy may be helpful in the detection of small deposits and in the differentiation of amyloid from other types of renal fibrillar deposits. Current treatment of systemic amyloidoses depends upon the type of amyloid deposits; thus, accurate typing, using a panel of antibodies, is of paramount importance. While the differential diagnosis of amyloidoses continues to expand with increased awareness of hereditary types, currently, the main challenge is diagnosis of AL/AH with confidence. Future goals include the development of more precise and sensitive diagnostic tools. This chapter presents the pathology of AL/AH, current standards of diagnosis and the differential diagnosis. Whenever possible, the most recent references, considered as being particularly useful to clinicians and pathologists serving patients with renal amyloidosis, have been selected.

  7. Enhanced factor VIII heavy chain for gene therapy of hemophilia A.

    Science.gov (United States)

    Chen, Lingxia; Lu, Hui; Wang, Jinhui; Sarkar, Rita; Yang, Xiao; Wang, Hongli; High, Katherine A; Xiao, Weidong

    2009-03-01

    Hemophilia A gene therapy using recombinant adenovirus-associated virus (AAV) vectors has been hampered by the size of the factor VIII (FVIII) cDNA. Previously, splitting the FVIII coding sequence into a heavy-chain (HC) fragment and a light-chain (LC) fragment for dual recombinant AAV vector delivery has been successfully explored. However, the main disadvantage of this approach is a "chain imbalance" problem in which LC secretion is approximately 1-2 logs higher than that of HC, and therefore, the majority of protein synthesized is nonfunctional. To improve HC secretion, we constructed alternate FVIII HCs based on our observation that LC facilitates HC secretion. To our surprise, most of the new HC molecules exhibited enhanced expression over the traditional HC molecule (HC(745)). The optimized HC mutein, HC(HL), including additional acidic-region-3 (ar3) sequences, exhibited three- to fivefold higher activity in both enzyme-linked immunosorbent assay (ELISA) and activated partial thromboplastin time (aPTT) assay in in vitro testing. Further characterization suggested ar3 sequences increased HC secretion, rather than promoting HC synthesis. Intravenous delivery of AAV8-HC(HL)+AAV8-LC or AAV8-HC(745)+AAV8-LC achieved phenotypic correction in hemophilia A mice. Mice receiving AAV8-HC(HL)+AAV8-LC achieved three- to fourfold higher HC expression than AAV8-HC(745)+AAV8-LC, consistent with the FVIII functional assays. HC(HL) should be substituted for HC(745) in a dual AAV vector strategy due to its enhanced expression.

  8. The 3D-structure of the Immunoglobulin Heavy Chain Locus: implications for long-range genomic interactions [supplemental data

    NARCIS (Netherlands)

    S. Jhunjhunwala (Suchit); M.C. van Zelm (Menno); M.M. Peak (Mandy); S. Cutchin (Steve); R. Riblet (Roy); J.J.M. van Dongen (Jacques); F.G. Grosveld (Frank); T.A. Knoch (Tobias); C. Murre (Cornelis)

    2008-01-01

    textabstractThe immunoglobulin heavy-chain (Igh) locus is organized into distinct regions that contain multiple variable (VH), diversity (DH), joining (JH) and constant (CH) coding elements. How the Igh locus is structured in 3D space is unknown. To probe the topography of the Igh locus,

  9. Humanization of Antibodies Using Heavy Chain Complementarity-determining Region 3 Grafting Coupled with in Vitro Somatic Hypermutation*

    Science.gov (United States)

    Bowers, Peter M.; Neben, Tamlyn Y.; Tomlinson, Geoffery L.; Dalton, Jennifer L.; Altobell, Larry; Zhang, Xue; Macomber, John L.; Wu, Betty F.; Toobian, Rachelle M.; McConnell, Audrey D.; Verdino, Petra; Chau, Betty; Horlick, Robert A.; King, David J.

    2013-01-01

    A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hβNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3-grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hβNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods. PMID:23355464

  10. Humanization of antibodies using heavy chain complementarity-determining region 3 grafting coupled with in vitro somatic hypermutation.

    Science.gov (United States)

    Bowers, Peter M; Neben, Tamlyn Y; Tomlinson, Geoffery L; Dalton, Jennifer L; Altobell, Larry; Zhang, Xue; Macomber, John L; Wu, Betty F; Toobian, Rachelle M; McConnell, Audrey D; Verdino, Petra; Chau, Betty; Horlick, Robert A; King, David J

    2013-03-15

    A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hβNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3-grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hβNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods.

  11. Mitochondrial Electron Transport Chain in Heavy Metal-Induced Neurotoxicity: Effects of Cadmium, Mercury, and Copper

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    Elena A. Belyaeva

    2012-01-01

    Full Text Available To clarify the role of mitochondrial electron transport chain (mtETC in heavy-metal-induced neurotoxicity, we studied action of Cd2+, Hg2+, and Cu2+ on cell viability, intracellular reactive oxygen species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd2+ beginning from 10 [mu]M and already at short incubation time (3 h significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 [mu]M Hg2+ or 500 [mu]M Cd2+, whereas even after 48 h exposure with 500 [mu]M Cu2+, only a 50% inhibition of the respiration occurred. Against the Cd2+-induced cell injury, not only different antioxidants and mitochondrial permeability transition pore inhibitors were protective but also such mtETC effectors as FCCP and stigmatellin (complex III inhibitor. However, all mtETC effectors used did not protect against the Hg2+- or Cu2+-induced cell damage. Notably, stigmatellin was shown to be one of the strongest protectors against the Cd2+-induced cell damage, producing a 15–20% increase in the cell viability. The mechanisms of the mtETC involvement in the heavy-metal-induced mitochondrial membrane permeabilization and cell death are discussed.

  12. The role of CTCF binding sites in the 3’ immunoglobulin heavy chain regulatory region

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    Barbara K Birshtein

    2012-11-01

    Full Text Available The immunoglobulin heavy chain locus undergoes a series of DNA rearrangements and modifications to achieve the construction and expression of individual antibody heavy chain genes in B cells. These events affect variable regions, through VDJ joining and subsequent somatic hypermutation, and constant regions through class switch recombination. Levels of IgH expression are also regulated during B cell development, resulting in high levels of secreted antibodies from fully-differentiated plasma cells. Regulation of these events has been attributed primarily to two cis-elements that work from long distances on their target sequences, i.e., an ~1 kb intronic enhancer, Eμ, located between the V region segments and the most 5′ constant region gene, Cμ; and an ~40 kb 3′ regulatory region (3′ RR that is located downstream of the most 3′ CH gene, Cα. The 3′ RR is a candidate for an end of B cell-specific regulation of the Igh locus. The 3′ RR contains several B cell-specific enhancers associated with DNase I hypersensitive sites (hs1-4, which are essential for class switch recombination and for high levels of IgH expression in plasma cells. Downstream of this enhancer-containing region is a region of high-density CTCF binding sites, which extends through hs5, 6, and 7 and further downstream. CTCF, with its enhancer-blocking activities, has been associated with all mammalian insulators and implicated in multiple chromosomal interactions. Here we address the 3′ RR CTCF-binding region as a potential insulator of the Igh locus, an independent regulatory element and a predicted modulator of the activity of 3’ RR enhancers. Using chromosome conformation capture technology, chromatin immunoprecipitation and genetic approaches, we have found that the 3’ RR with its CTCF binding region interacts with target sequences in the VH, Eμ and CH regions through DNA looping as regulated by protein binding. This region impacts on B cell-specific Igh

  13. Catabolism of human γG-immunoglobulins of different heavy chain subclasses

    Science.gov (United States)

    Spiegelberg, Hans L.; Fishkin, Ben G.; Grey, Howard M.

    1968-01-01

    The rates of catabolism of human γG-immunoglobulins of subclasses γG1, γG2, γG3, and γG4 were studied by determining the rates of elimination from the circulation of pairs of 131I-and 125I-labeled γG-myeloma proteins in 57 patients suffering from cancer other than multiple myeloma. On the average, γG1-, γG2-, and γG4-myeloma proteins were catabolized at a rate similar to that of normal γG-immunoglobulin, whereas γG3-myeloma proteins were catabolized more rapidly than normal γG-immunoglobulin. The average half-lives for the myeloma proteins were 12.3 days for normal γG, 11.6 days for γG1, 12.4 days for γG2, 8.2 days for γG3, and 11.3 days for γG4. However, significant differences in catabolic rates were observed when individual myeloma proteins of a single subclass were compared. These individual variations were present within all four heavy chain subclasses. The extent of differences ranged from 10 to 47%. The catabolic rate of normal γG was in an intermediate range when compared with myeloma proteins of relatively long and short half-lives. The rate of catabolism of an individual myeloma protein did not correlate with its light chain type, Gm factor, carbohydrate content, or electrophoretic mobility. These findings indicate that the structure(s) related to the catabolism of γG-immunoglobulins are complex and differ from one immunoglobulin molecule to another. Images PMID:4175542

  14. Electrophoretic Mobility of Cardiac Myosin Heavy Chain Isoforms Revisited: Application of MALDI TOF/TOF Analysis

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    Petra Arnostova

    2011-01-01

    Full Text Available The expression of two cardiac myosin heavy chain (MyHC isoforms in response to the thyroid status was studied in left ventricles (LVs of Lewis rats. Major MyHC isoform in euthyroid and hyperthyroid LVs had a higher mobility on SDS-PAGE, whereas hypothyroid LVs predominantly contained a MyHC isoform with a lower mobility corresponding to that of the control soleus muscle. By comparing the MyHC profiles obtained under altered thyroid states together with the control soleus, we concluded that MyHCα was represented by the lower band with higher mobility and MyHCβ by the upper band. The identity of these two bands in SDS-PAGE gels was confirmed by western blot and mass spectrometry. Thus, in contrast to the literature data, we found that the MyHCα possessed a higher mobility rate than the MyHCβ isoform. Our data highlighted the importance of the careful identification of the MyHCα and MyHCβ isoforms analyzed by the SDS-PAGE.

  15. A Mouse Neurodegenerative Dynein Heavy Chain Mutation Alters Dynein Motility and Localization in Neurospora crassa

    Science.gov (United States)

    Sivagurunathan, Senthilkumar; Schnittker, Robert R.; Nandini, Swaran; Plamann, Michael D.; King, Stephen J.

    2013-01-01

    Cytoplasmic dynein is responsible for the transport and delivery of cargoes in organisms ranging from humans to fungi. Dysfunction of dynein motor machinery due to mutations in dynein or its activating complex dynactin can result in one of several neurological diseases in mammals. The mouse Legs at odd angles (Loa) mutation in the tail domain of the dynein heavy chain has been shown to lead to progressive neurodegeneration in mice. The mechanism by which the Loa mutation affects dynein function is just beginning to be understood. In this work, we generated the dynein tail mutation observed in Loa mice into the Neurospora crassa genome and utilized cell biological and complementing biochemical approaches to characterize how that tail mutation affected dynein function. We determined that the Loa mutation exhibits several subtle defects upon dynein function in N. crassa that were not seen in mice, including alterations in dynein localization, impaired velocity of vesicle transport, and in the biochemical properties of purified motors. Our work provides new information on the role of the tail domain on dynein function and points out areas of future research that will be of interest to pursue in mammalian systems. PMID:22991199

  16. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration.

    Science.gov (United States)

    Morin, Nicole A; Oakes, Patrick W; Hyun, Young-Min; Lee, Dooyoung; Chin, Y Eugene; Chin, Eugene Y; King, Michael R; Springer, Timothy A; Shimaoka, Motomu; Tang, Jay X; Reichner, Jonathan S; Kim, Minsoo

    2008-01-21

    Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function-associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion.

  17. Iron Deposition and Ferritin Heavy Chain (Fth Localization in Rodent Teeth

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    Wen Xin

    2013-01-01

    Full Text Available Abstract Background An iron rich layer on the labial surface is characteristic of the enamel of rodent incisors. In order to address a role for iron content in continuously growing incisors during odontogenesis, we studied iron deposition patterns in enamel and dentine using Perls’ blue staining and ferritin heavy chain (Fth immunolocalization. Fth expression is regulated by iron level; therefore its localization can be used as a sensitive indicator for iron deposition. Results Sagittal sections of 4-week old rat incisors showed a gradual increase in iron level in the enamel organ from secretory to maturation stages. In addition, iron was detected in ameloblasts of erupting third molars of 4-week old rats, suggesting iron plays a role in both incisor and molar development. In odontoblasts, the presence of iron was demonstrated, and this is consistent with iron’s role in collagen synthesis. Using postnatal 3-, 6-, 9-day old mice, the spatial and temporal expression of Fth in tooth development again indicated the presence of iron in mature ameloblasts and odontoblasts. Conclusions While these data do not explain what functional role iron has in tooth formation, it does highlight a significant molecular activity associated with the formation of the rodent dentition.

  18. Myosin heavy chain composition of tiger (Panthera tigris) and cheetah (Acinonyx jubatus) hindlimb muscles.

    Science.gov (United States)

    Hyatt, Jon-Philippe K; Roy, Roland R; Rugg, Stuart; Talmadge, Robert J

    2010-01-01

    Felids have a wide range of locomotor activity patterns and maximal running speeds, including the very fast cheetah (Acinonyx jubatas), the roaming tiger (Panthera tigris), and the relatively sedentary domestic cat (Felis catus). As previous studies have suggested a relationship between the amount and type of activity and the myosin heavy chain (MHC) isoform composition of a muscle, we assessed the MHC isoform composition of selected hindlimb muscles from these three felid species with differing activity regimens. Using gel electrophoresis, western blotting, histochemistry, and immunohistochemistry with MHC isoform-specific antibodies, we compared the MHC composition in the tibialis anterior, medial gastrocnemius (MG), plantaris (Plt), and soleus muscles of the tiger, cheetah, and domestic cat. The soleus muscle was absent in the cheetah. At least one slow (type I) and three fast (types IIa, IIx, and IIb) MHC isoforms were present in the muscles of each felid. The tiger had a high combined percentage of the characteristically slower isoforms (MHCs I and IIa) in the MG (62%) and the Plt (86%), whereas these percentages were relatively low in the MG (44%) and Plt (55%) of the cheetah. In general, the MHC isoform characteristics of the hindlimb muscles matched the daily activity patterns of these felids: the tiger has daily demands for covering long distances, whereas the cheetah has requirements for speed and power. (c) 2009 Wiley-Liss, Inc.

  19. Myosin heavy chain composition of skeletal muscles in young rats growing under hypobaric hypoxia conditions.

    Science.gov (United States)

    Bigard, A X; Sanchez, H; Birot, O; Serrurier, B

    2000-02-01

    This study investigated the effects of voluntary wheel running on the myosin heavy chain (MHC) composition of the soleus (Sol) and plantaris muscles (Pla) in rats developing under hypobaric choronic hypoxia (CH) conditions during 4 wk in comparison with those of control rats maintained under local barometric pressure conditions (C) or rats pair-fed an equivalent quantity of food to that consumed by CH animals (PF). Compared with C animals, sedentary rats subjected to CH conditions showed a significant decrease in type I MHC in Sol (-12%, P difference in the MHC profile of Sol was shown between CH active and C active rats. The MHC distribution in Sol of PF rats was not significantly different from that found in C animals. CH resulted in a significant decrease in type I (P fast shift in the MHC profile was unaffected by spontaneous running activity. These results suggest that running exercise suppresses the hypoxia-induced slow-to-fast transition in the MHC expression in Sol muscles only. The hypoxia-induced decrease in food intake has no major influence on MHC expression in developing rats.

  20. Ozz-E3 ubiquitin ligase targets sarcomeric embryonic myosin heavy chain during muscle development.

    Directory of Open Access Journals (Sweden)

    Yvan Campos

    2010-03-01

    Full Text Available Muscle contractile proteins are expressed as a series of developmental isoforms that are in constant dynamic remodeling during embryogenesis, but how obsolete molecules are recognized and removed is not known. Ozz is a developmentally regulated protein that functions as the adaptor component of a RING-type ubiquitin ligase complex specific to striated muscle. Ozz(-/- mutants exhibit defects in myofibrillogenesis and myofiber differentiation. Here we show that Ozz targets the rod portion of embryonic myosin heavy chain and preferentially recognizes the sarcomeric rather than the soluble pool of myosin. We present evidence that Ozz binding to the embryonic myosin isoform within sarcomeric thick filaments marks it for ubiquitination and proteolytic degradation, allowing its replacement with neonatal or adult isoforms. This unique function positions Ozz within a system that facilitates sarcomeric myosin remodeling during muscle maturation and regeneration. Our findings identify Ozz-E3 as the ubiquitin ligase complex that interacts with and regulates myosin within its fully assembled cytoskeletal structure.

  1. Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania.

    Science.gov (United States)

    Parks, Tom; Mirabel, Mariana M; Kado, Joseph; Auckland, Kathryn; Nowak, Jaroslaw; Rautanen, Anna; Mentzer, Alexander J; Marijon, Eloi; Jouven, Xavier; Perman, Mai Ling; Cua, Tuliana; Kauwe, John K; Allen, John B; Taylor, Henry; Robson, Kathryn J; Deane, Charlotte M; Steer, Andrew C; Hill, Adrian V S

    2017-05-11

    The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61*02 allele. We show each copy of IGHV4-61*02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27-1.61, P=4.1 × 10(-9)). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.

  2. Requirement for enhancer specificity in immunoglobulin heavy chain locus regulation1

    Science.gov (United States)

    Kuzin, Igor I.; Bagaeva, Ludmila; Young, Faith M.; Bottaro, Andrea

    2008-01-01

    The intronic Eμ enhancer has been implicated in immunoglobulin heavy chain (IgH) locus transcription, VDJ recombination, class switch recombination (CSR)2 and somatic hypermutation (SHM). How Eμ controls these diverse mechanisms is still largely unclear, but transcriptional enhancer activity is thought to play a central role. Here we compare the phenotype of mice lacking the Eμ element (ΔEμ) with that of mice in which Eμ was replaced with the ubiquitous SV40 transcriptional enhancer (SV40eR mutation), and show that SV40e cannot functionally complement Eμ loss in pro-B cells. Surprisingly, in fact, the SV40eR mutation yields a more profound defect than ΔEμ, with an almost complete block in μ0 germline transcription in pro-B cells. This active transcriptional suppression caused by enhancer replacement appears to be specific to the early stages of B cell development, as mature SV40eR B cells express μ0 transcripts at higher levels than ΔEμ mice, and undergo complete DNA demethylation at the IgH locus. These results indicate an unexpectedly stringent, developmentally-restricted requirement for enhancer specificity in regulating IgH function during the early phases of B cell differentiation, consistent with the view that coordination of multiple independent regulatory mechanisms and elements is essential for locus activation and VDJ recombination. PMID:18490744

  3. Cross Talk between Immunoglobulin Heavy-Chain Transcription and RNA Surveillance during B Cell Development

    Science.gov (United States)

    Tinguely, Aurélien; Chemin, Guillaume; Péron, Sophie; Sirac, Christophe; Reynaud, Stéphane; Cogné, Michel

    2012-01-01

    Immunoglobulin (Ig) genes naturally acquire frequent premature termination codons during the error-prone V(D)J recombination process. Although B cell differentiation is linked to the expression of productive Ig alleles, the transcriptional status of nonfunctionally recombined alleles remains unclear. Here, we tracked transcription and posttranscriptional regulation for both Ig heavy-chain (IgH) alleles in mice carrying a nonfunctional knock-in allele. We show that productively and nonproductively VDJ-rearranged alleles are transcribed throughout B cell development, carry similar active chromatin marks, and even display equivalent RNA polymerase II (RNAPII) loading after B cell stimulation. Hence, these results challenge the idea that the repositioning of one allele to heterochromatin could promote the silencing of nonproductive alleles. Interestingly, the efficiency of downstream RNA surveillance mechanisms fluctuates according to B cell activation and terminal differentiation: unspliced nonfunctional transcripts accumulate in primary B cells, while B cell activation promotes IgH transcription, RNA splicing, and nonsense-mediated mRNA decay (NMD). Altogether, IgH transcription and RNA splicing rates determine by which RNA surveillance mechanisms a B cell can get rid of nonproductive IgH mRNAs. PMID:22037763

  4. Effect of Fetal Hypothyroidism on Cardiac Myosin Heavy Chain Expression in Male Rats.

    Science.gov (United States)

    Yousefzadeh, Nasibeh; Jeddi, Sajad; Alipour, Mohammad Reza

    2016-08-01

    Thyroid hormone deficiency during fetal life could affect the cardiac function in later life. The mechanism underlying this action in fetal hypothyroidism (FH) in rats has not been elucidated thus far. The aim of this study is to evaluation the effect of FH on cardiac function in male rats and to determine the contribution of α-myosin heavy chain (MHC) and β-MHC isoforms. Six pregnant female rats were randomly divided into two groups: The hypothyroid group received water containing 6-propyl-2-thiouracil during gestation and the controls consumed tap water. The offspring of the rats were tested in adulthood. Hearts from the FH and control rats were isolated and perfused with langendroff setup for measuring hemodynamic parameters; also, the heart mRNA expressions of α- MHC and β-MHC were measured by qPCR. Baseline LVDP (74.0 ± 3.1 vs. 92.5 ± 3.2 mmHg, p rats than controls. Also, these results showed the same significance in ±dp/dt. In the FH rats, β-MHC expression was higher (201%) and α- MHC expression was lower (47%) than control. Thyroid hormone deficiency during fetal life could attenuate normal cardiac functions in adult rats, an effect at least in part due to the increased expression of β-MHC to α- MHC ratio in the heart.

  5. Hypoxia favors myosin heavy chain beta gene expression in an Hif-1alpha-dependent manner

    Science.gov (United States)

    Binó, Lucia; Procházková, Jiřina; Radaszkiewicz, Katarzyna Anna; Kučera, Jan; Kudová, Jana; Pacherník, Jiří; Kubala, Lukáš

    2017-01-01

    The potentiation of the naturally limited regenerative capacity of the heart is dependent on an understanding of the mechanisms that are activated in response to pathological conditions such as hypoxia. Under these conditions, the expression of genes suggested to support cardiomyocyte survival and heart adaptation is triggered. Particularly important are changes in the expression of myosin heavy chain (MHC) isoforms. We propose here that alterations in the expression profiles of MHC genes are induced in response to hypoxia and are primarily mediated by hypoxia inducible factor (HIF). In in vitro models of mouse embryonic stem cell-derived cardiomyocytes, we showed that hypoxia (1% O2) or the pharmacological stabilization of HIFs significantly increased MHCbeta (Myh7) gene expression. The key role of HIF-1alpha is supported by the absence of these effects in HIF-1alpha-deficient cells, even in the presence of HIF-2alpha. Interestingly, ChIP analysis did not confirm the direct interaction of HIF-1alpha with putative HIF response elements predicted in the MHCalpha and beta encoding DNA region. Further analyses showed the significant effect of the mTOR signaling inhibitor rapamycin in inducing Myh7 expression and a hypoxia-triggered reduction in the levels of antisense RNA transcripts associated with the Myh7 gene locus. Overall, the recognized and important role of HIF in the regulation of heart regenerative processes could be highly significant for the development of novel therapeutic interventions in heart failure. PMID:29137374

  6. Combination of neurofilament heavy chain and complement c3 as CSF biomarkers for ALS

    Science.gov (United States)

    Ganesalingam, Jeban; An, Jiyan; Shaw, Christopher E; Shaw, Gerry; Lacomis, David; Bowser, Robert

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease with an average survival of 3 years from symptom onset. Rapid and conclusive early diagnosis is essential if interventions with disease-modifying therapies are to be successful. Cytoskeletal modification and inflammation are known to occur during the pathogenesis of ALS. We measured levels of cytoskeletal proteins and inflammatory markers in the cerebrospinal fluid (CSF) of ALS, disease controls and healthy subjects. We determined threshold values for each protein that provided the optimal sensitivity and specificity for ALS within a training set, as determined by receiver operating characteristic (ROC) analysis. Interestingly, the optimal assay was a ratio of the levels for phosphorylated neurofilament heavy chain and complement C3 (pNFH/C3). We next applied this assay to a separate test set of CSF samples to verify our results. Overall, the predictive pNFH/C3 ratio identified ALS with 87.3% sensitivity and 94.6% specificity in a total of 71 ALS subjects, 52 disease control subjects and 40 healthy subjects. In addition, the level of CSF pNFH correlated with survival of ALS patients. We also detected increased pNFH in the plasma of ALS patients and observed a correlation between CSF and plasma pNFH levels within the same subjects. These findings support large-scale prospective biomarker studies to determine the clinical utility of diagnostic and prognostic signatures in ALS. PMID:21418221

  7. Phosphorylated Neurofilament Heavy Chain Correlations to Visual Function, Optical Coherence Tomography, and Treatment

    Science.gov (United States)

    Pasol, Joshua; Feuer, William; Yang, Cui; Shaw, Gerry; Kardon, Randy; Guy, John

    2010-01-01

    Objective. To correlate visual and neurologic clinical scores and treatment of optic neuritis and multiple sclerosis (MS) patients with assays of serum phosphorylated neurofilament heavy chain (pNF-H) and optical coherence tomography (OCT) measurements of axonal loss. Design/Methods. The Optic Neuritis Treatment Trial (ONTT) randomized 457 patients with acute optic neuritis to intravenous methylprednisolone (IVMP) followed by oral prednisone, oral prednisone or placebo treatment arms. We quantified serum pNF-H levels in 175 ONTT patients 5 years after study entry. We performed OCT measurements of macular volume and the retinal nerve fiber layer (RNFL) in a subset of 51 patients at year 15. Results. Elevated pNF-H levels at year 5 correlated to poorer visual function at study entry. Lower 15 year macular volumes and RNFL thickness correlated better with follow-up than with baseline visual function measures. With IVMP treatment, 15 year RNFL differences of the fellow eye (FE) minus the affected eye (SE) RNFLFEmSE correlated with five-year pNF-H levels. PNF-H was reduced by half with IVMP relative to placebo or by 40% relative to prednisone. Conclusions/Relevance. Acute optic neuritis patients who have more severe visual loss during initial presentation have a higher incidence of axonal loss that was slightly suppressed with IVMP treatment. PMID:22096624

  8. Differential binding of heavy chain variable domain 3 antigen binding fragments to protein A chromatography resins.

    Science.gov (United States)

    Bach, Julia; Lewis, Nathaniel; Maggiora, Kathy; Gillespie, Alison J; Connell-Crowley, Lisa

    2015-08-28

    This work examines the binding of 15 different VH3 IgGs and their corresponding F(ab')2 fragments to two different protein A chromatography resins: MabSelect(®), which utilizes a recombinant protein A ligand, and MabSelect SuRe(®) (SuRe), which utilizes a tetrameric Z domain ligand. The results show that VH3 F(ab')2 fragments can exhibit a variety of binding behaviours for the two resins. Contrary to previously published data, a subset of these molecules show strong interaction with the Z domain of SuRe(®). Furthermore, the results show that sequence variability of residue 57 in the VH3 heavy chain CDR2 domain correlates with binding behaviour on MabSelect(®) and SuRe(®). Site-directed mutagenesis of this residue confers gain or loss of VH3 F(ab')2 binding to these resins in 3 mAbs, demonstrating that it plays a key role in both recombinant protein A and Z domain interaction. A fourth mAb with a longer CDR2 loop was not affected by mutation of residue 57, indicating that CDR2 domain length may alter the binding interface and lead to the involvement of other residues in protein A binding. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. The repertoire of heavy chain immunoglobulin genes in B‑cell chronic lymphocytic leukemia in Russia and Belarus

    Directory of Open Access Journals (Sweden)

    B. V. Biderman

    2014-07-01

    Full Text Available Mutation status of the heavy chain variable region genes has long been known as an important factor in long‑term prognosis in B‑cell chronic lymphocytic leukemia (B‑CLL. A more detailed study of the gene sequences of immunoglobulin heavy chain (IgVH led to the discovery of stereotyped antigen receptors (SAR — receptors that have the same set of VH‑, D‑ and JH‑genes used. Cells with SARs have been found almost in a quarter of all B‑CLL cases. This phenomenon is not observed in other lymphatic tumors. In our study, we confirmed and extended the basic observations concerning the repertoire of IgVH in B‑CLL. Differences in the B‑CLL IgVH gene repertoirs between Russia, Вelarus and other countries are also analysed and discussed.

  10. Effects of voluntary wheel running on cardiac function and myosin heavy chain in chemically gonadectomized rats.

    Science.gov (United States)

    Hydock, David S; Lien, Chia-Ying; Schneider, Carole M; Hayward, Reid

    2007-12-01

    Reducing testosterone and estrogen levels with a luteinizing hormone-releasing hormone agonist such as Zoladex (i.e., chemical gonadectomy) is a common treatment for many prostate and breast cancer patients, respectively. There are reports of surgical gonadectomy inducing cardiac dysfunction, and exercise has been shown to be cardioprotective under these circumstances. Minimal research has been done investigating the effects of chemical gonadectomy and increased physical activity on cardiac function. The purpose of this investigation was to examine the effects of chemical gonadectomy and physical activity on cardiac function. Male (M) and female (F) Sprague-Dawley rats received either Zoladex treatment (Zol) that suppressed gonadal function for 8 wk or control implants (Con) and either were allowed unlimited access to voluntary running wheels (WR) or remained sedentary (Sed) throughout the treatment period. In vivo and ex vivo left ventricle (LV) function were then assessed, and myosin heavy chain (MHC) expression was analyzed to help explain LV functional differences. Hearts from M Sed+Zol exhibited significantly lower aortic blood flow velocity, developed pressure, and maximal rate of pressure development and higher beta-MHC expression than M Sed+Con. Hearts from F Sed+Zol exhibited significantly lower LV wall thicknesses, fractional shortening, and developed pressure and higher beta-MHC expression than F Sed+Con. This cardiac dysfunction was not evident in hearts from M or F WR+Zol, and this was associated with a preservation of the MHC isoform distribution. Thus an 8-wk chemical gonadectomy with Zoladex promoted cardiac dysfunction in male and female rats, and voluntary wheel running protected against this cardiac dysfunction.

  11. The Ig heavy chain switch region is a hotspot for insertion of transfected DNA

    Energy Technology Data Exchange (ETDEWEB)

    Baar, J.; Shulman, M.J. [Univ. of Toronto, Ontario (Canada)

    1995-08-15

    The Ig heavy chain switch usually occurs by breaking and rejoining DNA in the switch (S) regions, which consist of tandemly repeated sequences 5{prime} of the constant region exons. Various studies have suggested that S DNA can also recombine with non-S sequences. To measure the frequency of such recombination events, the hybridoma cell line igm692, a deletion mutant that lacks the C{mu}1 and C{mu}2 exons and the 3{prime} end of the S{mu} region, was transfected with a fragment bearing the C{mu}1-2 exons, but no S{mu} DNA. Insertion of this fragment into the residual VDJ-C{mu} intron of igm692 can restore a functional {mu} gene, yielding a transformant that is detected as a plaque-forming cell (PFC). PFCs comprise {approximately}8 x 10{sup -7} of the surviving transfected cells. In 10 of 12 PFCs, the C{mu}1-2 fragment inserted into the 2.5-kb residual S{mu} region, whereas insertion in two cases occurred in the 3.5-kb segment 5{prime} of S{mu}. Using a PCR assay to measure the frequency of insertion of the tranferred fragment elsewhere in the hybridoma genome, we found that {approximately}9% of the surviving tranfected cells had stably acquired the C{mu}1-2 fragment. These results indicate that the S{mu} region is {approximately}100-fold more recombinogenic than the average genomic site, and {approximately}7-fold more recombinogenic than the non-S{mu} segment of the residual VDJ-C{mu}, i.e., the S{mu} region is a hotspot for insertion of transfected DNA.

  12. Effect of Fetal Hypothyroidism on Cardiac Myosin Heavy Chain Expression in Male Rats

    Directory of Open Access Journals (Sweden)

    Nasibeh Yousefzadeh

    2016-01-01

    Full Text Available Abstract Background: Thyroid hormone deficiency during fetal life could affect the cardiac function in later life. The mechanism underlying this action in fetal hypothyroidism (FH in rats has not been elucidated thus far. Objective: The aim of this study is to evaluation the effect of FH on cardiac function in male rats and to determine the contribution of α-myosin heavy chain (MHC and β-MHC isoforms. Methods: Six pregnant female rats were randomly divided into two groups: The hypothyroid group received water containing 6-propyl-2-thiouracil during gestation and the controls consumed tap water. The offspring of the rats were tested in adulthood. Hearts from the FH and control rats were isolated and perfused with langendroff setup for measuring hemodynamic parameters; also, the heart mRNA expressions of α- MHC and β-MHC were measured by qPCR. Results: Baseline LVDP (74.0 ± 3.1 vs. 92.5 ± 3.2 mmHg, p < 0.05 and heart rate (217 ± 11 vs. 273 ± 6 beat/min, p < 0.05 were lower in the FH rats than controls. Also, these results showed the same significance in ±dp/dt. In the FH rats, β-MHC expression was higher (201% and α- MHC expression was lower (47% than control. Conclusion: Thyroid hormone deficiency during fetal life could attenuate normal cardiac functions in adult rats, an effect at least in part due to the increased expression of β-MHC to α- MHC ratio in the heart.

  13. Epitope mapping of antibodies against ferritin heavy chain in giant cell arteritis and polymyalgia rheumatica.

    Science.gov (United States)

    Große, K; Schmidt, R E; Witte, T; Baerlecken, N T

    2013-01-01

    In a previous study we found an association between antibodies against the human ferritin heavy chain (HFC) protein and giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR), especially in GCA/PMR patients prior to glucocorticoid treatment. Antibodies against the N-terminal part of ferritin were present in 92% of untreated patients, 69% of patients with disease flare, and 13% of patients in remission. These antibodies appeared to be markers for the early detection of a disease complex usually diagnosed with considerable delay. Our aim in this study was to optimize the diagnostic test by epitope mapping of antibodies against HFC using peptide antigens in enzyme-linked immunosorbent assays (ELISAs). We evaluated serum samples from a selected group of GCA/PMR patients in whom the sensitivity of antibodies against the N-terminal ferritin peptide was only 35%. Patients with late-onset rheumatoid arthritis (LORA), patients with fever, patients with granulomatosis with polyangiitis (GPA), patients without any autoimmune disease at age > 65 years, and blood donors served as controls. By combining different ELISAs we were able to increase the frequency of human ferritin peptide antibodies in GCA/PMR (p < 0.0001) without significantly altering the false-positive rate (FPR) of the diagnostic test. The frequency of antibodies against human ferritin peptide increased from 53% to 74% in GCA/PMR patients with disease flare, from 29% to 40% in GCA/PMR patients in partial remission, and from 8% to 45% in GCA/PMR patients in complete remission. The potential diagnostic test for GCA/PMR can be improved by combining three human ferritin peptide antibodies.

  14. Role of kinesin heavy chain in Crumbs localization along the rhabdomere elongation in Drosophila photoreceptor.

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    Garrett P League

    Full Text Available BACKGROUND: Crumbs (Crb, a cell polarity gene, has been shown to provide a positional cue for the extension of the apical membrane domain, adherens junction (AJ, and rhabdomere along the growing proximal-distal axis during Drosophila photoreceptor morphogenesis. In developing Drosophila photoreceptors, a stabilized microtubule structure was discovered and its presence was linked to polarity protein localization. It was therefore hypothesized that the microtubules may provide trafficking routes for the polarity proteins during photoreceptor morphogenesis. This study has examined whether Kinesin heavy chain (Khc, a subunit of the microtubule-based motor Kinesin-1, is essential in polarity protein localization in developing photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS: Because a genetic interaction was found between crb and khc, Crb localization was examined in the developing photoreceptors of khc mutants. khc was dispensable during early eye differentiation and development. However, khc mutant photoreceptors showed a range of abnormalities in the apical membrane domain depending on the position along the proximal-distal axis in pupal photoreceptors. The khc mutant showed a progressive mislocalization in the apical domain along the distal-proximal axis during rhabdomere elongation. The khc mutation also led to a similar progressive defect in the stabilized microtubule structures, strongly suggesting that Khc is essential for microtubule structure and Crb localization during distal to proximal rhabdomere elongation in pupal morphogenesis. This role of Khc in apical domain control was further supported by khc's gain-of-function phenotype. Khc overexpression in photoreceptors caused disruption of the apical membrane domain and the stabilized microtubules in the developing photoreceptors. CONCLUSIONS/SIGNIFICANCE: In summary, we examined the role of khc in the regulation of the apical Crb domain in developing photoreceptors. Since the rhabdomeres in

  15. Analysis of Heavy-Chain Antibody Responses and Resistance to Parelaphostrongylus tenuis in Experimentally Infected Alpacas

    Science.gov (United States)

    Purdy, S. R.; Gagliardo, L. F.; Lefman, S.; Hamel, P. J. S.; Ku, S.; Mainini, T.; Hoyt, G.; Justus, K.; Daley-Bauer, L. P.; Duffy, M. S.

    2012-01-01

    The parasitic nematode Parelaphostrongylus tenuis is an important cause of neurologic disease of camelids in central and eastern North America. The aim of this study was to determine whether alpacas develop resistance to disease caused by P. tenuis in response to a previous infection or a combination of controlled infection and immunization. Alpacas were immunized with a homogenate of third-stage larvae (L3) and simultaneously implanted subcutaneously with diffusion chambers containing 20 live L3. Sham-treated animals received adjuvant alone and empty chambers. The protocol was not effective in inducing resistance to oral challenge with 10 L3, and disease developed between 60 and 71 days following infection. Immediately following the onset of neurologic disease, affected animals were treated with a regimen of anthelmintic and anti-inflammatory drugs, and all recovered. One year later, a subset of alpacas from this experiment was challenged with 20 L3 and the results showed that prior infection induced resistance to disease. Primary and secondary infections induced production of conventional and heavy-chain IgGs that reacted with soluble antigens in L3 homogenates but did not consistently recognize a recombinant form of a parasite-derived aspartyl protease inhibitor. Thus, the latter antigen may not be a good candidate for serology-based diagnostic tests. Antibody responses to parasite antigens occurred in the absence of overt disease, demonstrating that P. tenuis infection can be subclinical in a host that has been considered to be highly susceptible to disease. The potential for immunoprophylaxis to be effective in preventing disease caused by P. tenuis was supported by evidence of resistance to reinfection. PMID:22593238

  16. Muscle fiber type specific induction of slow myosin heavy chain 2 gene expression by electrical stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Crew, Jennifer R.; Falzari, Kanakeshwari [Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064 (United States); DiMario, Joseph X., E-mail: joseph.dimario@rosalindfranklin.edu [Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064 (United States)

    2010-04-01

    Vertebrate skeletal muscle fiber types are defined by a broad array of differentially expressed contractile and metabolic protein genes. The mechanisms that establish and maintain these different fiber types vary throughout development and with changing functional demand. Chicken skeletal muscle fibers can be generally categorized as fast and fast/slow based on expression of the slow myosin heavy chain 2 (MyHC2) gene in fast/slow muscle fibers. To investigate the cellular and molecular mechanisms that control fiber type formation in secondary or fetal muscle fibers, myoblasts from the fast pectoralis major (PM) and fast/slow medial adductor (MA) muscles were isolated, allowed to differentiate in vitro, and electrically stimulated. MA muscle fibers were induced to express the slow MyHC2 gene by electrical stimulation, whereas PM muscle fibers did not express the slow MyHC2 gene under identical stimulation conditions. However, PM muscle fibers did express the slow MyHC2 gene when electrical stimulation was combined with inhibition of inositol triphosphate receptor (IP3R) activity. Electrical stimulation was sufficient to increase nuclear localization of expressed nuclear-factor-of-activated-T-cells (NFAT), NFAT-mediated transcription, and slow MyHC2 promoter activity in MA muscle fibers. In contrast, both electrical stimulation and inhibitors of IP3R activity were required for these effects in PM muscle fibers. Electrical stimulation also increased levels of peroxisome-proliferator-activated receptor-{gamma} co-activator-1 (PGC-1{alpha}) protein in PM and MA muscle fibers. These results indicate that MA muscle fibers can be induced by electrical stimulation to express the slow MyHC2 gene and that fast PM muscle fibers are refractory to stimulation-induced slow MyHC2 gene expression due to fast PM muscle fiber specific cellular mechanisms involving IP3R activity.

  17. Postnatal development of cerebellar zones revealed by neurofilament heavy chain protein expression

    Directory of Open Access Journals (Sweden)

    Joshua J White

    2013-05-01

    Full Text Available The cerebellum is organized into parasagittal zones that control sensory-motor behavior. Although the architecture of adult zones is well understood, very little is known about how zones emerge during development. Understanding the process of zone formation is an essential step towards unraveling how circuits are constructed to support specific behaviors. Therefore, we focused this study on postnatal development to determine the spatial and temporal changes that establish zonal patterns during circuit formation. We used a combination of wholemount and tissue section immunohistochemistry in mice to show that the cytoskeletal protein neurofilament heavy chain (NFH is a robust marker for postnatal cerebellar zonal patterning. The patterned expression of NFH is initiated shortly after birth, and compared to the domains of several known zonal markers such as zebrin II, HSP25, neurogranin, and phospholipase Cβ4 (PLCβ4, NFH does not exhibit transient expression patterns that are typically remodeled between stages, and the adult zones do not emerge after a period of uniform expression in all lobules. Instead, we found that throughout postnatal development NFH gradually reveals distinct zones in each cerebellar lobule. The boundaries of individual NFH zones sharpen over time, as zones are refined during the second and third weeks after birth. Double labeling with neurogranin and PLCβ4 further revealed that although the postnatal expression of NFH is spatially and temporally unique, its pattern of zones respects a fundamental and well-known molecular topography in the cerebellum. The dynamics of NFH expression support the hypothesis that adult circuits are derived from an embryonic map that is refined into zones during the first three-weeks of life.

  18. Serum phosphorylated neurofilament-heavy chain levels in multiple sclerosis patients.

    Science.gov (United States)

    Gresle, M M; Liu, Y; Dagley, L F; Haartsen, J; Pearson, F; Purcell, A W; Laverick, L; Petzold, A; Lucas, R M; Van der Walt, A; Prime, H; Morris, D R; Taylor, B V; Shaw, G; Butzkueven, H

    2014-11-01

    We evaluated whether the measurement of serum phosphorylated neurofilament heavy chain (pNF-H) titre is likely to be a valid biomarker of axonal injury in multiple sclerosis (MS). Serum pNF-H concentrations were measured by ELISA in cases with relapsing-remitting (RR)-MS (n=81), secondary progressive (SP) MS (n=13) and primary progressive (PP)-MS; n=6) MS; first demyelinating event (FDE; n=82); and unaffected controls (n=135). A subset of MS cases (n=45) were re-sampled on one or multiple occasions. The Multiple Sclerosis Severity Score (MSSS) and MRI measures were used to evaluate associations between serum pNF-H status, disease severity and cerebral lesion load and activity. We confirmed the presence of pNF-H peptides in serum by ELISA. We showed that a high serum pNF-H titre was detectable in 9% of RR-MS and FDE cases, and 38.5% of SP-MS cases. Patients with a high serum pNF-H titre had higher average MSSS scores and T2 lesion volumes than patients with a low serum pNF-H titre. Repeated sampling of a subset of MS cases showed that pNF-H levels can fluctuate over time, likely reflecting temporal dynamics of axonal injury in MS. A subset of FDE/MS cases was found to have a high serum pNF-H titre, and this was associated with changes in clinical outcome measures. We propose that routine measurement of serum pNF-H should be further investigated for monitoring axonal injury in MS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Mutations in the Slow Skeletal Muscle Fiber Myosin Heavy Chain Gene ( MYH7) Cause Laing Early-Onset Distal Myopathy (MPD1)

    National Research Council Canada - National Science Library

    Meredith, Christopher; Herrmann, Ralf; Parry, Cheryl; Liyanage, Khema; Dye, Danielle E; Durling, Hayley J; Duff, Rachael M; Beckman, Kaye; de Visser, Marianne; van der Graaff, Maaike M; Hedera, Peter; Fink, John K; Petty, Elizabeth M; Lamont, Phillipa; Fabian, Vicki; Bridges, Leslie; Voit, Thomas; Mastaglia, Frank L; Laing, Nigel G

    2004-01-01

    .... One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles...

  20. Frequency patterns of T-cell exposed motifs in immunoglobulin heavy chain peptides presented by MHCs

    Directory of Open Access Journals (Sweden)

    Robert D. Bremel

    2014-10-01

    Full Text Available Immunoglobulins are highly diverse protein sequences that are processed and presented to T-cells by B-cells and other antigen presenting cells. We examined a large dataset of immunoglobulin heavy chain variable regions (IGHV to assess the diversity of T-cell exposed motifs (TCEM. TCEM comprise those amino acids in a MHC-bound peptide which face outwards, surrounded by the MHC histotope, and which engage the T-cell receptor. Within IGHV there is a distinct pattern of predicted MHC class II binding and a very high frequency of re-use of the TCEMs. The re-use frequency indicates that only a limited number of different cognate T-cells are required to engage many different clonal B-cells. The amino acids in each outward-facing TCEM are intercalated with the amino acids of inward-facing MHC groove-exposed motifs (GEM. Different GEM may have differing, allele-specific, MHC binding affinities. The intercalation of TCEM and GEM in a peptide allows for a vast combinatorial repertoire of epitopes, each eliciting a different response. Outcome of T-cell receptor binding is determined by overall signal strength, which is a function of the number of responding T-cells and the duration of engagement. Hence, the frequency of T-cell exposed motif re-use appears to be an important determinant of whether a T-cell response is stimulatory or suppressive. The frequency distribution of TCEMs implies that somatic hypermutation is followed by clonal expansion that develop along repeated pathways. The observations of TCEM and GEM derived from immunoglobulins suggest a relatively simple, yet powerful, mechanism to correlate T-cell polyspecificity, through re-use of TCEMs, with a very high degree of specificity achieved by combination with a diversity of GEMs. The frequency profile of TCEMs also points to an economical mechanism for maintaining T-cell memory, recall, and self-discrimination based on an endogenously generated profile of motifs.

  1. Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle

    Science.gov (United States)

    Baldwin, K. M.; Haddad, F.

    2001-01-01

    The goal of this mini-review is to summarize findings concerning the role that different models of muscular activity and inactivity play in altering gene expression of the myosin heavy chain (MHC) family of motor proteins in mammalian cardiac and skeletal muscle. This was done in the context of examining parallel findings concerning the role that thyroid hormone (T(3), 3,5,3'-triiodothyronine) plays in MHC expression. Findings show that both cardiac and skeletal muscles of experimental animals are initially undifferentiated at birth and then undergo a marked level of growth and differentiation in attaining the adult MHC phenotype in a T(3)/activity level-dependent fashion. Cardiac MHC expression in small mammals is highly sensitive to thyroid deficiency, diabetes, energy deprivation, and hypertension; each of these interventions induces upregulation of the beta-MHC isoform, which functions to economize circulatory function in the face of altered energy demand. In skeletal muscle, hyperthyroidism, as well as interventions that unload or reduce the weight-bearing activity of the muscle, causes slow to fast MHC conversions. Fast to slow conversions, however, are seen under hypothyroidism or when the muscles either become chronically overloaded or subjected to intermittent loading as occurs during resistance training and endurance exercise. The regulation of MHC gene expression by T(3) or mechanical stimuli appears to be strongly regulated by transcriptional events, based on recent findings on transgenic models and animals transfected with promoter-reporter constructs. However, the mechanisms by which T(3) and mechanical stimuli exert their control on transcriptional processes appear to be different. Additional findings show that individual skeletal muscle fibers have the genetic machinery to express simultaneously all of the adult MHCs, e.g., slow type I and fast IIa, IIx, and IIb, in unique combinations under certain experimental conditions. This degree of

  2. Phosphorylated neurofilament heavy chain is a marker of neurodegeneration in Leber hereditary optic neuropathy (LHON).

    Science.gov (United States)

    Guy, John; Shaw, Gerry; Ross-Cisneros, Fred N; Quiros, Peter; Salomao, Solange R; Berezovsky, Adriana; Carelli, Valerio; Feuer, William J; Sadun, Alfredo A

    2008-01-01

    To determine the profile of neurodegeneration in Leber hereditary optic neuropathy (LHON). We quantitated serum levels of phosphorylated neurofilament heavy chain (pNF-H) in a Brazilian pedigree of 16 affected patients and 59 carriers with LHON, both molecularly characterized as harboring the G to A mutation at nucleotide 11,778 of the mitochondrial genome. The association of subject characteristics to pNF-H levels was studied with multiple regression; pNF-H data were square-root transformed to effect normality of distribution of residuals. Relationships between the square-root of pNF-H and age and sex were investigated within groups with Pearson correlation and the two-sample t-test. Linear regression was used to assess the difference between groups and to determine if the relationship of age was different between affected individuals and carriers. Results of plotting pNF-H levels by age suggested a nonlinear, quadratic association so age squared was used in the statistical analysis. ANCOVA was used to assess the influence of age and group on pNF-H levels. In the carrier group, there was a significant correlation of square-root pNF-H (mean=0.24 ng/ml(2)) with age (r=0.30, p=0.022) and a stronger correlation with quadratic age (r=0.37, p=0.003). With a higher mean pNF-H (0.33 ng/ml(2)) for the affected group, correlations were of similar magnitude, although they were not statistically significant: age (r=0.22, p=0.42), quadratic age (r=0.22, p=0.45). There was no correlation between age and pNF-H levels (mean=0.34 ng/ml(2)) in the off-pedigree group: age (r=0.03, p=0.87), quadratic age (r=0.04, p=0.84). There was no difference between sexes and pNF-H levels in any of the groups (affected, p=0.65; carriers, p=0.19; off-pedigree, p=0.93). Elevated pNF-H released into the serum of some affected LHON patients may suggest that axonal degeneration occurs at some point after loss of visual function. Increases in pNF-H levels of carriers with increasing age, not seen in

  3. Influence of the Lurcher mutation on myosin heavy chain expression in skeletal and cardiac muscles.

    Science.gov (United States)

    Hartmann, N; Martrette, J M; Westphal, A

    2001-01-01

    This study evaluated the influence of Lurcher mutation, characterized by degeneration of cerebellar Purkinje cells, granule cells, and inferior olive neurons, on cardiac and skeletal muscles: one respiratory (diaphragm, Dia), three masticatory (anterior temporalis, AT; masseter superficialis, MS and anterior digastric, AD), one hind limb (soleus, S), entire tongue (T), and one cardiac (ventricle, V) muscles. Body and muscle weight, muscle protein content, and myosin heavy chain (MHC) isoforms relative expression were then compared in Lurcher mutant mice vs. normal, according to sex. Male body weight was always greater than female one, but there was no specific muscle difference in females, except for T relative weight which was greater in normal females. Muscle protein concentration was greater in normal males except for AD and T in which it was lower. Lurcher mutant mice showed a reduced whole body growth but no specific muscle atrophy (except in male AT), and a global decrease in muscle protein content which made muscles more fragile (except in female Dia and male T, in which it was greater). Lurcher mutation induced a global reduction of muscle protein concentration whereas a general influence of sex could not be disclosed. Concerning MHC relative composition, all the muscles were fast-twitch: Dia, AT, MS, AD, S, and T predominantly expressed the fast type 2 MHC isoforms, except female S, whereas V contained only MHC alpha, also a fast MHC. Female muscles were slower than male ones and classification of muscles in terms of shortening velocity was comparable in normal male and female. In other respects, male Lurcher mutant muscles were slower and consequently more fatigue resistant than normal, except T which became faster and less fatigue resistant. On the contrary, in female mutants, only the Dia was slower than normal one, MS and AD were comparable to normal ones and finally, AT, S, and T were faster than normal ones. It should be noted that a developmental

  4. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.

    Directory of Open Access Journals (Sweden)

    Colin J Powers

    2008-10-01

    Full Text Available The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference.

  5. Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

    Science.gov (United States)

    Xing, Ying; Ji, Qiuhe; Lin, Ying; Fu, Meng; Gao, Jixin; Zhang, Ping; Hu, Xingbin; Feng, Lei; Liu, Yufeng; Han, Hua; Li, Wei

    2015-01-01

    Natural autoreactive B cells are important mediators of autoimmune diseases. Receptor editing is known to play an important role in both central and peripheral B cell tolerance. However, the role of allelic inclusion in the development of natural autoreactive B cells is not clear. Previously, we generated μ chain (TgV(H)3B4I) and μ/κ chains (TgV(H/L)3B4) transgenic mice using transgene derived from the 3B4 hybridoma, which produce poly-reactive natural autoantibodies. In this study, we demonstrate that a considerable population of B cells edited their B cells receptors (BCRs) via light chain or heavy chain allelic inclusion during their development in TgV(H)3B4I mice. Additionally, allelic inclusion occurred more frequently in the periphery and promoted the differentiation of B cells into marginal zone or B-1a cells in TgV(H)3B4I mice. B cells from TgV(H/L)3B4 mice expressing the intact transgenic 3B4 BCR without receptor editing secreted poly-reactive 3B4 antibody. Interestingly, however, B cell that underwent allelic inclusion in TgV(H)3B4I mice also produced poly-reactive autoantibodies in vivo and in vitro. Our findings suggest that receptor editing plays a minor role in the positive selection of B cells expressing natural poly-reactive BCRs, which can be positively selected through heavy chain allelic inclusion to retain their poly-reactivity in the periphery.

  6. Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

    Directory of Open Access Journals (Sweden)

    Ying Xing

    Full Text Available Natural autoreactive B cells are important mediators of autoimmune diseases. Receptor editing is known to play an important role in both central and peripheral B cell tolerance. However, the role of allelic inclusion in the development of natural autoreactive B cells is not clear. Previously, we generated μ chain (TgV(H3B4I and μ/κ chains (TgV(H/L3B4 transgenic mice using transgene derived from the 3B4 hybridoma, which produce poly-reactive natural autoantibodies. In this study, we demonstrate that a considerable population of B cells edited their B cells receptors (BCRs via light chain or heavy chain allelic inclusion during their development in TgV(H3B4I mice. Additionally, allelic inclusion occurred more frequently in the periphery and promoted the differentiation of B cells into marginal zone or B-1a cells in TgV(H3B4I mice. B cells from TgV(H/L3B4 mice expressing the intact transgenic 3B4 BCR without receptor editing secreted poly-reactive 3B4 antibody. Interestingly, however, B cell that underwent allelic inclusion in TgV(H3B4I mice also produced poly-reactive autoantibodies in vivo and in vitro. Our findings suggest that receptor editing plays a minor role in the positive selection of B cells expressing natural poly-reactive BCRs, which can be positively selected through heavy chain allelic inclusion to retain their poly-reactivity in the periphery.

  7. Complement component C1r mediated cleavage of the heavy chain of the major histocompatibility class I antigens

    DEFF Research Database (Denmark)

    Eriksson, H; Nissen, Mogens Holst

    1992-01-01

    Apart from cleaving C1s, we demonstrate for the first time that: 1) at concentrations found in serum, the activated forms of the complement components C1r in addition to C1s can cleave the heavy chain of MHC class I antigens, 2) the cleavage by C1r and C1s is seemingly dependent upon a native con......-chain of MHC class I was shown to take place between the alpha 2- and alpha 3- domains as estimated by the Con A-Sepharose precipitation pattern on SDS-PAGE. The alpha 1/alpha 2 fragment was still shown to interact with beta 2-microglobulin as shown by immunoprecipitation.......Apart from cleaving C1s, we demonstrate for the first time that: 1) at concentrations found in serum, the activated forms of the complement components C1r in addition to C1s can cleave the heavy chain of MHC class I antigens, 2) the cleavage by C1r and C1s is seemingly dependent upon a native...... configuration of the MHC class I antigen, since heat denaturation of the HLA antigens reduce the cleavage. The proteolytic fragments following C1 cleavage were characterized by precipitation with Con A-Sepharose, anti-MHC class I and anti-beta 2-microglobulin antibodies. The proteolysis of the alpha...

  8. Transgenic rabbits with lymphocytic leukemia induced by the c-myc oncogene fused with the immunoglobulin heavy chain enhancer.

    Science.gov (United States)

    Knight, K L; Spieker-Polet, H; Kazdin, D S; Oi, V T

    1988-01-01

    Transgenic rabbits with the rabbit c-myc oncogene fused with the rabbit immunoglobulin heavy chain enhancer region (E mu) DNA were developed by microinjecting pronuclei of single cell zygotes with the gene construct and implanting the microinjected eggs into pseudopregnant females. At age 17-20 days, 3 of 21 offspring born to seven females were found to have peripheral blood leukocyte counts of greater than 100,000 per mm3. Histology analyses showed extensive lymphocytic infiltration in the liver and kidney, indicating that these rabbits had a malignant lymphocytic leukemia. Genomic DNA analyses of thymus and peripheral blood lymphocytes revealed that the leukemic rabbits were transgenic and that both immunoglobulin heavy and kappa light chain genes were rearranged in the leukemic cells; thus, the leukemic cells are of B-cell lineage. One to four heavy and light chain gene rearrangements were observed, suggesting that the B-cell tumors were oligoclonal. Stable tissue culture cell lines from the bone marrow and peripheral blood of one of the transgenic rabbits have been developed. The development of B-cell leukemias in rabbits with the E mu-myc transgene contrasts with the development of B-cell lymphomas in mice carrying a similar transgene. The lymphomas in mice develop in adults and are monoclonal in origin. The leukemias in rabbits develop in juveniles, less than 3 weeks after birth, and appear oligoclonal in origin. The leukemias seem to develop in rabbit at a specific stage of development, and we suggest that a normal developmental signal may be involved in the oncogenesis. Images PMID:2834733

  9. Post-mortem degradation of myosin heavy chain in intact fish muscle: Effects of pH and enzyme inhibitors

    OpenAIRE

    Wang, P. A.; Vang, B.; Pedersen, A M; Martínez, Iciar; Olsen, R L

    2011-01-01

    Fish muscle is rapidly degraded during post-mortem storage, due to proteolytic enzymes acting probably both on muscle cells and connective tissue. In this work we have developed a model system which may be used to study the enzymatic degradation occurring in intact post-mortem fish muscle. Degradation of myosin heavy chain (MHC) was monitored in muscle with pH adjusted to 6.05, 6.3 and 6.9 and in the presence of the enzyme inhibitors PMSF, EDTA, phenanthroline, pepstatin A, antipain, E-64 and...

  10. Isolation, purification, and characterization of fragment B, the NH2-terminal half of the heavy chain of tetanus toxin.

    OpenAIRE

    Matsuda, M; Lei, D L; N. Sugimoto; Ozutsumi, K; Okabe, T.

    1989-01-01

    Fragment B, the N-terminal half of the heavy chain, an important domain of the tetanus neurotoxin molecule, was isolated for the first time. Tetanus toxin (composed of three domains, A, B, and C) was prepared from culture filtrates. Fragment A-B, derived from the toxin treated mildly with papain, was used for the isolation of fragment B. Fragment A-B obtained was dissociated into fragments A and B by reduction with 100 mM dithiothreitol and treatment with 2 M urea. Fragment B was separated fr...

  11. Antibody diversity in trouts obtained by gynogenesis or self-fertilization. Comparative analysis of the heavy chain spectrotypes.

    Science.gov (United States)

    Desvaux, F X; Cossarini-Dunier, M; Chilmonzcyk, S; Charlemagne, J

    1987-01-01

    Conventionnal (C) trouts and trouts obtained by gynogenesis (G) or self-fertilization (SF) were immunized with DNP-KLH and anti-DNP antibodies were individually purified by affinity chromatography. The isolated IgM-like antibodies were separated by an iso-electrofocusing technique in reducing conditions and electroblotted onto nitrocellulose. The transfers were probed with a mouse monoclonal antibody specific for trout heavy (H) antibody chain and revealed with a rabbit anti-mouse IgG horse-radish peroxydase conjugate. When comparing the IEF H chain spectrotypes of C, G and SF trouts, it was observed that individual C spectrotypes are more different between themselves than G and SF spectrotypes, and that individual SF spectrotypes were less heterogeneous than C or G ones. These results suggest that in trout, inbreeding induces a reduction of antibody diversity and heterogeneity. The inheritance of antibody repertoire might be taken in account in the inbreeding selection schedules for fish of economical interest.

  12. Application of Monoclonal Antibodies in Functional and Comparative Investigations of Heavy-Chain Immunoglobulins in New World Camelids

    Science.gov (United States)

    Daley, L. P.; Gagliardo, L. F.; Duffy, M. S.; Smith, M. C.; Appleton, J. A.

    2005-01-01

    Of the three immunoglobulin G (IgG) isotypes described to occur in camelids, IgG2 and IgG3 are distinct in that they do not incorporate light chains. These heavy-chain antibodies (HCAbs) constitute approximately 50% of the IgG in llama serum and as much as 75% of the IgG in camel serum. We have produced isotype-specific mouse monoclonal antibodies (MAbs) in order to investigate the roles of HCAbs in camelid immunity. Seventeen stable hybridomas were cloned, and three MAbs that were specific for epitopes on the γ chains of llama IgG1, IgG2, or IgG3 were characterized in detail. Affinity chromatography revealed that each MAb bound its isotype in solution in llama serum. The antibodies bound to the corresponding alpaca IgGs, to guanaco IgG1 and IgG2, and to camel IgG1. Interestingly, anti-IgG2 MAbs bound three heavy-chain species in llama serum, confirming the presence of three IgG2 subisotypes. Two IgG2 subisotypes were detected in alpaca and guanaco sera. The MAbs detected llama serum IgGs when they were bound to antigen in enzyme-linked immunosorbent assays and were used to discern among isotypes induced during infection with a parasitic nematode. Diseased animals, infected with Parelaphostrongylus tenuis, did not produce antigen-specific HCAbs; rather, they produced the conventional isotype, IgG1, exclusively. Our data document the utility of these MAbs in functional and physiologic investigations of the immune systems of New World camelids. PMID:15753251

  13. Bacterial extracellular polymeric substances (EPS): A carrier of heavy metals in the marine food-chain

    Digital Repository Service at National Institute of Oceanography (India)

    Bhaskar, P.V.; Bhosle, N

    The ecological implications of metal binding properties of bacterial EPS and its possible role in the bioaccumulation of pollutants in the marine food-chain was investigated using a partially purified and chemically characterized microbial EPS...

  14. Analyses of Dynein Heavy Chain Mutations Reveal Complex Interactions Between Dynein Motor Domains and Cellular Dynein Functions

    Science.gov (United States)

    Sivagurunathan, Senthilkumar; Schnittker, Robert R.; Razafsky, David S.; Nandini, Swaran; Plamann, Michael D.; King, Stephen J.

    2012-01-01

    Cytoplasmic dynein transports cargoes for a variety of crucial cellular functions. However, since dynein is essential in most eukaryotic organisms, the in-depth study of the cellular function of dynein via genetic analysis of dynein mutations has not been practical. Here, we identify and characterize 34 different dynein heavy chain mutations using a genetic screen of the ascomycete fungus Neurospora crassa, in which dynein is nonessential. Interestingly, our studies show that these mutations segregate into five different classes based on the in vivo localization of the mutated dynein motors. Furthermore, we have determined that the different classes of dynein mutations alter vesicle trafficking, microtubule organization, and nuclear distribution in distinct ways and require dynactin to different extents. In addition, biochemical analyses of dynein from one mutant strain show a strong correlation between its in vitro biochemical properties and the aberrant intracellular function of that altered dynein. When the mutations were mapped to the published dynein crystal structure, we found that the three-dimensional structural locations of the heavy chain mutations were linked to particular classes of altered dynein functions observed in cells. Together, our data indicate that the five classes of dynein mutations represent the entrapment of dynein at five separate points in the dynein mechanochemical and transport cycles. We have developed N. crassa as a model system where we can dissect the complexities of dynein structure, function, and interaction with other proteins with genetic, biochemical, and cell biological studies. PMID:22649085

  15. Identification of an Arg403Gln beta myosin heavy chain gene mutation in a Portuguese family with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Gonçalves, L M; Vieira, M; Faro, C; Ventura, M; Pires, E; Providência, L A

    2000-04-01

    The etiology of Familial Hypertrophic Cardiomyopathy (HCM) is attributed to the mutation of genes that encode sarcomeric proteins in the heart. Until now no gene mutations had been identified in Portuguese families with HCM. The main objective of this study is to describe a Portuguese family with HCM carrying an Arg403Gln mutation in the beta myosin heavy chain gene. With the help of several Molecular Biology tools, 40 families with HCM were studied. In all these families, one member was identified as carrying an Arg403Gln mutation in the beta myosin heavy chain gene. All family members were submitted to a physical exam, EKG and echocardiography. Those carrying a gene mutation were also submitted to Holter monitoring and to magnetic ressonance imaging. Molecular biology techniques are extremely important for the diagnosis of HCM, particularly in healthy carriers. The use of molecular diagnostic tools in HCM is very useful because it allows us to identify the healthy carriers and establish earlier clinical and prevention programs for these individuals.

  16. Muscular tissues of the squid Doryteuthis pealeii express identical myosin heavy chain isoforms: an alternative mechanism for tuning contractile speed.

    Science.gov (United States)

    Shaffer, Justin F; Kier, William M

    2012-01-15

    The speed of muscle contraction is largely controlled at the sarcomere level by the ATPase activity of the motor protein myosin. Differences in amino acid sequence in catalytically important regions of myosin yield different myosin isoforms with varying ATPase activities and resulting differences in cross-bridge cycling rates and interfilamentary sliding velocities. Modulation of whole-muscle performance by changes in myosin isoform ATPase activity is regarded as a universal mechanism to tune contractile properties, especially in vertebrate muscles. Invertebrates such as squid, however, may exhibit an alternative mechanism to tune contractile properties that is based on differences in muscle ultrastructure, including variable myofilament and sarcomere lengths. To determine definitively whether contractile properties of squid muscles are regulated via different myosin isoforms (i.e. different ATPase activities), the nucleotide and amino acid sequences of the myosin heavy chain from the squid Doryteuthis pealeii were determined from the mantle, arm, tentacle, fin and funnel retractor musculature. We identified three myosin heavy chain isoforms in squid muscular tissues, with differences arising at surface loop 1 and the carboxy terminus. All three isoforms were detected in all five tissues studied. These results suggest that the muscular tissues of D. pealeii express identical myosin isoforms, and it is likely that differences in muscle ultrastructure, not myosin ATPase activity, represent the most important mechanism for tuning contractile speeds.

  17. Retargeted oncolytic adenovirus displaying a single variable domain of camelid heavy-chain-only antibody in a fiber protein

    Directory of Open Access Journals (Sweden)

    Elisabeth A van Erp

    2015-01-01

    Full Text Available Conditionally replicative adenoviruses are promising agents for oncolytic virotherapy. Various approaches have been attempted to retarget adenoviruses to tumor-specific antigens to circumvent deficiency of receptor for adenoviral binding and to provide an additional level of tumor specificity. Functional incorporation of highly specific targeting molecules into the viral capsid can potentially retarget adenoviral infection. However, conventional antibodies are not compatible with the cytoplasmic adenovirus capsid synthesis. The goal of this study was to evaluate the utility of single variable domains derived from heavy chain camelid antibodies for retargeting of adenovirus infection. We have combined transcriptional targeting using a tumor-specific promoter with transductional targeting through viral capsid incorporation of antihuman carcinoembryonic antigen single variable domains. Obtained data demonstrated that employment of a single variable domain genetically incorporated into an adenovirus fiber increased specificity of infection and efficacy of replication of single variable domain-targeted oncolytic adenovirus. The double targeting, both transcriptional through the C-X-C chemokine receptor type 4 promoter and transductional using the single variable domain, is a promising means to improve the therapeutic index for these advanced generation conditionally replicative adenoviruses. A successful strategy to transductional retargeting of oncolytic adenovirus infection has not been shown before and therefore we believe this is the first employment of transductional targeting using single variable domains derived from heavy chain camelid antibodies to enhance specificity of conditionally replicative adenoviruses.

  18. SNPs within the beta myosin heavy chain (MYH7 and the pyruvate kinase muscle (PKM2 genes in horse

    Directory of Open Access Journals (Sweden)

    Vincenzo Russo

    2010-01-01

    Full Text Available Two highly expressed skeletal muscle genes (the MYH7 gene encoding the myosin heavy chain slow/β-cardiac isoform and the PKM2 gene encoding the pyruvate kinase muscle isoforms were investigated with the objective to identify DNA markers in horses. A panel of DNA samples from different horse breeds was analysed using a PCR-single strand conformation polymorphism (SSCP approach. Four and two alleles were identified for the MYH7 and PKM2 loci, respectively. Mendelian inheritance of alleles of the two investigated genes was confirmed analysing horse families. Sequencing of PCR products obtained from the MYH7 and PKM2 genes made it possible to characterise two SSCP alleles for each gene. The polymorphisms found in the MYH7 and PKM2 genes were further studied in 61 and 68 horses of three (Italian Heavy Draught Horse, Italian Saddler and Murgese and five (Franches-Montagnes, Haflinger, Italian Heavy Draught Horse, Murgese and Standardbred breeds, respectively. Allele frequencies of the two loci varied among the considered breeds. The SNPs discovery in MYH7 and PKM2 genes makes it possible to locate new molecular markers to ECA1. The identified markers could be used in association analysis with performance traits in horses.

  19. Production of anti TNF-α antibodies in eukaryotic cells using different combinations of vectors carrying heavy and light chains.

    Science.gov (United States)

    Balabashin, Dmitriy; Kovalenko, Elena; Toporova, Viktoria; Aliev, Teimur; Panina, Anna; Svirshchevskaya, Elena; Dolgikh, Dmitry; Kirpichnikov, Mikhail

    2015-10-01

    Tumor necrosis factor-α (TNF-α) plays a key role in rheumatoid arthritis and some other autoimmune diseases. Therapy with anti-TNF-α recombinant antibodies (Ab) appears to be highly effective. Production of new hyper-producing eukaryotic cell lines can decrease the treatment cost, which currently is very high. However, due to the complexity of protein transcription, translation, processing, and secretion in mammalian cells, the stages at which antibody expression is affected are still poorly determined. The aim of this work was to compare the productivity of two cell lines developed in CHO DG44 cells, deficient in dihydrofolate reductase, transfected with vectors carrying either heavy (H) or light (L) chains of chimeric antibody under different combinations of selective elements. Both H and L chains were cloned either in pOptiVEC or pcDNA3.3 vectors and different combinations were used to produce HL and LH cell lines. We have shown that Ab production has been low and comparable between HL and LH cells until selection on methotrexate (MTX) when LH but not HL cells have responded with 3.5 times increased productivity. Flow cytometry analysis has demonstrated that intracellular concentration of full size Abs in LH cells was 5.6 times higher than in HL ones due to higher amount of H chain synthesis. No differences in viability between HL and LH cells have been found. We have concluded that the expression of H chain in the pOptiVEC vector, which is responsible for MTX resistance, has led to the suppression of H chain synthesis and limitation in full Ab assembly.

  20. Depletion of conventional mature B cells and compromised specific antibody response in bovine immunoglobulin μ heavy-chain transgenic mice

    Directory of Open Access Journals (Sweden)

    Min ZHANG,Xueqian CHENG,Dan CHU,Jingwen LIANG,Yi SUN,Li MA,Beilei XU,Min ZHENG,Meili WANG,Liming REN,Xiaoxiang HU,Qingyong MENG,Ran ZHANG,Ying GUO,Yunping DAI,Robert AITKEN,Ning LI,Yaofeng ZHAO

    2014-06-01

    Full Text Available In this study, we introduced the bovine immunoglobulin μ heavy-chain gene (the orphaned gene on BTA11 into mouse germline cells. Bovine IgM was highly expressed in selected transgenic lines, and it largely inhibited rearrangements of the endogenous immunoglobulin heavy chain (IgH genes in these lines. The forced expression of bovine IgM resulted in reduced numbers of pro- and pre-B cells but increased the number of immature B cells in the transgenic mice. Bovine IgM-expressing B cells can migrate from the bone marrow to the spleen, but most of the cells are arrested at the T1 transitional B cell stage, leading to a significantly lower number of T2 transitional and mature B cells in the spleen. Although the serum concentrations of endogenous IgM and IgG in the transgenic mice were significantly decreased, the IgA levels were slightly increased compared to the WT mice. The bovine IgM level in the serum was only one-tenth to one-fifth of that of endogenous mouse IgM, suggesting that most of the serum immunoglobulin were contributed by endogenous IgH gene-expressing B cells. These transgenic mice also exhibited a lower frequency of unique complementarity determining region 3 (CDR3 sequences in their VH repertoire and V&Kgr; repertoire but exhibited an increased frequency of unique CDR3 in their V&Lgr; repertoire. Compared to the WT mice, the transgenic mice had a significantly higher percentage of mouse IgM-expressing B cells that expressed &Lgr; chains. Finally, we showed that the transgenic mice were deficient in a specific antibody response to antigen stimulation.

  1. State of the VA

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2016-01-01

    Full Text Available No abstract available. Article truncated at 150 words. Earlier this week, President Obama gave his last State of the Union Address. Although this usually is a speech giving the President the opportunity of flaunt his accomplishments, no mention was made of the VA (1. Given the troubles at the VA, there seems little to tout. Over 70% of the VA medical centers were discovered to have falsified wait times (2. Because of the wait scandal, VA Secretary Eric Shinseki resigned and VA undersecretary, Robert Petzel MD, retired under pressure. Ironically, Shinseki, a retired Army general and member of the Joint Chiefs of Staff, was viewed in a favorable light by the current administration because of a spat with the Bush administration's Secretary of Defense, Donald Rumsfeld, over the number of troops needed to secure Iran and Afghanistan (3. However, during Shinseki's tenure the number of VA "medical troops", doctors and nurses, was insufficient to care for the number …

  2. Flow cytometric analysis of immunoglobulin heavy chain expression in B-cell lymphoma and reactive lymphoid hyperplasia

    Science.gov (United States)

    Grier, David D; Al-Quran, Samer Z; Cardona, Diana M; Li, Ying; Braylan, Raul C

    2012-01-01

    The diagnosis of B-cell lymphoma (BCL) is often dependent on the detection of clonal immunoglobulin (Ig) light chain expression. In some BCLs, the determination of clonality based on Ig light chain restriction may be difficult. The aim of our study was to assess the utility of flow cytometric analysis of surface Ig heavy chain (HC) expression in lymphoid tissues in distinguishing lymphoid hyperplasias from BCLs, and also differentiating various BCL subtypes. HC expression on B-cells varied among different types of hyperplasias. In follicular hyperplasia, IgM and IgD expression was high in mantle cells while germinal center cells showed poor HC expression. In other hyperplasias, B cell compartments were blurred but generally showed high IgD and IgM expression. Compared to hyperplasias, BCLs varied in IgM expression. Small lymphocytic lymphomas had lower IgM expression than mantle cell lymphomas. Of importance, IgD expression was significantly lower in BCLs than in hyperplasias, a finding that can be useful in differentiating lymphoma from reactive processes. PMID:22400070

  3. Expression of porcine myosin heavy chain 1 gene in Berkshire loins ...

    African Journals Online (AJOL)

    user

    An important factor in evaluating porcine meat quality is the pH at post-mortem 24 h (pH24). In the current work, we conducted a GeneFishing polymerase chain reaction (PCR)–based screen to identify differentially expressed genes in Berkshire loins with high versus low pH24. Total RNAs were extracted from Berkshire ...

  4. Production of Recombinant Human scFv Against Tetanus Toxin Heavy Chain by Phage Display Technology.

    Science.gov (United States)

    Khalili, Ehsan; Lakzaei, Mostafa; Rasaee, Mohhamad Javad; Aminian, Mahdi

    2015-10-01

    Tetanus, as a major cause of death in developing countries, is caused by tetanus neurotoxin. Recombinant antibodies against tetanus neurotoxin can be useful in tetanus management. Phage display of antibody fragments from immune human antibody libraries with single chain constructs combining the variable fragments (scFv) has been one of the most prominent technologies in antibody engineering. The aim of this study was the generation of a single chain fragment of variable region (scFv) library and selection of specific antibodies with high affinity against tetanus toxin. Immune human single chain fragment variable (HuscFv) antibody phagemid library was displayed on pIII of filamentous bacteriophage. Selection of scFv clones was performed against tetanus toxin antigens after three rounds of panning. The selected scFv clones were analyzed for inhibition of tetanus toxin binding to ganglioside GT1b. After the third round of panning, over 35 HuscFv phages specific for tetanus toxin were isolated from this library of which 15 clones were found to bind specifically to tetanus toxin. The selected HuscFv phages expressed as a soluble HuscFv peptide and some clones showed positive signals against tetanus toxin. We found that six HuscFv clones inhibit toxin binding to ganglioside GT1b. These selected antibodies can be used in the management of tetanus.

  5. [Screening and analysis of the mutations on beta-myosin heavy chain gene in 3 Chinese families with hypertrophic cardiomyopathy].

    Science.gov (United States)

    Feng, Xiu-li; Fan, Xin-ping; Yang, Zhong-wei; Yang, Fu-hui

    2011-02-01

    To detect gene mutations on beta-myosin heavy chain gene MYH7 in 3 Chinese families with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between genotype and phenotype. A denaturing high-performance liquid chromatography (DHPLC) and sequencing mutation screening of the exons (exon3-23) coding for MYH7 gene were performed in 3 Chinese families with HCM. In this study, we identified several mutations in MYH7. A mutation of Thr441Met previously reported in a patient with Laing distal myopathy was first identified in one Chinese pedigree. This study illustrated the high frequency of mutation in MYH7 gene in Chinese HCM families. Different mutations and carriers of the MYH7 gene present phenotypic heterogeneity. Mutation screening and analysis in HCM family could therefore facilitate the early HCM diagnosis and would be helpful for the prediction, prevention and early treatment of HCM linked with MYH7 gene mutation.

  6. Myosin Heavy Chain Gene Expression in Developing Neonatal Skeletal Muscle: Involvement of the Nerve, Gravity, and Thyroid State

    Science.gov (United States)

    Baldwin, K. M.; Adams, G.; Haddad, F.; Zeng, M.; Qin, A.; Qin, L.; McCue, S.; Bodell, P.

    1999-01-01

    The myosin heavy chain (MHC) gene family encodes at least six MHC proteins (herein designated as neonatal, embryonic, slow type I (beta), and fast IIa, IIx, and IIb) that are expressed in skeletal muscle in a muscle-specific and developmentally-regulated fashion. At birth, both antigravity (e.g. soleus) and locomotor (e.g., plantaris) skeletal muscles are undifferentiated relative to the adult MHC phenotype such that the neonatal and embryonic MHC isoforms account for 80 - 90% of the MHC pool in a fast locomotor muscle; whereas, the embryonic and slow, type I isoforms account for approx. 90% of the pool in a typical antigravity muscle. The goal of this study was to investigate the role of an intact nerve, gravity and thyroid hormone (T3), as well as certain interactions of these interventions, on MHC gene expression in developing neonatal skeletal muscles of rodents.

  7. Myosin heavy-chain isoform distribution, fibre-type composition and fibre size in skeletal muscle of patients on haemodialysis

    DEFF Research Database (Denmark)

    Molsted, Stig; Eidemak, Inge; Sorensen, Helle Tauby

    2007-01-01

    Objective. Chronic uraemia is associated with abnormalities in skeletal muscles, which can affect their working capacity. It is also well known that the fibre-type composition of skeletal muscles influences endurance, muscle strength and power. In this study we therefore determined the size...... and distribution of muscle fibres and the myosin heavy-chain (MHC) isoform composition in patiens on haemodialysis (HD) in order to establish any differences with values for untrained control subjects. Material and methods. Muscle biopsies were obtained from the vastus lateralis muscle of 14 non-diabetic patients...... determined fibre-type composition of the vastus lateralis muscle. The mean fibre area of type 1 and 2 fibres was 3283±873 and 3594±1483 µm2, respectively. The MHC composition and the size of the type 1 fibres of the patients on HD were significantly different from those of the control subjects. Conclusions...

  8. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease

    DEFF Research Database (Denmark)

    Pecci, A.; Panza, E.; Pujol-Moix, N.

    2008-01-01

    MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness......, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. No consistent correlations have been identified between the 27 different MYH9 mutations identified so far and the variable clinical evolution of the disease. We have evaluated 108 consecutive MYH9-RD patients belonging...... or 1841 result in intermediate clinical pictures. These findings are relevant not only to patients' clinical management but also to the elucidation of the pathogenesis of the disease Udgivelsesdato: 2008/3...

  9. Immunoglobulin Tau Heavy Chain (IgT in Flounder, Paralichthys olivaceus: Molecular Cloning, Characterization, and Expression Analyses

    Directory of Open Access Journals (Sweden)

    Yang Du

    2016-09-01

    Full Text Available Immunoglobulin tau (IgT is a new teleost immunoglobulin isotype, and its potential function in adaptive immunity is not very clear. In the present study, the membrane-bound and secreted IgT (mIgT and sIgT heavy chain genes were cloned for the first time and characterized in flounder (Paralichthys olivaceus, and found the nucleic acid sequence were exactly same in the Cτ1–Cτ4 constant domains of mIgT and sIgT, but different in variable regions and the C-terminus. The amino acid sequence of mIgT shared higher similarity with Bovichtus diacanthus (51.2% and Dicentrarchus labrax (45.0%. Amino acid of flounder IgT, IgM, and IgD heavy chain was compared and the highest similarity was found between IgT Cτ1 and IgM Cμ1 (38%. In healthy flounder, the transcript levels of IgT mRNA were the highest in gill, spleen, and liver, and higher in peripheral blood leucocytes, skin, and hindgut. After infection and vaccination with Edwardsiella tarda via intraperitoneal injection and immersion, the qRT-PCR analysis demonstrated that the IgT mRNA level was significantly upregulated in all tested tissues, with similar dynamic tendency that increased firstly and then decreased, and higher in gill, skin, hindgut, liver, and stomach in immersion than in the injection group, but no significant difference existed in spleen and head kidney between immersion and injection groups. These results revealed that IgT responses could be simultaneously induced in both mucosal and systemic tissues after infection/vaccination via injection and immersion route, but IgT might play a more important role in mucosal immunity than in systemic immunity.

  10. Immunoglobulin analysis tool: a novel tool for the analysis of human and mouse heavy and light chain transcripts.

    Science.gov (United States)

    Rogosch, Tobias; Kerzel, Sebastian; Hoi, Kam Hon; Zhang, Zhixin; Maier, Rolf F; Ippolito, Gregory C; Zemlin, Michael

    2012-01-01

    Sequence analysis of immunoglobulin (Ig) heavy and light chain transcripts can refine categorization of B cell subpopulations and can shed light on the selective forces that act during immune responses or immune dysregulation, such as autoimmunity, allergy, and B cell malignancy. High-throughput sequencing yields Ig transcript collections of unprecedented size. The authoritative web-based IMGT/HighV-QUEST program is capable of analyzing large collections of transcripts and provides annotated output files to describe many key properties of Ig transcripts. However, additional processing of these flat files is required to create figures, or to facilitate analysis of additional features and comparisons between sequence sets. We present an easy-to-use Microsoft(®) Excel(®) based software, named Immunoglobulin Analysis Tool (IgAT), for the summary, interrogation, and further processing of IMGT/HighV-QUEST output files. IgAT generates descriptive statistics and high-quality figures for collections of murine or human Ig heavy or light chain transcripts ranging from 1 to 150,000 sequences. In addition to traditionally studied properties of Ig transcripts - such as the usage of germline gene segments, or the length and composition of the CDR-3 region - IgAT also uses published algorithms to calculate the probability of antigen selection based on somatic mutational patterns, the average hydrophobicity of the antigen-binding sites, and predictable structural properties of the CDR-H3 loop according to Shirai's H3-rules. These refined analyses provide in-depth information about the selective forces acting upon Ig repertoires and allow the statistical and graphical comparison of two or more sequence sets. IgAT is easy to use on any computer running Excel(®) 2003 or higher. Thus, IgAT is a useful tool to gain insights into the selective forces and functional properties of small to extremely large collections of Ig transcripts, thereby assisting a researcher to mine a data set

  11. Thrombin Cleavage of Inter-α-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix.

    Science.gov (United States)

    Petrey, Aaron C; de la Motte, Carol A

    2016-11-18

    Dynamic alterations of the extracellular matrix in response to injury directly modulate inflammation and consequently the promotion and resolution of disease. During inflammation, hyaluronan (HA) is increased at sites of inflammation where it may be covalently modified with the heavy chains (HC) of inter-α-trypsin inhibitor. Deposition of this unique, pathological form of HA (HC-HA) leads to the formation of cable-like structures that promote adhesion of leukocytes. Naive mononuclear leukocytes bind specifically to inflammation-associated HA matrices but do not adhere to HA constitutively expressed under homeostatic conditions. In this study, we have directly investigated a role for the blood-coagulation protease thrombin in regulating the adhesion of monocytic cells to smooth muscle cells producing an inflammatory matrix. Our data demonstrate that the proteolytic activity of thrombin negatively regulates the adhesion of monocytes to an inflammatory HC-HA complex. This effect is independent of protease-activated receptor activation but requires proteolytic activity toward a novel substrate. Components of HC-HA complexes were predicted to contain conserved thrombin-susceptible cleavage sites based on sequence analysis, and heavy chain 1 (HC1) was confirmed to be a substrate of thrombin. Thrombin treatment is sufficient to cleave HC1 associated with either cell-surface HA or serum inter-α-trypsin inhibitor. Furthermore, thrombin treatment of the inflammatory matrix leads to dissolution of HC-HA cable structures and abolishes leukocyte adhesion. These data establish a novel mechanism whereby thrombin cleavage of HC1 regulates the adhesive properties of an inflammatory HA matrix. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Application of principal component analysis in the pollution assessment with heavy metals of vegetable food chain in the old mining areas

    OpenAIRE

    Gergen Iosif; Harmanescu Monica

    2012-01-01

    Abstract Background The aim of the paper is to assess by the principal components analysis (PCA) the heavy metal contamination of soil and vegetables widely used as food for people who live in areas contaminated by heavy metals (HMs) due to long-lasting mining activities. This chemometric technique allowed us to select the best model for determining the risk of HMs on the food chain as well as on people's health. Results Many PCA models were computed with different variables: heavy metals con...

  13. Expression of myosin heavy chain isoforms mRNA transcripts in the temporalis muscle of common chimpanzees (Pan troglodytes).

    Science.gov (United States)

    Ciurana, Neus; Artells, Rosa; Muñoz, Carmen; Arias-Martorell, Júlia; Bello-Hellegouarch, Gaëlle; Casado, Aroa; Cuesta, Elisabeth; Pérez-Pérez, Alejandro; Pastor, Juan Francisco; Potau, Josep Maria

    2017-11-01

    The common chimpanzee (Pan troglodytes) is the primate that is phylogenetically most closely related to humans (Homo sapiens). In order to shed light on the anatomy and function of the temporalis muscle in the chimpanzee, we have analyzed the expression patterns of the mRNA transcripts of the myosin heavy chain (MyHC) isoforms in different parts of the muscle. We dissected the superficial, deep and sphenomandibularis portions of the temporalis muscle in five adult P. troglodytes and quantified the expression of the mRNA transcripts of the MyHC isoforms in each portion using real-time quantitative polymerase chain reaction. We observed significant differences in the patterns of expression of the mRNA transcripts of the MyHC-IIM isoform between the sphenomandibularis portion and the anterior superficial temporalis (33.6% vs 47.0%; P=0.032) and between the sphenomandibularis portion and the anterior deep temporalis (33.6% vs 43.0; P=0.016). We also observed non-significant differences between the patterns of expression in the anterior and posterior superficial temporalis. The differential expression patterns of the mRNA transcripts of the MyHC isoforms in the temporalis muscle in P. troglodytes may be related to the functional differences that have been observed in electromyographic studies in other species of primates. Our findings can be applicable to the fields of comparative anatomy, evolutionary anatomy, and anthropology. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. Resistance of Cloned 1F5 Chimeric Anti-CD20 Antibody Heavy-Chain Gene to DNA Polymerase due to a Predicted Hairpin Structure

    Directory of Open Access Journals (Sweden)

    Fatemeh Khademi

    2016-11-01

    Full Text Available Background: Formation of secondary structure such as DNA hairpins or loops may influence molecular genetics methods and PCR based approaches necessary for genetic engineering, in addition to gene regulation. Materials and Methods: A polymerase chain reaction with splice overlap extension (SOE-PCR was used to create fully synthetic 1F5 chimeric anti-CD20 heavy- and light-chain genes. The chimeric genes were cloned into the pCR-Blunt II-TOPO vector following by cloning into the pBudCE4.1 expression vector. Prediction of secondary structure was performed with the Vienna RNAfold webserver. PCR and sequencing across the predicted secondary structure of chimeric 1F5 heavy-chain gene was performed with multiple protocols for standard and GC-rich templates. Results: In our attempt to design vectors aimed to generate mouse-human chimeric antibody against CD20 (1F5, we found that the coding sequence of 1F5 chimeric heavy-chain gene constructed by SOE-PCR was resistant to polymerase during both PCR and sequencing reactions. Furthermore, we were also unable to analysis some positive transformants by restriction enzyme digestion. Encountering such difficulties to identify the cloned anti-CD20 chimeric heavy-chain gene, we found that the chimeric heavy-chain sequence is highly GC-rich and predicted to form a stable secondary structure. Conclusion: In conclusion, for the first time, we reported several difficulties with production of therapeutic chimeric 1F5 anti-CD20 antibody due to a predicted hairpin cluster correlates with barriers to PCR, sequencing and possibly restriction analysis. Our findings provide a probable note for researchers experiencing technical difficulties with construction of chimeric anti-CD20 antibody 1F5 gene vectors and also with other genes and molecular biology techniques requiring PCR-based method or restriction enzyme analysis. 

  15. Measurements on Pb27+ Sources for the CERN Heavy Ion Injection Chain

    CERN Document Server

    Chamings, J A

    2004-01-01

    CERN, the world's largest particle physics laboratory near Geneva, is currently in the process of building the Large Hadron Collider (LHC). Lead-208 will be used in this accelerator and to meet the injection requirements much work is required to find a suitable and reliable heavy ion source. The work in this report covers two ion sources, the Laser Ion Source (LIS), and the Electron Cyclotron Resonance Ion Source (ECRIS). An emittance measurement, using a pepper pot and CCD camera, was completed on the recently re-installed LIS, measured and analysed to be 140mm.mrad un-normalised and 0.8mm.mrad normalised 4rms for the maximum intensity charge state, Pb27+. A Visual Basic Program was modified to allow Charge State Distribution (CSD) and other scans of the ECRIS at CERN to be taken. Chapter 5 presents the results of the CSD scans taken. This program provided a new method to take 1 dimensional transverse beam profiles. From this a direct emittance measurement was formed for the first time since the source was o...

  16. 3D Architecture, dynamics as well as functional implications of genome organization of the Prader-Willi/Angelmann syndrome region & the Immunoglobin Heavy-Chain locus

    NARCIS (Netherlands)

    T.A. Knoch (Tobias)

    2008-01-01

    textabstractThe general 3D architecture of the immunoglobin heavy-chain (Igh) locus was determined by a novel interdisciplinary combination of high-resolution FISH and high-resolution epifluorescence spectral distance microscopy with analytical analysis, computer simulations, as well as

  17. Coexpression of the human HLA-A2 or HLA-B7 heavy chain gene and human beta 2-microglobulin gene in L cells

    NARCIS (Netherlands)

    Bernabeu, C.; Maziarz, R.; Spits, H.; de Vries, J.; Burakoff, S. J.; Terhorst, C.

    1984-01-01

    L cells expressing human HLA-A2 or HLA-B7 class I antigen heavy chains are not recognized by human cytotoxic T lymphocytes directed at HLA-A2 or HLA-B7 antigens. To test whether the absence of human beta 2-m was the cause of the lack of recognition by the human cytotoxic T lymphocytes, coexpression

  18. Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin

    DEFF Research Database (Denmark)

    Kriajevska, M; Bronstein, I B; Scott, D J

    2000-01-01

    of Mts1. The short C-terminal fragment of the myosin heavy chain was totally soluble in the presence of an equimolar amount of Mts1 at low ionic conditions (50 mM NaCl). Depolymerization was found to be calcium-dependent and could be blocked by EGTA. Our data suggest that Mts1 can increase myosin...... a regulatory role in the myosin assembly. In the presence of calcium, Mts1 binds at the C-terminal end of the myosin heavy chain close to the site of phosphorylation by protein kinase CK2 (Ser1944). In the present study, we have shown that interaction of Mts1 with the human platelet myosin or C......-terminal fragment of the myosin heavy chain inhibits phosphorylation of the myosin heavy chain by protein kinase CK2 in vitro. Mts1 might also bind directly the beta subunit of protein kinase CK2, thereby modifying the enzyme activity. Our results indicate that myosin oligomers were disassembled in the presence...

  19. Production of bifunctional proteins by Aspergillus awamori: Llama variable heavy chain antibody fragment (VHH) R9 coupled to Arthromyces ramosus peroxidase (ARP)

    NARCIS (Netherlands)

    Joosten, V.; Roelofs, M.S.; Dries, N. van den; Goosen, T.; Verrips, C.T.; Hondel, C.A.M.J.J. van den; Lokman, B.C.

    2005-01-01

    The Arthromyces ramosus peroxidase gene (arp) was genetically fused to either the 5′- or 3′-terminal ends of the gene encoding llama variable heavy chain antibody fragment VHH R9, resulting in the fusion expression cassettes ARP-R9 or R9-ARP. Aspergillus awamori transformants were obtained which

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

    DEFF Research Database (Denmark)

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

    2003-01-01

    disulfide bonding are formed under non-reducing denaturing conditions and separated from scrambled disulfide bond forms by hydrophobic interaction chromatography. In the second step, rapid refolding of the oxidized heavy chains is afforded by disulfide bond-assisted folding in the presence of beta(2...

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

    DEFF Research Database (Denmark)

    Ferré, Henrik; Ruffet, Emmanuel; Blicher, Thomas

    2003-01-01

    with correct disulfide bonding are formed under non-reducing denaturing conditions and separated from scrambled disulfide bond forms by hydrophobic interaction chromatography. In the second step, rapid refolding of the oxidized heavy chains is afforded by disulfide bond-assisted folding in the presence of beta...

  2. Reduced expression of androgen receptor and myosin heavy chain mRNA in cremaster muscle of boys with nonsyndromic cryptorchidism.

    Science.gov (United States)

    Barthold, Julia Spencer; Wang, Yanping; Reilly, Anita; Robbins, Alan; Figueroa, T Ernesto; Banihani, Ahmad; Hagerty, Jennifer; Akins, Robert E

    2012-10-01

    To better define the developmental mechanisms of nonsyndromic cryptorchidism, we measured the expression of hormone receptor and muscle type specific mRNAs in target tissues of boys with and those without nonsyndromic cryptorchidism. Prospectively collected cremaster muscle and/or hernia sac tissues from boys with congenital (79) or acquired (66) nonsyndromic cryptorchidism and hernia/hydrocele (controls, 84) were analyzed for hormone receptor (RXFP2, AR, ESR1, ESR2) and myosin heavy chain specific (MYH1, MYH2, MYH7) mRNA expression using real-time reverse transcriptase polymerase chain reaction. Log transformed mRNA, phenotype and feeding history data were statistically analyzed using Pearson's correlation, ANOVA and 2-sample t tests. AR mRNA expression was higher in cremaster muscle than in sac tissue, and significantly lower in congenital and acquired nonsyndromic cryptorchidism cases vs controls (p MYH7 mRNA expression was also significantly reduced in both nonsyndromic cryptorchidism groups (p ≤ 0.002), while a reduction in type 2 (fast) MYH2 expression was more modest and significant only for the congenital cryptorchidism group (p MYH7 and AR levels were strongly correlated (r(2) = 0.751, p MYH7 and ESR1 mRNA levels were higher and lower, respectively, in boys with nonsyndromic cryptorchidism who were fed soy formula. Expression of other genes was not measurable. Our data suggest that boys with congenital and acquired nonsyndromic cryptorchidism differentially express AR and slow twitch specific MYH7 mRNA in the cremaster muscle, and that MYH7 expression is correlated with AR levels and soy formula use. These differences in gene expression may reflect aberrant hormonal signaling and/or innervation during development with the potential for secondary functional effects and failed testicular descent. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  3. Contributions of Conventional and Heavy-Chain IgG to Immunity in Fetal, Neonatal, and Adult Alpacas▿

    Science.gov (United States)

    Daley-Bauer, L. P.; Purdy, S. R.; Smith, M. C.; Gagliardo, L. F.; Davis, W. C.; Appleton, J. A.

    2010-01-01

    In addition to conventional immunoglobulins, camelids produce antibodies that do not incorporate light chains into their structures. These so-called heavy-chain (HC) antibodies have incited great interest in the biomedical community, as they have considerable potential for biotechnological and therapeutic application. Recently, we have begun to elucidate the immunological functions of HC antibodies, yet little is known about their significance in maternal immunity or about the B lymphocytes that produce them. This study describes the application of isotype-specific reagents toward physiological assessments of camelid IgGs and the B cells that produce them. We document the specificities of monoclonal antibodies that distinguish two conventional IgG1 isotypes and two HC IgG3 variants produced by alpacas. Next, we report that the relative concentrations of five isotypes are similar in serum, milk, and colostrum; however, following passive transfer, the concentrations of HC IgG2 and IgG3 declined more rapidly than the concentration of conventional IgG1 in the sera of neonates. Finally, we assessed the distribution of B cells of distinct isotypes within lymphoid tissues during fetal and adult life. We detected IgG1, IgG2, and IgG3 in lymphocytes located in lymph node follicles, suggesting that HC B cells affinity mature and/or class switch. One IgG3 isotype was present in B cells located in ileal Peyer's patches, and one conventional IgG1 isotype was detected in splenic marginal zone B cells. Our findings contribute to the growing body of knowledge pertaining to HC antibodies and are compatible with functional specialization among conventional and HC IgGs in the alpaca. PMID:20926693

  4. A Novel Method to Measure Glucose Uptake and Myosin Heavy Chain Isoform Expression of Single Fibers From Rat Skeletal Muscle

    Science.gov (United States)

    MacKrell, James G.; Cartee, Gregory D.

    2012-01-01

    Skeletal muscle includes many individual fibers with diverse phenotypes. A barrier to understanding muscle glucose uptake at the cellular level has been the absence of a method to measure glucose uptake by single fibers from mammalian skeletal muscle. This study’s primary objective was to develop a procedure to measure glucose uptake by single fibers from rat skeletal muscle. Rat epitrochlearis muscles were incubated ex vivo with [3H]-2-deoxy-d-glucose, with or without insulin or AICAR, before isolation of ~10–30 single fibers from each muscle. Fiber type (myosin heavy chain [MHC] isoform) and glucose uptake were determined for each single fiber. Insulin-stimulated glucose uptake (which was cytochalasin B inhibitable) varied according to MHC isoform expression, with ~2-fold greater values for IIA versus IIB or IIX fibers and ~1.3-fold greater for hybrid (IIB/X) versus IIB fibers. In contrast, AICAR-stimulated glucose uptake was ~1.5-fold greater for IIB versus IIA fibers. A secondary objective was to assess insulin resistance of single fibers from obese versus lean Zucker rats. Genotype differences were observed for insulin-stimulated glucose uptake and inhibitor κB (IκB)-β abundance in single fibers (obese less than lean), with decrements for glucose uptake (44–58%) and IκB-β (25–32%) in each fiber type. This novel method creates a unique opportunity for future research focused on understanding muscle glucose uptake at the cellular level. PMID:22396201

  5. Chronic oral administration of beta-adrenoceptor agonist clenbuterol affects myosin heavy chain (MHC) expression in adult mouse heart.

    Science.gov (United States)

    Patiyal, S N; Sharma, S

    2007-01-01

    The aim of this study was to analyze the effects of chronic administration of the beta-adrenoceptor agonist clenbuterol (2 mg/kg body weight/day for a period of 30 days) on the major contractile protein (myosin) in the left ventricular muscle of the adult mouse heart. Separation of myosin heavy chain (MHC) isoforms on 7.5 % glycerol SDS-PAGE and subsequent quantification of the gels by laser densitometry showed a 6.5-fold increase in the beta-isoform of MHC in the clenbuterol-treated group. The alpha : beta ratio of these two isoforms in the control group was 98.16+/-0.14 %: 1.83+/-0.14 %, whereas in the treated group it was 88.05+/-1.15 % : 11.95+/-1.15 %. Actomyosin ATPase activity assay demonstrated a significant (20 %) decline in ATPase activity of the tissue in the beta-agonist-treated group. These results suggest that chronic clenbuterol treatment is capable to induced the transformation of MHC isoforms increasing the slow beta-MHC isoform, which may contribute to the altered contractile mechanics of clenbuterol-treated hearts.

  6. A catalytic antibody heavy chain HpU-2 degrading its epitope peptide and H. pylori urease.

    Science.gov (United States)

    Hifumi, Emi; Yamada, Yukiko; Uda, Taizo

    2006-02-28

    The HpU-2 monoclonal antibody (mAb) raised against Helicobacter pylori urease mainly recognized the alpha-subunit of the urease. On the other hand, the heavy chain of HpU-2 mAb (HpU-2-H) isolated from the parent mAb recognized both the alpha- and beta-subunit, in which the beta-subunit was recognized more strongly than the beta-subunit. HpU-2-H cleaved a peptide, SVELIDIGGNRRIFGFNALVD, which is the epitope sequence recognized by HpU-2 mAb, showing a double-phase reaction profile at 25 degrees C in a phosphate buffer. After an induction time of 24h, the cleavage of the peptide was initiated by HpU-2-H at a high rate and it was completed at 80 h of incubation. By mass spectroscopy, two main fragmented peptides, SVELIDIGGNRR and SVELIDIGGNRRIFG, were identified. In addition, many small peptide fragments were produced by successive cleavage of the fragmented peptides. Cleavage tests for H. pylori urease by HpU-2-H revealed that the beta-subunit of the urease was cleaved first and completely decomposed at 20 h of incubation. Cleavage of the alpha-subunit started after the complete decomposition of the beta-subunit. These cleavage results were in good agreement with the immunological features of HpU-2-H. The irrelevant proteins, BSA and HSA, were hardly cleaved by HpU-2-H.

  7. Improving the accuracy of the structure prediction of the third hypervariable loop of the heavy chains of antibodies.

    KAUST Repository

    Messih, Mario Abdel

    2014-06-13

    MOTIVATION: Antibodies are able to recognize a wide range of antigens through their complementary determining regions formed by six hypervariable loops. Predicting the 3D structure of these loops is essential for the analysis and reengineering of novel antibodies with enhanced affinity and specificity. The canonical structure model allows high accuracy prediction for five of the loops. The third loop of the heavy chain, H3, is the hardest to predict because of its diversity in structure, length and sequence composition. RESULTS: We describe a method, based on the Random Forest automatic learning technique, to select structural templates for H3 loops among a dataset of candidates. These can be used to predict the structure of the loop with a higher accuracy than that achieved by any of the presently available methods. The method also has the advantage of being extremely fast and returning a reliable estimate of the model quality. AVAILABILITY AND IMPLEMENTATION: The source code is freely available at http://www.biocomputing.it/H3Loopred/ .

  8. The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions.

    Science.gov (United States)

    Jhunjhunwala, Suchit; van Zelm, Menno C; Peak, Mandy M; Cutchin, Steve; Riblet, Roy; van Dongen, Jacques J M; Grosveld, Frank G; Knoch, Tobias A; Murre, Cornelis

    2008-04-18

    The immunoglobulin heavy-chain (Igh) locus is organized into distinct regions that contain multiple variable (V(H)), diversity (D(H)), joining (J(H)) and constant (C(H)) coding elements. How the Igh locus is structured in 3D space is unknown. To probe the topography of the Igh locus, spatial distance distributions were determined between 12 genomic markers that span the entire Igh locus. Comparison of the distance distributions to computer simulations of alternative chromatin arrangements predicted that the Igh locus is organized into compartments containing clusters of loops separated by linkers. Trilateration and triple-point angle measurements indicated the mean relative 3D positions of the V(H), D(H), J(H), and C(H) elements, showed compartmentalization and striking conformational changes involving V(H) and D(H)-J(H) elements during early B cell development. In pro-B cells, the entire repertoire of V(H) regions (2 Mbp) appeared to have merged and juxtaposed to the D(H) elements, mechanistically permitting long-range genomic interactions to occur with relatively high frequency.

  9. Sulfasalazine Treatment Suppresses the Formation of HLA-B27 Heavy Chain Homodimer in Patients with Ankylosing Spondylitis.

    Science.gov (United States)

    Yu, Hui-Chun; Lu, Ming-Chi; Huang, Kuang-Yung; Huang, Hsien-Lu; Liu, Su-Qin; Huang, Hsien-Bin; Lai, Ning-Sheng

    2015-12-29

    Human leukocytic antigen-B27 heavy chain (HLA-B27 HC) has the tendency to fold slowly, in turn gradually forming a homodimer, (B27-HC)₂ via a disulfide linkage to activate killer cells and T-helper 17 cells and inducing endoplasmic reticulum (ER) stress to trigger the IL-23/IL-17 axis for pro-inflammatory reactions. All these consequences lead to the pathogenesis of ankylosing spondylitis (AS). Sulfasalazine (SSA) is a common medication used for treatment of patients with AS. However, the effects of SSA treatment on (B27-HC)₂ formation and on suppression of IL-23/IL-17 axis of AS patients remain to be determined. In the current study, we examine the (B27-HC)₂ of peripheral blood mononuclear cells (PBMC), the mean grade of sarcoiliitis and lumbar spine Bath Ankylosing Spondylitis Radiology Index (BASRI) scores of 23 AS patients. The results indicated that AS patients without (B27-HC)₂ on PBMC showed the lower levels of mean grade of sarcoiliitis and the lumbar spine BASRI scores. In addition, after treatment with SSA for four months, the levels of (B27-HC)₂ on PBMCs were significantly reduced. Cytokines mRNA levels, including TNFα, IL-17A, IL-17F and IFNγ, were also significantly down-regulated in PBMCs. However, SSA treatment did not affect the levels of IL-23 and IL-23R mRNAs.

  10. The Florida manatee (Trichechus manatus latirostris) immunoglobulin heavy chain suggests the importance of clan III variable segments in repertoire diversity

    Science.gov (United States)

    Breaux, Breanna; Deiss, Thaddeus C.; Chen, Patricia L.; Cruz-Schneider, Maria Paula; Sena, Leonardo; Hunter, Margaret E.; Bonde, Robert K.; Criscitiello, Michael F.

    2017-01-01

    Manatees are a vulnerable, charismatic sentinel species from the evolutionarily divergent Afrotheria. Manatee health and resistance to infectious disease is of great concern to conservation groups, but little is known about their immune system. To develop manatee-specific tools for monitoring health, we first must have a general knowledge of how the immunoglobulin heavy (IgH) chain locus is organized and transcriptionally expressed. Using the genomic scaffolds of the Florida manatee (Trichechus manatus latirostris), we characterized the potential IgH segmental diversity and constant region isotypic diversity and performed the first Afrotherian repertoire analysis. The Florida manatee has low V(D)J combinatorial diversity (3744 potential combinations) and few constant region isotypes. They also lack clan III V segments, which may have caused reduced VH segment numbers. However, we found productive somatic hypermutation concentrated in the complementarity determining regions. In conclusion, manatees have limited IGHV clan and combinatorial diversity. This suggests that clan III V segments are essential for maintaining IgH locus diversity.

  11. Pattern of myosin heavy chain isoforms in different fibre types of canine trunk and limb skeletal muscles.

    Science.gov (United States)

    Strbenc, M; Smerdu, V; Zupanc, M; Tozon, N; Fazarinc, G

    2004-01-01

    The aim of this study was to determine the pattern of myosin heavy chain (MHC) isoform expressions within the muscle fibres of functionally diverse trunk and limb dog muscles using monoclonal antibodies that are specific to MHC isoforms. We found that three MHC isoforms are expressed in dog skeletal muscles. The pattern of their expressions determined the existence of 'pure' fibres, i.e. I and IIa, both expressing only one MHC isoform, and 'hybrid' fibres, i.e. I/IIa and IIa/x, that co-expressed two MHC isoforms. While the MHCI, MHCIIa and MHCI/IIa fibres corresponded to the myofibrillar ATPase type fibres I, IIA and IIC, respectively, the hybrid MHCIIa/x fibres mostly behaved like the IIDog fibre type in myofibrillar ATPase reaction as described by Latorre et al. No pure MHCIIx fibres were found. Though MHCIIa/x fibres were quite numerous, their presence varied not only within different muscles but within the same muscle of different animals as well. We suggest that the discrepancies in the classification of fibre types according to their myofibrillar ATPase activity between different studies of dog skeletal muscles are probably a consequence of the variable content of the MHCIIa and MHCIIx isoforms in the MHCIIa/x hybrid fibres. Estimating the histochemical metabolic profile of fibres we found that in all fast fibres oxidative-glycolytic metabolism prevailed, whereas in slow fibres oxidative metabolism was more pronounced. Copyright 2004 S. Karger AG, Basel

  12. Intermediate filament-co-localized molecules with myosin heavy chain epitopes define distinct cellular domains in hair follicles and epidermis

    Directory of Open Access Journals (Sweden)

    Hughes Simon M

    2003-08-01

    Full Text Available Abstract Background Proteins linking intermediate filaments to other cytoskeletal components have important functions in maintaining tissue integrity and cell shape. Results We found a set of monoclonal antibodies raised against specific human sarcomeric myosin heavy chain (MyHC isoforms labels cells in distinct regions of the mammalian epidermis. The antigens co-localize with intermediate filament-containing structures. A slow MyHC-related antigen is punctate on the cell surface and co-localizes with desmoplakin at desmosomal junctions of all suprabasal epidermal layers from rat fœtal day 16 onwards, in the root sheath of the hair follicle and in intercalated disks of cardiomyocytes. A fast MyHC-related antigen occurs in cytoplasmic filaments in a subset of basal cells of skin epidermis and bulb, but not neck, of hair follicles. A fast IIA MyHC-related antigen labels filaments of a single layer of cells in hair bulb. This 230 000 Mr antigen co-purifies with keratin. No obvious candidate for any of the antigens appears in the literature. Conclusions We describe a set of molecules that co-localize with intermediate filament in specific cell subsets in epithelial tissues. These antigens presumably influence intermediate filament structure or function.

  13. MR molecular imaging of tumours using ferritin heavy chain reporter gene expression mediated by the hTERT promoter

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yan [Third Military Medical University, Department of Radiology, XinQiao Hospital, ChongQing (China); The First Affiliated Hospital of ChengDu Medical College, Department of Radiology, ChengDu (China); Gong, Ming-fu; Yang, Hua; Zhang, Song; Wang, Guang-xian; Su, Tong-sheng; Wen, Li; Zhang, Dong [Third Military Medical University, Department of Radiology, XinQiao Hospital, ChongQing (China)

    2016-11-15

    Using the human telomerase reverse transcriptase (hTERT) promoter and the modified ferritin heavy chain (Fth) reporter gene, reporter gene expression for MRI was examined in telomerase positive and negative tumour cells and xenografts. Activity of the reporter gene expression vector Lenti-hTERT-Fth1-3FLAG-Puro was compared to constitutive CMV-driven expression and to the untransfected parental control in five tumour cell lines: A549, SKOV3, 293T, U2OS and HPDLF. In vitro, transfected cells were evaluated for FLAG-tagged protein expression, iron accumulation and transverse relaxation. In vivo, tumours transduced by lentiviral vector injection were imaged using T2*WI. Changes in tumour signal intensity were validated by histology. Only telomerase positive tumour cells expressed FLAG-tagged Fth and displayed an increase in R2* above the parental control, with a corresponding change in T2*WI. In addition, only telomerase positive tumours, transduced by injection of the reporter gene expression construct, exhibited a change in signal intensity on T2*WI. Tumour histology verified the expression of FLAG-tagged Fth and iron accumulation in telomerase positive tissue. Reporter gene expression for MRI, using the Fth reporter and the hTERT promoter, may be a useful strategy for the non-invasive diagnosis of many types of cancer. (orig.)

  14. Modular Construction of Large Non-Immune Human Antibody Phage-Display Libraries from Variable Heavy and Light Chain Gene Cassettes.

    Science.gov (United States)

    Lee, Nam-Kyung; Bidlingmaier, Scott; Su, Yang; Liu, Bin

    2018-01-01

    Monoclonal antibodies and antibody-derived therapeutics have emerged as a rapidly growing class of biological drugs for the treatment of cancer, autoimmunity, infection, and neurological diseases. To support the development of human antibodies, various display techniques based on antibody gene repertoires have been constructed over the last two decades. In particular, scFv-antibody phage display has been extensively utilized to select lead antibodies against a variety of target antigens. To construct a scFv phage display that enables efficient antibody discovery, and optimization, it is desirable to develop a system that allows modular assembly of highly diverse variable heavy chain and light chain (Vκ and Vλ) repertoires. Here, we describe modular construction of large non-immune human antibody phage-display libraries built on variable gene cassettes from heavy chain and light chain repertoires (Vκ- and Vλ-light can be made into independent cassettes). We describe utility of such libraries in antibody discovery and optimization through chain shuffling.

  15. Detection of monoclonal immunoglobulin heavy chain gene rearrangement (FR3 in Thai malignant lymphoma by High Resolution Melting curve analysis

    Directory of Open Access Journals (Sweden)

    Pongpruttipan Tawatchai

    2010-05-01

    Full Text Available Abstract Malignant lymphoma, especially non-Hodgkin lymphoma, is one of the most common hematologic malignancies in Thailand. The diagnosis of malignant lymphoma is often problematic, especially in early stages of the disease. Detection of antigen receptor gene rearrangement including T cell receptor (TCR and immunoglobulin heavy chain (IgH by polymerase chain reaction followed by heteroduplex has currently become standard whereas fluorescent fragment analysis (GeneScan has been used for confirmation test. In this study, three techniques had been compared: thermocycler polymerase chain reaction (PCR followed by heteroduplex and polyacrylamide gel electrophoresis, GeneScan analysis, and real time PCR with High Resolution Melting curve analysis (HRM. The comparison was carried out with DNA extracted from paraffin embedded tissues diagnosed as B- cell non-Hodgkin lymphoma. Specific PCR primers sequences for IgH gene variable region 3, including fluorescence labeled IgH primers were used and results were compared with HRM. In conclusion, the detection IgH gene rearrangement by HRM in the LightCycler System showed potential for distinguishing monoclonality from polyclonality in B-cell non-Hodgkin lymphoma. Introduction Malignant lymphoma, especially non-Hodgkin lymphoma, is one of the most common hematologic malignancies in Thailand. The incidence rate as reported by Ministry of Public Health is 3.1 per 100,000 population in female whereas the rate in male is 4.5 per 100,000 population 1. At Siriraj Hospital, the new cases diagnosed as malignant lymphoma were 214.6 cases/year 2. The diagnosis of malignant lymphoma is often problematic, especially in early stages of the disease. Therefore, detection of antigen receptor gene rearrangement including T cell receptor (TCR and immunoglobulin heavy chain (IgH by polymerase chain reaction (PCR assay has recently become a standard laboratory test for discrimination of reactive from malignant clonal

  16. Development of a Bioinformatics Framework for the Detection of Gene Conversion and the Analysis of Combinatorial Diversity in Immunoglobulin Heavy Chains in Four Cattle Breeds.

    Science.gov (United States)

    Walther, Stefanie; Tietze, Manfred; Czerny, Claus-Peter; König, Sven; Diesterbeck, Ulrike S

    2016-01-01

    We have developed a new bioinformatics framework for the analysis of rearranged bovine heavy chain immunoglobulin (Ig) variable regions by combining and refining widely used alignment algorithms. This bioinformatics framework allowed us to investigate alignments of heavy chain framework regions (FRHs) and the separate alignments of FRHs and heavy chain complementarity determining regions (CDRHs) to determine their germline origin in the four cattle breeds Aubrac, German Black Pied, German Simmental, and Holstein Friesian. Now it is also possible to specifically analyze Ig heavy chains possessing exceptionally long CDR3Hs. In order to gain more insight into breed specific differences in Ig combinatorial diversity, somatic hypermutations and putative gene conversions of IgG, we compared the dominantly transcribed variable (IGHV), diversity (IGHD), and joining (IGHJ) segments and their recombination in the four cattle breeds. The analysis revealed the use of 15 different IGHV segments, 21 IGHD segments, and two IGHJ segments with significant different transcription levels within the breeds. Furthermore, there are preferred rearrangements within the three groups of CDR3H lengths. In the sequences of group 2 (CDR3H lengths (L) of 11-47 amino acid residues (aa)) a higher number of recombination was observed than in sequences of group 1 (L≤10 aa) and 3 (L≥48 aa). The combinatorial diversity of germline IGHV, IGHD, and IGHJ-segments revealed 162 rearrangements that were significantly different. The few preferably rearranged gene segments within group 3 CDR3H regions may indicate specialized antibodies because this length is unique in cattle. The most important finding of this study, which was enabled by using the bioinformatics framework, is the discovery of strong evidence for gene conversion as a rare event using pseudogenes fulfilling all definitions for this particular diversification mechanism.

  17. Effects of low-level α-myosin heavy chain expression on contractile kinetics in porcine myocardium

    Science.gov (United States)

    Razumova, Maria V.; Stelzer, Julian E.; Norman, Holly S.; Moss, Richard L.

    2011-01-01

    Myosin heavy chain (MHC) isoforms are principal determinants of work capacity in mammalian ventricular myocardium. The ventricles of large mammals including humans normally express ∼10% α-MHC on a predominantly β-MHC background, while in failing human ventricles α-MHC is virtually eliminated, suggesting that low-level α-MHC expression in normal myocardium can accelerate the kinetics of contraction and augment systolic function. To test this hypothesis in a model similar to human myocardium we determined composite rate constants of cross-bridge attachment (fapp) and detachment (gapp) in porcine myocardium expressing either 100% α-MHC or 100% β-MHC in order to predict the MHC isoform-specific effect on twitch kinetics. Right atrial (∼100% α-MHC) and left ventricular (∼100% β-MHC) tissue was used to measure myosin ATPase activity, isometric force, and the rate constant of force redevelopment (ktr) in solutions of varying Ca2+ concentration. The rate of ATP utilization and ktr were approximately ninefold higher in atrial compared with ventricular myocardium, while tension cost was approximately eightfold greater in atrial myocardium. From these values, we calculated fapp to be ∼10-fold higher in α- compared with β-MHC, while gapp was 8-fold higher in α-MHC. Mathematical modeling of an isometric twitch using these rate constants predicts that the expression of 10% α-MHC increases the maximal rate of rise of force (dF/dtmax) by 92% compared with 0% α-MHC. These results suggest that low-level expression of α-MHC significantly accelerates myocardial twitch kinetics, thereby enhancing systolic function in large mammalian myocardium. PMID:21217059

  18. Developing Cardiac and Skeletal Muscle Share Fast-Skeletal Myosin Heavy Chain and Cardiac Troponin-I Expression

    Science.gov (United States)

    Powell, Mary C.; Liu, Li J.; Huard, Johnny; Keller, Bradley B.; Tobita, Kimimasa

    2012-01-01

    Skeletal muscle derived stem cells (MDSCs) transplanted into injured myocardium can differentiate into fast skeletal muscle specific myosin heavy chain (sk-fMHC) and cardiac specific troponin-I (cTn-I) positive cells sustaining recipient myocardial function. We have recently found that MDSCs differentiate into a cardiomyocyte phenotype within a three-dimensional gel bioreactor. It is generally accepted that terminally differentiated myocardium or skeletal muscle only express cTn-I or sk-fMHC, respectively. Studies have shown the presence of non-cardiac muscle proteins in the developing myocardium or cardiac proteins in pathological skeletal muscle. In the current study, we tested the hypothesis that normal developing myocardium and skeletal muscle transiently share both sk-fMHC and cTn-I proteins. Immunohistochemistry, western blot, and RT-PCR analyses were carried out in embryonic day 13 (ED13) and 20 (ED20), neonatal day 0 (ND0) and 4 (ND4), postnatal day 10 (PND10), and 8 week-old adult female Lewis rat ventricular myocardium and gastrocnemius muscle. Confocal laser microscopy revealed that sk-fMHC was expressed as a typical striated muscle pattern within ED13 ventricular myocardium, and the striated sk-fMHC expression was lost by ND4 and became negative in adult myocardium. cTn-I was not expressed as a typical striated muscle pattern throughout the myocardium until PND10. Western blot and RT-PCR analyses revealed that gene and protein expression patterns of cardiac and skeletal muscle transcription factors and sk-fMHC within ventricular myocardium and skeletal muscle were similar at ED20, and the expression patterns became cardiac or skeletal muscle specific during postnatal development. These findings provide new insight into cardiac muscle development and highlight previously unknown common developmental features of cardiac and skeletal muscle. PMID:22808244

  19. Size and myosin heavy chain profiles of rat hindlimb extensor muscle fibers after 2 weeks at 2G.

    Science.gov (United States)

    Roy, R R; Roy, M E; Talmadge, R J; Mendoza, R; Grindeland, R E; Vasques, M

    1996-09-01

    The effects of 14 d of continuous centrifugation at approximately 2G on the hindlimb extensor musculature of male rats were studied. The mean body mass of centrifuged rats was 17% smaller than age-matched controls. In centrifuged rats, the mean absolute masses of the soleus and medial gastrocnemius (MG) were similar to control, while the mean relative masses (expressed as milligram muscle mass/gram of body mass) were larger than control. Based on a battery of monoclonal antibodies for specific myosin heavy chains (MHC), the soleus of centrifuged rats had a lower percentage (68 vs. 74%) of fibers expressing type I MHC only and a higher percentage (15 vs. 10%) that co-expressed type I and IIa MHC's. The MHC composition of fibers from the deep portion of the MG was unaffected by centrifugation. The MHC compositions based on SDS-PAGE gel electrophoresis for each muscle were similar in the two groups. Mean fiber size of each fiber type in the soleus was unaffected by centrifugation. In the MG, the fibers, expressing only type IIb MHC were smaller in the centrifuge compared to control rats. Although 2 weeks of chronic centrifugation at 2G resulted in a cessation of body growth, there was essentially no effect on the muscle masses or fiber size in either a slow or fast extensor muscle. These data suggest that periods of centrifugation may be beneficial in maintaining extensor muscle mass in an animal that is not growing at a normal rate e.g., during chronic unloading.

  20. Effects of creatine supplementation during resistance training on myosin heavy chain (MHC) expression in rat skeletal muscle fibers.

    Science.gov (United States)

    Aguiar, Andreo F; Aguiar, Danilo H; Felisberto, Alan D S; Carani, Fernanda R; Milanezi, Rachel C; Padovani, Carlos R; Dal-Pai-Silva, Maeli

    2010-01-01

    The purpose of this study was to utilize a rodent model to test the hypothesis that creatine (Cr) supplementation during resistance training would influence the pattern of slow-twitch muscle myosin heavy chain (MHC) isoforms expression. Male Wistar rats (2-3 months old, 250-300 g) were divided into 4 groups: Nontrained without creatine supplementation (CO), nontrained with creatine supplementation (CR), trained without creatine supplementation (TR), and trained with creatine supplementation (TRCR). TR and TRCR groups were submitted to a resistance training program for 5 weeks (5 days/week) for morphological and biochemical analysis of the soleus muscle. Weightlifting exercise involved jump sessions into water, carrying progressive overload equivalent to percentage of body weight. CR and TRCR groups were given creatine at 0.5 g/kg(-1)/d(-1). Both Cr supplementation and resistance training alone or associated did not result in significant alterations (p > 0.05) in body weight gain, food intake, and muscle weight in the CR, TR and TRCR groups compared to the CO group. Also compared to the CO group, the CR group showed a significant (p 0.05) changes in MHC content of the TRCR group compared to the CO group. The data show that Cr supplementation provides a potential action to abolish the exercise-induced MHC isoform transitions from slow to fast in slow-twitch muscle. Thus, Cr supplementation might be a suitable strategy to maintaining a slow phenotype in slow muscle during resistance training, which may be favorable to maintenance of muscle oxidative capacity of endurance athletes.

  1. Thyroid hormone partially corrects the effect of diabetes on mysoin heavy chain RNAs in the rat ventricle

    Energy Technology Data Exchange (ETDEWEB)

    Barrieux, A.; Dillmann, W.H.

    1986-05-01

    The relative abundance of the 2 cardiac myosin heavy chains (MHH-..cap alpha.. and MHC-..beta..) and their corresponding RNAs is similarly affected by hypothyroidism and diabetes in the rat ventricle. Since circulating levels of thyroid hormone (T/sub 3/) are significantly decreased in diabetes the decreased RNA-..cap alpha.. and increased RNA-..beta.. associated with diabetes may be related to T/sub 3/ deficiency. Chronically diabetic rats were injected with T/sub 3/, insulin (I), or both and sacrificed between 1 and 12 hrs after injection, MHC RNA was quantified by hybridization of total RNA to a (/sup 32/P)-cDNA MHC-..cap alpha.. probe. Total MHC RNA was measured by retention of S1-resistant label on DE-81 while RNA-..cap alpha.. and RNA-..beta.. were quantified by separation of intact (..cap alpha..) and partially digested (..beta..) probe by gel electrophoresis. Total MHC RNA was not changed by T/sub 3/ or I (.9-1.2 ng/..mu..g of cellular RNA). T/sub 3/ and I elicited a very rapid increase in RNA-..cap alpha.. (18% in untreated to 38% (I) and 47% (T/sub 3/ within 1 hr). I administered either 7 hr before or 1 hr after T/sub 3/ did not modify the RNA-..cap alpha.. increase observed after T/sub 3/ alone. However, the response of diabetic rats to T/sub 3/ was markedly different from that of hypothyroid rats. Conclusions: 1) T/sub 3/ in diabetic rats does not mimick the effect of T/sub 3/ in hypothyroid rats; it may simply impose a hyperthyroid state on the existing diabetes and 2) since neither T/sub 3/ nor I are able to increase RNA-..cap alpha.. to control levels within 12 hrs, neither hormone is sufficient to regulate the expression of MHC RNAs.

  2. Isolation, purification, and characterization of fragment B, the NH2-terminal half of the heavy chain of tetanus toxin.

    Science.gov (United States)

    Matsuda, M; Lei, D L; Sugimoto, N; Ozutsumi, K; Okabe, T

    1989-11-01

    Fragment B, the N-terminal half of the heavy chain, an important domain of the tetanus neurotoxin molecule, was isolated for the first time. Tetanus toxin (composed of three domains, A, B, and C) was prepared from culture filtrates. Fragment A-B, derived from the toxin treated mildly with papain, was used for the isolation of fragment B. Fragment A-B obtained was dissociated into fragments A and B by reduction with 100 mM dithiothreitol and treatment with 2 M urea. Fragment B was separated from fragment A by ion-exchange column chromatography on a Mono Q column equilibrated with 20 mM Tris hydrochloride buffer (pH 7.6), containing 1 mM dithiothreitol and 2 M urea, in a fast-protein liquid chromatography system by elution with a linear gradient of 0 to 0.5 M NaCl. Fragment B was obtained in two forms having molecular weights of 48,000 +/- 2,000, which were indistinguishable by sodium dodecyl sulfate-gel electrophoresis or antigenic specificity, but distinguishable on polyacrylamide gel electrophoresis without sodium dodecyl sulfate and on isoelectric focusing (pI 6.7 and 7.3). The recovery of fragment B was 50 to 72% of that of fragment A-B on a molar basis. Purified fragment B was not toxic to mice on intravenous or intramuscular injection at doses of up to 100 micrograms, but was found to form channels (ca. 2.3 pS) in a lipid bilayer membrane by a patch clamp technique. The role of domain B of the tetanus toxin molecule in the mechanism of action of the toxin is discussed.

  3. Noncompaction of the Ventricular Myocardium Is Associated with a De Novo Mutation in the β-Myosin Heavy Chain Gene

    Science.gov (United States)

    Budde, Birgit S.; Binner, Priska; Waldmüller, Stephan; Höhne, Wolfgang; Blankenfeldt, Wulf; Hassfeld, Sabine; Brömsen, Jürgen; Dermintzoglou, Anastassia; Wieczorek, Marcus; May, Erik; Kirst, Elisabeth; Selignow, Carmen; Rackebrandt, Kirsten; Müller, Melanie; Goody, Roger S.; Vosberg, Hans-Peter; Nürnberg, Peter; Scheffold, Thomas

    2007-01-01

    Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the α- and β-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium. PMID:18159245

  4. Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene.

    Directory of Open Access Journals (Sweden)

    Birgit S Budde

    Full Text Available Noncompaction of the ventricular myocardium (NVM is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the alpha- and beta-myosin heavy chain, respectively were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T. In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA and atrial septal defect (ASD. A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.

  5. Frequency Patterns of T-Cell Exposed Amino Acid Motifs in Immunoglobulin Heavy Chain Peptides Presented by MHCs.

    Science.gov (United States)

    Bremel, Robert D; Homan, E Jane

    2014-01-01

    Immunoglobulins are highly diverse protein sequences that are processed and presented to T-cells by B-cells and other antigen presenting cells. We examined a large dataset of immunoglobulin heavy chain variable regions (IGHV) to assess the diversity of T-cell exposed motifs (TCEMs). TCEM comprise those amino acids in a MHC-bound peptide, which face outwards, surrounded by the MHC histotope, and which engage the T-cell receptor. Within IGHV there is a distinct pattern of predicted MHC class II binding and a very high frequency of re-use of the TCEMs. The re-use frequency indicates that only a limited number of different cognate T-cells are required to engage many different clonal B-cells. The amino acids in each outward-facing TCEM are intercalated with the amino acids of inward-facing MHC groove-exposed motifs (GEM). Different GEM may have differing, allele-specific, MHC binding affinities. The intercalation of TCEM and GEM in a peptide allows for a vast combinatorial repertoire of epitopes, each eliciting a different response. Outcome of T-cell receptor binding is determined by overall signal strength, which is a function of the number of responding T-cells and the duration of engagement. Hence, the frequency of TCEM re-use appears to be an important determinant of whether a T-cell response is stimulatory or suppressive. The frequency distribution of TCEMs implies that somatic hypermutation is followed by T-cell clonal expansion that develops along repeated pathways. The observations of TCEM and GEM derived from immunoglobulins suggest a relatively simple, yet powerful, mechanism to correlate T-cell polyspecificity, through re-use of TCEMs, with a very high degree of specificity achieved by combination with a diversity of GEMs. The frequency profile of TCEMs also points to an economical mechanism for maintaining T-cell memory, recall, and self-discrimination based on an endogenously generated profile of motifs.

  6. Serum Phosphorylated Neurofilament-Heavy Chain, a Potential Biomarker, is Associated With Peripheral Neuropathy in Patients With Type 2 Diabetes.

    Science.gov (United States)

    Qiao, Xiaona; Zhang, Shuo; Zhao, Weiwei; Ye, Hongying; Yang, Yehong; Zhang, Zhaoyun; Miao, Qing; Hu, Renming; Li, Yiming; Lu, Bin

    2015-11-01

    Neurofilament (NF), one of the major axonal cytoskeletal proteins, plays a critical role in degenerative diseases in both the central and the peripheral nervous systems. The aim of this study is to explore the relationship between serum phosphorylated neurofilament-heavy chain (pNF-H) and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes.Serum pNF-H concentrations were measured by ELISA in hospitalized patients with and without DPN (n = 118). DPN was assessed by clinical symptoms, signs, and electromyography.Compared with the non-DPN group (311.98 [189.59-634.12] pg/mL), the confirmed group (605.99 [281.17-1332.78] pg/mL) patients had the higher serum pNF-H levels (P = 0.007). DPN was significantly correlated with C-peptide (r = -0.269), total cholesterol (TC) (r = 0.185), and pNF-H (r = 0.258). Serum pNF-H levels were independently associated with DPN (P = 0.004), even after adjusting for age, sex, duration of diabetes, fasting plasma glucose, glycosylated hemoglobin A1c, TC, C-peptide, urinary albuminto/creatinine ratio, and estimated glomerular filtration rate. Compared with pNF-H quartile 1 (referent), patients in quartile 3 (odds ratio [OR], 3.977; 95% confidence interval [CI], 1.243-12.728; P = 0.021) and quartile 4 (OR, 10.488; 95% CI, 3.020-34.429; P = 0.000) had the higher risk of DPN after adjusting for the confounders.Serum pNF-H levels might be associated with the DPN, and the correlationship between serum pNF-H and DPN should be further studied.

  7. Shared gene structures and clusters of mutually exclusive spliced exons within the metazoan muscle myosin heavy chain genes.

    Directory of Open Access Journals (Sweden)

    Martin Kollmar

    Full Text Available Multicellular animals possess two to three different types of muscle tissues. Striated muscles have considerable ultrastructural similarity and contain a core set of proteins including the muscle myosin heavy chain (Mhc protein. The ATPase activity of this myosin motor protein largely dictates muscle performance at the molecular level. Two different solutions to adjusting myosin properties to different muscle subtypes have been identified so far: Vertebrates and nematodes contain many independent differentially expressed Mhc genes while arthropods have single Mhc genes with clusters of mutually exclusive spliced exons (MXEs. The availability of hundreds of metazoan genomes now allowed us to study whether the ancient bilateria already contained MXEs, how MXE complexity subsequently evolved, and whether additional scenarios to control contractile properties in different muscles could be proposed, By reconstructing the Mhc genes from 116 metazoans we showed that all intron positions within the motor domain coding regions are conserved in all bilateria analysed. The last common ancestor of the bilateria already contained a cluster of MXEs coding for part of the loop-2 actin-binding sequence. Subsequently the protostomes and later the arthropods gained many further clusters while MXEs got completely lost independently in several branches (vertebrates and nematodes and species (for example the annelid Helobdella robusta and the salmon louse Lepeophtheirus salmonis. Several bilateria have been found to encode multiple Mhc genes that might all or in part contain clusters of MXEs. Notable examples are a cluster of six tandemly arrayed Mhc genes, of which two contain MXEs, in the owl limpet Lottia gigantea and four Mhc genes with three encoding MXEs in the predatory mite Metaseiulus occidentalis. Our analysis showed that similar solutions to provide different myosin isoforms (multiple genes or clusters of MXEs or both have independently been developed

  8. Purification of chimeric heavy chain monoclonal antibody EG2-hFc using hydrophobic interaction membrane chromatography: an alternative to protein-A affinity chromatography.

    Science.gov (United States)

    Sadavarte, Rahul; Spearman, Maureen; Okun, Natalie; Butler, Michael; Ghosh, Raja

    2014-06-01

    Heavy chain monoclonal antibodies are being considered as alternative to whole-IgG monoclonal antibodies for certain niche applications. Protein-A chromatography which is widely used for purifying IgG monoclonal antibodies is also used for purifying heavy chain monoclonal antibodies as these molecules possess fully functional Fc regions. However, the acidic conditions used to elute bound antibody may sometimes also leach protein-A, which is immunotoxic. Low pH conditions also tend to make the mAb molecules unstable and prone to aggregation. Moreover, protein-A affinity chromatography does not remove aggregates already present in the feed. Hydrophobic interaction membrane chromatography (or HIMC) has already been studied as an alternative to protein-A chromatography for purifying whole-IgG monoclonal antibodies. This paper describes the use of HIMC for capturing a humanized chimeric heavy chain monoclonal antibody (EG2-hFC). Binding and eluting conditions were suitably optimized using pure EG2-hFC. Based on this, an HIMC method was developed for capture of EG2-hFC directly from cell culture supernatant. The EG2-hFc purity obtained in this single-step process was high. The glycan profiles of protein-A and HIMC purified monoclonal antibody samples were similar, clearly demonstrating that both techniques captured similarly glycosylated population of EG2-hFc. Moreover, this technique was able to resolve aggregates from monomeric form of the EG2-hFc. © 2014 Wiley Periodicals, Inc.

  9. VA Health Care Facilities Locator

    Science.gov (United States)

    ... map [a-z] More VA More VA Health Health Care Information A-Z Health Topic Finder My Health ... General QUICK LIST Apply for Benefits Apply for Health Care Prescriptions My Health e Vet eBenefits Life Insurance ...

  10. Expression profiles of myostatin, myogenin, and Myosin heavy chain in skeletal muscles of two rabbit breeds differing in growth rate.

    Science.gov (United States)

    Kuang, Liangde; Xie, Xiaohong; Zhang, Xiangyu; Lei, Min; Li, Congyan; Ren, Yongjun; Zheng, Jie; Guo, Zhiqiang; Zhang, Cuixia; Yang, Chao; Zheng, Yucai

    2014-01-01

    The purpose of the present study was to compare mRNA levels of myostatin (MSTN), myogenin (MyoG), and fiber type compositions in terms of myosin heavy chain (MyHC) in skeletal muscles of two rabbit breeds with different body sizes and growth rates. Longissimus dorsi and biceps femoris muscles of 16 Californian rabbits (CW) and 16 Germany great line of ZIKA rabbits (GZ) were collected at the ages of 35d and 84d (slaughter age). The results showed that the live weights of GZ rabbits of 35d and 84d old were approximately 36% and 26% greater than those of CW rabbits, respectively. Quantitative real-time PCR analysis revealed that at the age of 84d GZ rabbits contained significantly lower MSTN mRNA level and higher MyoG mRNA level in both longissimus dorsi and biceps femoris muscles than CW rabbits, and mRNA levels of MSTN and MyoG exhibited opposite changes from the age of 35d to 84d, suggesting that GZ rabbits were subjected to less growth inhibition from MSTN at slaughter age, which occurred most possibly in skeletal muscles. Four types of fiber were identified by real-time PCR in rabbit muscles, with MyHC-1 and MyHC-2D, MyHC-2B were the major types in biceps femoris and longissimus dorsi muscles, respectively. At the age of 84d, GZ rabbits contained greater proportion of MyHC-1 and decreased proportion of MyHC-2D and decreased lactate dehydrogenase activity in biceps femoris than CW rabbits, and the results were exactly opposite in longissimus dorsi, suggesting that GZ rabbits show higher oxidative capacity in biceps femoris muscle than CW rabbits. In conclusion, the trends of mRNA levels of MSTN and fiber types in GZ rabbits' skeletal muscles might be consistent with the putative fast growth characteristic of GZ rabbits compared to CW rabbits.

  11. Responses of Myosin Heavy Chain Phenotypes and Gene Expressions in Neck Muscle to Micro- an Hyper-Gravity in Mice

    Science.gov (United States)

    Ohira, Tomotaka; Ohira, Takashi; Kawano, F.; Shibaguchi, T.; Okabe, H.; Ohno, Y.; Nakai, N.; Ochiai, T.; Goto, K.; Ohira, Y.

    2013-02-01

    Neck muscles are known to play important roles in the maintenance of head posture against gravity. However, it is not known how the properties of neck muscle are influenced by gravity. Therefore, the current study was performed to investigate the responses of neck muscle (rhomboideus capitis) in mice to inhibition of gravity and/or increase to 2-G for 3 months to test the hypothesis that the properties of neck muscles are regulated in response to the level of mechanical load applied by the gravitational load. Three male wild type C57BL/10J mice (8 weeks old) were launched by space shuttle Discovery (STS-128) and housed in Japanese Experimental Module “KIBO” on the International Space Station in mouse drawer system (MDS) project, which was organized by Italian Space Agency. Only 1 mouse returned to the Earth alive after 3 months by space shuttle Atlantis (STS-129). Neck muscles were sampled from both sides within 3 hours after landing. Cage and laboratory control experiments were also performed on the ground. Further, 3-month ground-based control experiments were performed with 6 groups, i.e. pre-experiment, 3-month hindlimb suspension, 2-G exposure by using animal centrifuge, and vivarium control (n=5 each group). Five mice were allowed to recover from hindlimb suspension (including 5 cage control) for 3 months in the cage. Neck muscles were sampled bilaterally before and after 3-month suspension and 2-G exposure, and at the end of 3-month ambulation recovery. Spaceflight-associated shift of myosin heavy chain phenotype from type I to II and atrophy of type I fibers were observed. In response to spaceflight, 17 genes were up-regulated and 13 genes were down-regulated vs. those in the laboratory control. Expression of 6 genes were up-regulated and that of 88 genes were down-regulated by 3-month exposure to 2-G vs. the age-matched cage control. In response to chronic hindlimb suspension, 4 and 20 genes were up- or down-regulated. Further, 98 genes responded

  12. Application of principal component analysis in the pollution assessment with heavy metals of vegetable food chain in the old mining areas.

    Science.gov (United States)

    Gergen, Iosif; Harmanescu, Monica

    2012-12-13

    The aim of the paper is to assess by the principal components analysis (PCA) the heavy metal contamination of soil and vegetables widely used as food for people who live in areas contaminated by heavy metals (HMs) due to long-lasting mining activities. This chemometric technique allowed us to select the best model for determining the risk of HMs on the food chain as well as on people's health. Many PCA models were computed with different variables: heavy metals contents and some agro-chemical parameters which characterize the soil samples from contaminated and uncontaminated areas, HMs contents of different types of vegetables grown and consumed in these areas, and the complex parameter target hazard quotients (THQ). Results were discussed in terms of principal component analysis. There were two major benefits in processing the data PCA: firstly, it helped in optimizing the number and type of data that are best in rendering the HMs contamination of the soil and vegetables. Secondly, it was valuable for selecting the vegetable species which present the highest/minimum risk of a negative impact on the food chain and human health.

  13. Application of principal component analysis in the pollution assessment with heavy metals of vegetable food chain in the old mining areas

    Directory of Open Access Journals (Sweden)

    Gergen Iosif

    2012-12-01

    Full Text Available Abstract Background The aim of the paper is to assess by the principal components analysis (PCA the heavy metal contamination of soil and vegetables widely used as food for people who live in areas contaminated by heavy metals (HMs due to long-lasting mining activities. This chemometric technique allowed us to select the best model for determining the risk of HMs on the food chain as well as on people's health. Results Many PCA models were computed with different variables: heavy metals contents and some agro-chemical parameters which characterize the soil samples from contaminated and uncontaminated areas, HMs contents of different types of vegetables grown and consumed in these areas, and the complex parameter target hazard quotients (THQ. Results were discussed in terms of principal component analysis. Conclusion There were two major benefits in processing the data PCA: firstly, it helped in optimizing the number and type of data that are best in rendering the HMs contamination of the soil and vegetables. Secondly, it was valuable for selecting the vegetable species which present the highest/minimum risk of a negative impact on the food chain and human health.

  14. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma.

    Science.gov (United States)

    Kleinfield, R; Hardy, R R; Tarlinton, D; Dangl, J; Herzenberg, L A; Weigert, M

    The early stages of murine B-cell differentiation are characterized by a series of immunoglobulin gene rearrangements which are required for the assembly of heavy(H) and light(L)-chain variable regions from germline gene segments. Rearrangement at the heavy-chain locus is initiated first and consists of the joining of a diversity (DH) gene segment to a joining (JH) gene segment. This forms a DJH intermediate to which a variable (VH) gene segment is subsequently added. Light-chain gene rearrangement follows and consists of the joining of a VL gene segment to a JL gene segment: once a productive light-chain gene has been formed the cell initiates synthesis of surface immunoglobulin M (sIgM) receptors (reviewed in ref. 1). These receptors are clonally distributed and may undergo further diversification either by somatic mutation or possibly by continued recombinational events. Such recombinational events have been detected in the Ly 1+ B-cell lymphoma NFS-5, which has been shown to rearrange both lambda and H-chain genes subsequent to the formation of sIgM (mu kappa) molecules. Here we have analysed a rearrangement of the productive allele of NFS-5 and found that it is due to a novel recombination event between VH genes which results in the replacement of most or all of the coding sequence of the initial VHQ52 rearrangement by a germline VH7183 gene. Embedded in the VH coding sequence close to the site of the cross-over is the sequence 5' TACTGTG 3', which is identical to the signal heptamer found 5' of many DH gene segments. This embedded heptamer is conserved in over 70% of known VH genes. We suggest that this heptamer mediates VH gene replacement and may play an important part in the development of the antibody repertoire.

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

    DEFF Research Database (Denmark)

    Wang, M; Harhaji, L; Lamberth, K

    2009-01-01

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

  16. Anion exchange chromatographic distribution of human monoclonal immunoglobulin G is determined by heavy chain subclass and level of sialic acid expression

    Directory of Open Access Journals (Sweden)

    Ilić Vesna

    2012-01-01

    Full Text Available Anion exchange chromatography is widely accepted method for purification of immunoglobulins. In this work, we used human monoclonal immunoglobulin G (IgG with structure and solubility of normal human IgG as a model for studying chromatographic behavior of particular molecular forms of IgG. Human sera with monoclonal IgG were fractionated on strong anion exchanger, Q Sepharose Fast Flow. With 20 mM Tris pH 7.5 as a start buffer, 42% of human monoclonal IgG passed through column, and 58% of them remained adsorbed. Bound monoclonal IgG were eluted from the exchanger by linear increasing of concentration of NaCl from 0 to 0.5 M. Chromatographic distribution of human monoclonal IgG correlated with their electrophoretic mobility in agarose gels, and it was dependent on γ heavy chain isotype. Light chain type, as well as serum concentration of monoclonal IgG did not influence their chromatographic behavior. The level of heavy chain sialic acid expression, but not of galactose and N-acetylglucosamine, significantly determined chromatographic distribution of serum monoclonal IgG. Additionally to the information on the chromatographic behavior of human monoclonal IgG, we believe that presented data could provide useful information about the possible use of Q Sepharose Fast Flow matrix for the isolation of specific molecular forms of human IgG.

  17. Mapping of the chicken immunoglobulin heavy-chain constant region gene locus reveals an inverted α gene upstream of a condensed υ gene

    Science.gov (United States)

    Zhao, Y; Rabbani, H; Shimizu, A; Hammarström, L

    2000-01-01

    Chicken antibodies are increasingly being used as diagnostic and therapeutic tools. As only the genomic organization of the µ encoding gene was previously known, we analysed the chicken immunoglobulin Y (IgY) and IgA (υ and α chain) immunoglobulin heavy-chain constant region (IGHC) genes and the organization of the chicken IGHC locus. The α gene is encoded by four separate exons, whereas, surprisingly, there is no intervening DNA sequence between the CH1 and CH2 domains of the IgY heavy chain, which is thus encoded by three exons separated by two introns. DNA sequence analysis shows that the exon boundaries of the chicken IGHC genes are not consistent with published domain borders. Furthermore, differences in DNA sequence confirm the existence of IgY, IgA and IgM allotypes in chickens. Finally, our results show that the IGHC genes of chicken (IgY, IgA and IgM) are all colocated on chromosome E18C15W15, where the α gene is located upstream of the υ gene in an inverted transcriptional orientation. The distances between the µ and α genes and the α and υ genes are about 18 and 15 kilobases, respectively, and thus, the size of the whole chicken IGHC locus is approximately 67 kilobases. PMID:11106938

  18. Myosin heavy chain-like localizes at cell contact sites during Drosophila myoblast fusion and interacts in vitro with Rolling pebbles 7

    Energy Technology Data Exchange (ETDEWEB)

    Bonn, Bettina R.; Rudolf, Anja; Hornbruch-Freitag, Christina; Daum, Gabor; Kuckwa, Jessica; Kastl, Lena; Buttgereit, Detlev [Developmental Biology, Department of Biology, Philipps-Universität Marburg, Karl-von-Frisch-Strasse 8, 35037 Marburg (Germany); Renkawitz-Pohl, Renate, E-mail: renkawit@biologie.uni-marburg.de [Developmental Biology, Department of Biology, Philipps-Universität Marburg, Karl-von-Frisch-Strasse 8, 35037 Marburg (Germany)

    2013-02-15

    Besides representing the sarcomeric thick filaments, myosins are involved in many cellular transport and motility processes. Myosin heavy chains are grouped into 18 classes. Here we show that in Drosophila, the unconventional group XVIII myosin heavy chain-like (Mhcl) is transcribed in the mesoderm of embryos, most prominently in founder cells (FCs). An ectopically expressed GFP-tagged Mhcl localizes in the growing muscle at cell–cell contacts towards the attached fusion competent myoblast (FCM). We further show that Mhcl interacts in vitro with the essential fusion protein Rolling pebbles 7 (Rols7), which is part of a protein complex established at cell contact sites (Fusion-restricted Myogenic-Adhesive Structure or FuRMAS). Here, branched F-actin is likely needed to widen the fusion pore and to integrate the myoblast into the growing muscle. We show that the localization of Mhcl is dependent on the presence of Rols7, and we postulate that Mhcl acts at the FuRMAS as an actin motor protein. We further show that Mhcl deficient embryos develop a wild-type musculature. We thus propose that Mhcl functions redundantly to other myosin heavy chains in myoblasts. Lastly, we found that the protein is detectable adjacent to the sarcomeric Z-discs, suggesting an additional function in mature muscles. - Highlights: ► The class XVIII myosin encoding gene Mhcl is transcribed in the mesoderm. ► Mhcl localization at contact sites of fusing myoblasts depends on Rols7. ► Mhcl interacts in vitro with Rols7 which is essential for myogenesis. ► Functional redundancy with other myosins is likely as mutants show no muscle defects. ► Mhcl localizes adjacent to Z-discs of sarcomeres and might support muscle integrity.

  19. Designing Optimal LNG Station Network for U.S. Heavy-Duty Freight Trucks using Temporally and Spatially Explicit Supply Chain Optimization

    Science.gov (United States)

    Lee, Allen

    The recent natural gas boom has opened much discussion about the potential of natural gas and specifically Liquefied Natural Gas (LNG) in the United States transportation sector. The switch from diesel to natural gas vehicles would reduce foreign dependence on oil, spur domestic economic growth, and potentially reduce greenhouse gas emissions. LNG provides the most potential for the medium to heavy-duty vehicle market partially due to unstable oil prices and stagnant natural gas prices. As long as the abundance of unconventional gas in the United States remains cheap, fuel switching to natural gas could provide significant cost savings for long haul freight industry. Amid a growing LNG station network and ever increasing demand for freight movement, LNG heavy-duty truck sales are less than anticipated and the industry as a whole is less economic than expected. In spite of much existing and mature natural gas infrastructure, the supply chain for LNG is different and requires explicit and careful planning. This thesis proposes research to explore the claim that the largest obstacle to widespread LNG market penetration is sub-optimal infrastructure planning. No other study we are aware of has explicitly explored the LNG transportation fuel supply chain for heavy-duty freight trucks. This thesis presents a novel methodology that links a network infrastructure optimization model (represents supply side) with a vehicle stock and economic payback model (represents demand side). The model characterizes both a temporal and spatial optimization model of future LNG transportation fuel supply chains in the United States. The principal research goal is to assess the economic feasibility of the current LNG transportation fuel industry and to determine an optimal pathway to achieve ubiquitous commercialization of LNG vehicles in the heavy-duty transport sector. The results indicate that LNG is not economic as a heavy-duty truck fuel until 2030 under current market conditions

  20. Heavy-chain isotype patterns of human antibody-secreting cells induced by Haemophilus influenzae type b conjugate vaccines in relation to age and preimmunity

    DEFF Research Database (Denmark)

    Barington, T; Juul, Lars; Gyhrs, A

    1994-01-01

    The influence of preexisting immunity on the heavy-chain isotypes of circulating antibody-secreting cells (AbSC) induced by vaccination with Haemophilus influenzae type b (Hib) capsular polysaccharide (HibCP) coupled to tetanus toxoid (TT) or diphtheria toxoid (DT) and by vaccination with TT or DT...... of natural HibCP antibodies (r = 0.59; P = 0.00002). A possible role of natural exposure for Hib or cross-reactive bacteria on the mucosal surfaces in the shaping of the isotype response to HibCP conjugate vaccines is discussed....

  1. Overexpression of core-binding factor alpha (CBF alpha) reverses cellular transformation by the CBF beta-smooth muscle myosin heavy chain chimeric oncoprotein.

    OpenAIRE

    Hajra, A; Liu, P P; Speck, N A; Collins, F S

    1995-01-01

    A fusion between the transcription factor core-binding factor beta (CBF beta; also known as PEBP2 beta) and the tail region of smooth muscle myosin heavy chain (SMMHC) is generated by an inversion of chromosome 16 [inv(16) (p13q22)] associated with the M4Eo subtype of acute myeloid leukemia. We have previously shown that this CBF beta-SMMHC chimeric protein can transform NIH 3T3 cells and that this process requires regions of the chimeric protein necessary for association with the CBF alpha s...

  2. Segmental duplication as one of the driving forces underlying the diversity of the human immunoglobulin heavy chain variable gene region

    Directory of Open Access Journals (Sweden)

    Gao Richeng

    2011-01-01

    Full Text Available Abstract Background Segmental duplication and deletion were implicated for a region containing the human immunoglobulin heavy chain variable (IGHV gene segments, 1.9III/hv3005 (possible allelic variants of IGHV3-30 and hv3019b9 (a possible allelic variant of IGHV3-33. However, very little is known about the ranges of the duplication and the polymorphic region. This is mainly because of the difficulty associated with distinguishing between allelic and paralogous sequences in the IGHV region containing extensive repetitive sequences. Inability to separate the two parental haploid genomes in the subjects is another serious barrier. To address these issues, unique DNA sequence tags evenly distributed within and flanking the duplicated region implicated by the previous studies were selected. The selected tags in single sperm from six unrelated healthy donors were amplified by multiplex PCR followed by microarray detection. In this way, individual haplotypes of different parental origins in the sperm donors could be analyzed separately and precisely. The identified polymorphic region was further analyzed at the nucleotide sequence level using sequences from the three human genomic sequence assemblies in the database. Results A large polymorphic region was identified using the selected sequence tags. Four of the 12 haplotypes were shown to contain consecutively undetectable tags spanning in a variable range. Detailed analysis of sequences from the genomic sequence assemblies revealed two large duplicate sequence blocks of 24,696 bp and 24,387 bp, respectively, and an incomplete copy of 961 bp in this region. It contains up to 13 IGHV gene segments depending on haplotypes. A polymorphic region was found to be located within the duplicated blocks. The variants of this polymorphism unusually diverged at the nucleotide sequence level and in IGHV gene segment number, composition and organization, indicating a limited selection pressure in general. However

  3. Non-muscle (NM) myosin heavy chain phosphorylation regulates the formation of NM myosin filaments, adhesome assembly and smooth muscle contraction.

    Science.gov (United States)

    Zhang, Wenwu; Gunst, Susan J

    2017-07-01

    Non-muscle (NM) and smooth muscle (SM) myosin II are both expressed in smooth muscle tissues, however the role of NM myosin in SM contraction is unknown. Contractile stimulation of tracheal smooth muscle tissues stimulates phosphorylation of the NM myosin heavy chain on Ser1943 and causes NM myosin filament assembly at the SM cell cortex. Expression of a non-phosphorylatable NM myosin mutant, NM myosin S1943A, in SM tissues inhibits ACh-induced NM myosin filament assembly and SM contraction, and also inhibits the assembly of membrane adhesome complexes during contractile stimulation. NM myosin regulatory light chain (RLC) phosphorylation but not SM myosin RLC phosphorylation is regulated by RhoA GTPase during ACh stimulation, and NM RLC phosphorylation is required for NM myosin filament assembly and SM contraction. NM myosin II plays a critical role in airway SM contraction that is independent and distinct from the function of SM myosin. The molecular function of non-muscle (NM) isoforms of myosin II in smooth muscle (SM) tissues and their possible role in contraction are largely unknown. We evaluated the function of NM myosin during contractile stimulation of canine tracheal SM tissues. Stimulation with ACh caused NM myosin filament assembly, as assessed by a Triton solubility assay and a proximity ligation assay aiming to measure interactions between NM myosin monomers. ACh stimulated the phosphorylation of NM myosin heavy chain on Ser1943 in tracheal SM tissues, which can regulate NM myosin IIA filament assembly in vitro. Expression of the non-phosphorylatable mutant NM myosin S1943A in SM tissues inhibited ACh-induced endogenous NM myosin Ser1943 phosphorylation, NM myosin filament formation, the assembly of membrane adhesome complexes and tension development. The NM myosin cross-bridge cycling inhibitor blebbistatin suppressed adhesome complex assembly and SM contraction without inhibiting NM myosin Ser1943 phosphorylation or NM myosin filament assembly. Rho

  4. An Improved Homologous Recombination Method for Rapid Cloning of the Antibody Heavy Chain Gene and Its Comparison with the Homologous Recombination and Traditional Cloning Methods

    Directory of Open Access Journals (Sweden)

    Masoumeh Hajirezaei

    2015-10-01

    Full Text Available Background: The homologous recombination (HR is one of the conventional cloning methods for the production of recombinant DNA. It is a quick method for in vivo DNA cloning without using the high cost restriction enzymes. A few modifications in the cloning procedure can increase the efficiency of this method.Materials and Methods: In this study, effect of heating on the rate of the IgG1 heavy chain gene cloning was investigated in the HR method and then it was compared with HR method without heating and traditional cloning method. For doing this comparison, three cloning methods including HR, HR with the heat treatment, and traditional cloning were used to clone the human IgG1 heavy chain into the pcDNA3.1(+ plasmid.Results: The results showed that adding heat in the HR method converts insert and vector from the double strand DNA to the single strand DNA. This allows them to copulate with each other better and faster than the two other methods. The heat addition also helps the cell enzyme system for a faster and easier recombination and moreover it increases the cloning efficiency of the HR method in case of in vitro processing.Conclusion: The results showed that giving heat in the HR method increases cloning rate 7.5% and this increase reaches 10% in comparison with the traditional method. 

  5. β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

    Science.gov (United States)

    Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian; Deenen, René; Seidman, J G; Seidman, Christine E; Lohse, Martin J; Schmitt, Joachim P

    2014-07-07

    Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations. © 2014 American Heart Association, Inc.

  6. Heavy metal concentrations in a soil-plant-snail food chain along a terrestrial soil pollution gradient.

    NARCIS (Netherlands)

    Notten, M.J.M.; Oosthoek, A.; Rozema, J.; Aerts, R.

    2005-01-01

    We investigated concentrations of Zn, Cu, Cd and Pb in the compartments of a soil-plant (Urtica dioica)-snail (Cepaea nemoralis) food chain in four polluted locations in the Biesbosch floodplains, the Netherlands, and two reference locations. Total soil metal concentrations in the polluted locations

  7. Hosn va Del: Sufist Reading of Khosro va Shirin

    Directory of Open Access Journals (Sweden)

    s jabri

    2013-02-01

    Full Text Available The existence of eight imitations and five translations of Hosn va Del into other languages such as English and German shows the importance of this Persian book of verse. Many researchers have sought the sources of this work and some sources have been mentioned, but the imitation of Sibak Neishaburi from Nezami’s Khosrow va Shirin, as the most important source of this work, has not yet been mentioned. Due to the innovative mixing of symbolic story, folk tale and love story which is done by changing the names of characters into abstract concepts resulting in creating two layers of primary and interpretive meaning in the text of Hosn va Del, the similarities between the two books have not yet been discovered. The fruit of such mixing is the creation of a sufist and interpretive reading of Khosrow va Shirin (named Hosn va Del which is a love story at the primary level and is very similar to Nezami’s Khosrow va Shirin. At the interpretive level, it is a mystical book of verse which narrates the story of the Progression and reaching Knowledge and Immortality. This article tries to study the similarities between the two stories through comparing the texts of these two books and using the method of textual criticism. The results show that the love between lover and beloved is common between the two books. The structure and organization of the two books are very similar and there are very causes and motivations in the plot of the two stories. Also, more than half of the characters of the two stories are of common characteristics. There are similar events as well as places in the two stories. Also, many similarities can be seen in the content of dialogues. The results of this study show that Khosrow va Shirin is the main source of Hosn va Del and Sibak Neishaburi is among the imitators of Nezami in composing love story.

  8. Efficient heterologous expression and secretion in Aspergillus oryzae of a llama variable heavy-chain antibody fragment V(HH) against EGFR.

    Science.gov (United States)

    Okazaki, Fumiyoshi; Aoki, Jun-ichi; Tabuchi, Soichiro; Tanaka, Tsutomu; Ogino, Chiaki; Kondo, Akihiko

    2012-10-01

    We have constructed a filamentous fungus Aspergillus oryzae that secretes a llama variable heavy-chain antibody fragment (V(HH)) that binds specifically to epidermal growth factor receptor (EGFR) in a culture medium. A major improvement in yield was achieved by fusing the V(HH) with a Taka-amylase A signal sequence (sTAA) and a segment of 28 amino acids from the N-terminal region of Rhizopus oryzae lipase (N28). The yields of secreted, immunologically active anti-EGFR V(HH) reached 73.8 mg/1 in a Sakaguchi flask. The V(HH) fragments were released from the sTAA or N28 proteins by an indigenous A. oryzae protease during cultivation. The purified recombinant V(HH) fragment was specifically recognized and could bind to the EGFR with a high affinity.

  9. Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).

    Science.gov (United States)

    Meredith, Christopher; Herrmann, Ralf; Parry, Cheryl; Liyanage, Khema; Dye, Danielle E; Durling, Hayley J; Duff, Rachael M; Beckman, Kaye; de Visser, Marianne; van der Graaff, Maaike M; Hedera, Peter; Fink, John K; Petty, Elizabeth M; Lamont, Phillipa; Fabian, Vicki; Bridges, Leslie; Voit, Thomas; Mastaglia, Frank L; Laing, Nigel G

    2004-10-01

    We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.

  10. Differential effects of docoosahexaenoic and arachidonic acid on fatty acid composition and myosin heavy chain-related genes of slow- and fast-twitch skeletal muscle tissues.

    Science.gov (United States)

    Hashimoto, Michio; Inoue, Takayuki; Katakura, Masanori; Hossain, Shahdat; Mamun, Abdullah Al; Matsuzaki, Kentaro; Arai, Hiroyuki; Shido, Osamu

    2016-04-01

    Myosin heavy chain (MHC) mediates the metabolic and contractile responses of skeletal muscles. MHC displays different isoforms, each of which has different characteristics. To better understand the effect of polyunsaturated fatty acids in skeletal muscles, rats were fed with control-, docosahexaenoic acid (DHA)-, and arachidonic acid (ARA)-oil, and the effects on plasma and muscular fatty acid profile, oxidative stress, mRNA levels of myosin heavy chain isoforms MHC1 of slow-twitch muscle (SO) and MHC2A, MHC2X, and MHCB isoforms of extensor digitorum longus (EDL) of fast-twitch muscle were evaluated. Concomitantly, mRNA levels of anti-oxidative enzymes, such as, catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD were determined. The expressions of MHC1, MHC2A, MHC2X, and MHC2B were lower in the SO of the DHA-fed rats. In the EDL muscles of DHA-fed rats, the expressions of MHC1 and MHC2A increased; however, the expressions of MHC2X increased and that of the MHC2 were not altered. Oxidative stress, as indicated by the levels of LPO, was significantly higher in the plasma of the ARA-fed rats, when compared with that of the DHA-fed rats. The LPO levels were higher both in the SO and EDL muscles of ARA-fed rats. Compared with ARA oil intake, DHA oil showed higher mRNA levels of GPx and SOD. Catalase expression was higher only in the EDL but not in the SO-type muscles. Our studies finally indicate that DHA and ARA differentially affect the regulation of contractile and metabolic properties of slow- and fast-twitch skeletal muscles.

  11. Inventory of heavy metal content in organic waste applied as fertilizer in agriculture: evaluating the risk of transfer into the food chain.

    Science.gov (United States)

    Lopes, Carla; Herva, Marta; Franco-Uría, Amaya; Roca, Enrique

    2011-07-01

    In this work, an environmental risk assessment of reusing organic waste of differing origins and raw materials as agricultural fertilizers was carried out. An inventory of the heavy metal content in different organic wastes (i.e., compost, sludge, or manure) from more than 80 studies at different locations worldwide is presented. The risk analysis was developed by considering the heavy metal (primarily Cd, Cu, Ni, Pb, and Zn) concentrations in different organic residues to assess their potential environmental accumulation and biotransfer to the food chain and humans. A multi-compartment model was used to estimate the fate and distribution of metals in different environmental compartments, and a multi-pathway model was used to predict human exposure. The obtained hazard index for each waste was concerning in many cases, especially in the sludge samples that yielded an average value of 0.64. Among the metals, Zn was the main contributor to total risk in all organic wastes due to its high concentration in the residues and high biotransfer potential. Other more toxic metals, like Cd or Pb, represented a negligible contribution. These results suggest that the Zn content in organic waste should be reduced or more heavily regulated to guarantee the safe management and reuse of waste residues according to the current policies promoted by the European Union.

  12. The Geometric-VaR Backtesting Method

    DEFF Research Database (Denmark)

    Wei, Wei; Pelletier, Denis

    2014-01-01

    This paper develops a new test to evaluate Value af Risk (VaR) forecasts. VaR is a standard risk measure widely utilized by financial institutions and regulators, yet estimating VaR is a challenging problem, and popular VaR forecast relies on unrealistic assumptions. Hence, assessing the performa......This paper develops a new test to evaluate Value af Risk (VaR) forecasts. VaR is a standard risk measure widely utilized by financial institutions and regulators, yet estimating VaR is a challenging problem, and popular VaR forecast relies on unrealistic assumptions. Hence, assessing...

  13. VA National Bed Control System

    Data.gov (United States)

    Department of Veterans Affairs — The VA National Bed Control System records the levels of operating, unavailable and authorized beds at each VAMC, and it tracks requests for changes in these levels....

  14. Urine of patients with early prostate cancer contains lower levels of light chain fragments of inter-alpha-trypsin inhibitor and saposin B but increased expression of an inter-alpha-trypsin inhibitor heavy chain 4 fragment.

    Science.gov (United States)

    Jayapalan, Jaime J; Ng, Keng L; Shuib, Adawiyah S; Razack, Azad H A; Hashim, Onn H

    2013-06-01

    The present study was aimed at the identification of proteins that are differentially expressed in the urine of patients with prostate cancer (PCa), those with benign prostatic hyperplasia (BPH) and age-matched healthy male control subjects. Using a combination of 2DE and MS/MS, significantly lower expression of urinary saposin B and two different fragments of inter-alpha-trypsin inhibitor light chain (ITIL) was demonstrated in the PCa patients compared to the controls. However, only one of the ITIL fragments was significantly different between the PCa and BPH patients. When image analysis was performed on urinary proteins that were transferred onto NC membranes and detected using a lectin that binds to O-glycans, a truncated fragment of inter-alpha-trypsin inhibitor heavy chain 4 was the sole protein found to be significantly enhanced in the PCa patients compared to the controls. Together, these urinary peptide fragments might be useful complementary biomarkers to indicate PCa as well as to distinguish it from BPH, although further epidemiological evidence on the specificity and sensitivity of the protein candidates is required. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Another Phoenix VA director leaves

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2016-08-01

    Full Text Available No abstract available. Article truncated after 150 words. The Arizona Republic reports that the director at the Phoenix VA Medical Center, Deborah Amdur, will retire after only 9 months for health reasons (1. Amdur will be replaced by Barbara Fallen, director of the VA Loma Linda Healthcare System. Fallen will be interim director until a permanent replacement for Amdur can be found. This is the fifth hospital director since former Director Sharon Helman was removed in mid-2014 amid the nationwide veterans health-care scandal that was first exposed at the Phoenix VA. The Veterans Integrated Service Network (VISN in Gilbert, which oversees the VA Medical Center in Arizona, New Mexico and West Texas has also been through a series of 4 directors since Susan Bowers retired under pressure in the wake of the VA scandal. Marie Weldon, current acting regional director, also oversees the Los Angeles-based VA Desert Pacific Healthcare System. Weldon described Fallen as “an experienced leader who ...

  16. Identification of an altered immunoglobulin heavy-chain gene rearrangement in the central nervous system in B-precursor acute lymphoblastic leukemia.

    Science.gov (United States)

    Wasserman, R; Felix, C A; McKenzie, S E; Shane, S; Lange, B; Finger, L R

    1993-08-01

    In B-precursor acute lymphoblastic leukemia (ALL), the nucleotide sequence of the complementarity determining region III (CDRIII) in the rearranged immunoglobulin heavy chain gene (IgH) has been used as a molecular fingerprint to identify the leukemic cells. In a child with B-precursor ALL without central nervous system (CNS) disease at diagnosis and a subsequent isolated CNS relapse, we examined the stability of the rearranged IgH by comparing the nucleotide sequences of the CDRIII in the leukemic cells from the marrow at diagnosis to the sequences in the leukemic cells from the cerebrospinal fluid at relapse. Whereas two of the three IgH sequences isolated from the leukemic cells at CNS relapse were identical to sequences originally isolated from the marrow lymphoblasts at diagnosis, the third CNS sequence was similar but not identical to the third marrow sequence. The third IgH sequence identified in the CNS differed from the marrow sequence only at the variable gene segment adjoining the CDRIII. Using a detection method based on the polymerase chain reaction, the altered IgH sequence identified in the leukemic cells from the cerebrospinal fluid was noted to be present in the CNS at a higher frequency than the related diagnostic sequence and was not detected in the marrow either at diagnosis or at CNS relapse. These findings indicate that the clonal pattern of leukemia in the CNS may differ from that in the marrow.

  17. Heavy metals in the habitat and throughout the food chain of the Neotropical otter, Lontra longicaudis, in protected Mexican wetlands.

    Science.gov (United States)

    Ramos-Rosas, Nadia N; Valdespino, Carolina; García-Hernández, Jaqueline; Gallo-Reynoso, Juan P; Olguín, Eugenia J

    2013-02-01

    Top predators like the Neotropical otter, Lontra longicaudis annectens, are usually considered good bioindicators of habitat quality. In this study, we evaluated heavy metal contamination (Hg(tot), Pb, Cd) in the riverine habitat, prey (crustaceans and fish), and otter feces in two Ramsar wetlands with contrasting upstream contamination discharges: Río Blanco and Río Caño Grande in Veracruz, Mexico, during the dry, the wet, and the nortes seasons. Most comparisons revealed no differences between sites while seasonal differences were repeatedly detected for all of the compartments. Higher concentrations of Pb during the dry season and of Cd during the wet season in otter feces mirrored differences detected in the most seasonally consumed prey. Compared with fecal methylmercury values reported for the European otter (0.25-0.75 mg kg(-1)) in unprotected areas, the Hg(tot) levels that we measured were lower (0.02-0.17 mg kg(-1)). However, Pb (117.87 mg kg(-1)) and Cd (9.14 mg kg(-1)) concentrations were higher (Pb, 38.15 mg kg(-1) and Cd, 4.72 mg kg(-1)) in the two Ramsar wetlands. Protected areas may shelter species, but those with water-linked diets may suffer the effect of chemicals used upstream.

  18. Spatial distribution of "tissue-specific" antigens in the developing human heart and skeletal muscle. II. An immunohistochemical analysis of myosin heavy chain isoform expression patterns in the embryonic heart

    NARCIS (Netherlands)

    Wessels, A.; Vermeulen, J. L.; Virágh, S.; Kálmán, F.; Lamers, W. H.; Moorman, A. F.

    1991-01-01

    The spatial distribution of alpha- and beta-myosin heavy chain isoforms (MHCs) was investigated immunohistochemically in the embryonic human heart between the 4th and the 8th week of development. The development of the overall MHC isoform expression pattern can be outlined as follows: (1) In all

  19. Heavy metal concentrations in a soil-plant-snail food chain along a terrestrial soil pollution gradient

    Energy Technology Data Exchange (ETDEWEB)

    Notten, M.J.M. [Institute of Ecological Science, Department of Systems Ecology, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam (Netherlands)]. E-mail: martje.notten@ecology.falw.vu.nl; Oosthoek, A.J.P. [Institute of Ecological Science, Department of Systems Ecology, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam (Netherlands); Rozema, J. [Institute of Ecological Science, Department of Systems Ecology, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam (Netherlands); Aerts, R. [Institute of Ecological Science, Department of Systems Ecology, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam (Netherlands)

    2005-11-15

    We investigated concentrations of Zn, Cu, Cd and Pb in the compartments of a soil-plant (Urtica dioica)-snail (Cepaea nemoralis) food chain in four polluted locations in the Biesbosch floodplains, the Netherlands, and two reference locations. Total soil metal concentrations in the polluted locations were 4-20 times higher than those in the reference locations. Positive relationships between the generally low leaf concentrations and the soil concentrations were found for Zn only (r {sup 2} = 0.20). Bioaccumulation of Zn, Cu and Cd was observed in the snail tissues. We found positive relationships between the snail and leaf concentrations for all metals (range r {sup 2} = 0.19-0.46). The relationships between soil and snail concentrations were also positive, except for Cu (range r {sup 2} = 0.15-0.33). These results suggest transfer of metals to C. nemoralis snails from U. dioica leaves and from the soil. Metal transfer from polluted leaves to C. nemoralis is more important than transfer from the soil. - Bioaccumulation and positive snail-leaf relationships suggest metal transfer from Urtica dioica leaves to Cepaea nemoralis snails.

  20. IgAT (Immunoglobulin Analysis Tool: A novel tool for the analysis of human and mouse heavy and light chain transcripts

    Directory of Open Access Journals (Sweden)

    Tobias eRogosch

    2012-06-01

    Full Text Available Sequence analysis of immunoglobulin (Ig heavy and light chain transcripts can refine categorization of B cell subpopulations and can shed light on the selective forces that act during immune responses or immune dysregulation, such as autoimmunity, allergy, and B cell malignancy. High-throughput sequencing yields Ig transcript collections of unprecedented size. The authoritative web-based IMGT/HighV-QUEST program is capable of analyzing large collections of transcripts and provides annotated output files to describe many key properties of Ig transcripts. However, additional processing of these flat files is required to create figures, or to facilitate analysis of additional features and comparisons between sequence sets. We present an easy-to-use Microsoft® Excel® based software, named Immunoglobulin Analysis Tool (IgAT, for the summary, interrogation, and further processing of IMGT/HighV-QUEST output files. IgAT generates descriptive statistics and high-quality figures for collections of murine or human Ig heavy or light chain transcripts ranging from 1 to 150,000 sequences. In addition to traditionally studied properties of Ig transcripts—such as the usage of germline gene segments, or the length and composition of the CDR-3 region—IgAT also uses published algorithms to calculate the probability of antigen selection based on somatic mutational patterns, the average hydrophobicity of the antigen-binding sites, and predictable structural properties of the CDR-H3 loop according to Shirai’s H3-rules. These refined analyses provide in-depth information about the selective forces acting upon Ig repertoires and allow the statistical and graphical comparison of two or more sequence sets. IgAT is easy to use on any computer running Excel® 2003 or higher. Thus, IgAT is a useful tool to gain insights into the selective forces and functional properties of small to extremely large collections of Ig transcripts, thereby assisting a researcher to

  1. Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody

    Science.gov (United States)

    Rouzière, Anne-Sophie; Kneitz, Christian; Palanichamy, Arumugam; Dörner, Thomas; Tony, Hans-Peter

    2005-01-01

    B-cell depletive therapies have beneficial effects in patients suffering from rheumatoid arthritis. Nevertheless, the role of B cells in the pathogenesis of the disease is not clear. In particular, it is not known how the regeneration of the B-cell repertoire takes place. Two patients with active rheumatoid arthritis were treated with rituximab, and the rearranged immunoglobulin heavy-chain genes (Ig-VH) were analysed to follow the B-cell regeneration. Patient A was treated with two courses of rituximab, and B-cell regeneration was followed over 27 months by analysing more than 680 Ig-VH sequences. Peripheral B-cell depletion lasted 7 months and 10 months, respectively, and each time was accompanied by a clinical improvement. Patient B received one treatment course. B-cell depletion lasted 5 months and was accompanied by a good clinical response. B cells regenerated well in both patients, and the repopulated B-cell repertoire was characterised by a polyclonal and diverse use of Ig-VH genes, as expected in adult individuals. During the early phase of B-cell regeneration we observed the expansion and recirculation of a highly mutated B-cell population. These cells expressed very different Ig-VH genes. They were class-switched and could be detected for a short period only. Patient A was followed long term, whereby some characteristic changes in the VH2 family as well as in specific mini-genes like VH3–23, VH 4–34 or VH 1–69 were observed. In addition, rituximab therapy resulted in the loss of clonal B cells for the whole period. Our data show that therapeutic transient B-cell depletion by anti-CD20 antibodies results in the regeneration of a diverse and polyclonal heavy-chain repertoire. During the early phase of B-cell regeneration, highly mutated B cells recirculate for a short time period in both the patients analysed. The longitudinal observation of a single patient up to 27 months shows subtle intraindividual changes, which may indicate repertoire

  2. Calcineurin-NFAT Signaling and Neurotrophins Control Transformation of Myosin Heavy Chain Isoforms in Rat Soleus Muscle in Response to Aerobic Treadmill Training

    Directory of Open Access Journals (Sweden)

    Wenfeng Liu, Gan Chen, Fanling Li, Changfa Tang

    2014-12-01

    Full Text Available This study elucidated the role of CaN-NFAT signaling and neurotrophins on the transformation of myosin heavy chain isoforms in the rat soleus muscle fiber following aerobic exercise training. To do so, we examined the content and distribution of myosin heavy chain (MyHC isoforms in the rat soleus muscle fiber, the activity of CaN and expression of NFATc1 in these fibers, and changes in the expression of nerve growth factor (NGF, brain-derived neurotrophic factor (BDNF and neutrophin-3 (NT-3 in the soleus and striatum following high-and medium-intensity aerobic treadmill training. Specific pathogen-free 2 month old male Sprague-Dawley (SD rats were randomly divided into three groups: Control group (Con, n = 8, moderate-intensity aerobic exercise group (M-Ex, n = 8 and high-intensity aerobic exercise group (H-Ex, n = 8. We used ATPase staining to identify the muscle fiber type I and II, SDS-PAGE to separate and analyze the isoforms MyHCI, MyHCIIA, MyHCIIB and MyHCIIx, and performed western blots to determine the expression of NFATc1, NGF, BDNF and NT-3. CaN activity was measured using a colorimetric assay. In the soleus muscle, 8 weeks of moderate-intensity exercise can induce transformation of MyHC IIA and MyHC IIB to MyHC IIX and MyHC I (p < 0.01, while high-intensity treadmill exercise can induce transform MyHC IIx to MyHC IIB, MyHC IIA and MyHC I (p < 0.01. In comparison to the control group, CaN activity and NFATcl protein level were significantly increased in both the M-Ex and H-Ex groups (p < 0.05, p < 0.01, with a more pronounced upregulation in the M-Ex group (p < 0.05. Eight weeks of moderate- and high-intensity aerobic exercise induced the expression of NGF, BDNF and NT-3 in the soleus muscle and the striatum (p < 0.01, with the most significant increase in the H-Ex group (p < 0.01. In the rat soleus muscle, (1 CaN–NFATcl signaling contributes to the conversion of MyHC I isoform in response to moderate-intensity exercise; (2

  3. 75 FR 24510 - Drug and Drug-Related Supply Promotion by Pharmaceutical Company Sales Representatives at VA...

    Science.gov (United States)

    2010-05-05

    ... ethical conduct. Pharmaceutical sales representatives have heavy interaction with local VA staff each year... de minimis value set forth in the standards of ethical conduct for Federal employees, and would.... Currently, Sec. 1.218, regarding security and law enforcement at VA facilities, describes general behavior...

  4. Prognostic Impact of Serum Heavy/Light Chain Pairs in Patients With Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma: Long-Term Results From a Single Institution.

    Science.gov (United States)

    Magnano, Laura; Fernández de Larrea, Carlos; Elena, Montserrat; Cibeira, María Teresa; Tovar, Natalia; Aróstegui, Juan I; Pedrosa, Fabiola; Rosiñol, Laura; Filella, Xavier; Yagüe, Jordi; Bladé, Joan

    2016-06-01

    Asymptomatic monoclonal gammopathies, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), are clinical conditions that usually precede symptomatic multiple myeloma. Therefore, risk stratification is crucial owing to the heterogeneous progression rate among these patients. In previous years, suppression of the uninvolved chain of specific heavy/light chain (HLC) pairs in serum has been identified as a new risk factor in MGUS. The aim of the present study was to investigate the prognostic effect of involved and uninvolved HLC pairs and HLC ratios on progression in a series of patients with MGUS and SMM. All specific serum HLC pairs were measured in 114 patients diagnosed with SMM (n = 27) and MGUS (n = 87) from 1983 to 2003. Also, the HLC ratios were calculated. Progression to symptomatic multiple myeloma was observed in 13 patients (8 with SMM and 5 with MGUS). The risk of progression was 6 times greater in those with SMM (P = .001) and 4 times greater for those with the IgA isotype (P = .01). The suppression of any IgM isotypes (IgMκ or IgMλ) in patients with IgA or IgG gammopathy or any IgA isotypes (IgAκ or IgAλ) in patients with IgG or IgM gammopathy was associated with a shorter time to progression to symptomatic gammopathy (P = .001 and P = .03, respectively). On multivariate analysis, the evolving pattern and suppression of any IgM HLC pair remained significant. HLC ratios could be a valuable tool in the risk stratification of patients with SMM and MGUS, especially patients with IgG isotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. VA administrators breahe a sigh of relief

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-06-01

    Full Text Available No abstract available. Article truncated at 150 words. On May 30, Eric Shinseki, the Secretary for Veterans Affairs (VA, resigned under pressure amidst a growing scandal regarding falsification of patient wait times at nearly 40 VA medical centers. Before leaving office Shinseki fired Sharon Helman, the former hospital director at the Phoenix VA, where the story first broke, along with her deputy and another unnamed administrator. In addition, Susan Bowers, director of VA Veterans Integrated Service Network (VISN 18 and Helman’s boss, resigned. Robert Petzel, undersecretary for the Veterans Health Administration (VHA, head of the VA hospitals and clinics, had resigned earlier. You could hear the sigh of relief from the VA administrators. With their bosses resigning left and right, the VA leadership in shambles and the reputation of the VA soiled for many years to come, why are the VA administrators relieved? The simple answer is that nothing has really changed. There for a moment it looked ...

  6. Molecular cloning and mRNA expression analysis of myosin heavy chain (MyHC) from fast skeletal muscle of grass carp, Ctenopharyngodon idella

    Science.gov (United States)

    Chu, Wuying; Fu, Guihong; Bing, Shiyu; Meng, Tao; Zhou, Ruixue; Cheng, Jia; Zhao, Falan; Zhang, Hongfang; Zhang, Jianshe

    2010-03-01

    The myosin heavy chain (MyHC) is one of the major structural and contracting proteins of muscle. We have isolated the cDNA clone encoding MyHC of the grass carp, Ctenopharyngodon idella. The sequence comprises 5 934 bp, including a 5 814 bp open reading frame encoding an amino acid sequence of 1 937 residues. The deduced amino acid sequence showed 69% homology to rabbit fast skeletal MyHC and 73%-76% homology to the MyHCs from the mandarin fish, walleye pollack, white croaker, chum salmon, and carp. The putative sequences of subfragment-1 and the light meromyosin region showed 61.4%-80% homology to the corresponding regions of other fish MyHCs. The tissue-specific and developmental stage-specific expressions of the MyHC gene were analyzed by quantitative real-time PCR. The MyHC gene showed the highest expression in the muscles compared with the kidney, spleen and intestine. Developmentally, there was a gradual increase in MyHC mRNA expression from the neural formation stage to the tail bud stage. The highest expression was detected in hatching larva. Our work on the MyHC gene from the grass carp has provided useful information for fish molecular biology and fish genomics.

  7. Muscle precursor cells in the developing limbs of two isopods (Crustacea, Peracarida): an immunohistochemical study using a novel monoclonal antibody against myosin heavy chain

    Science.gov (United States)

    Kreissl, S.; Uber, A.

    2008-01-01

    In the hot debate on arthropod relationships, Crustaceans and the morphology of their appendages play a pivotal role. To gain new insights into how arthropod appendages evolved, developmental biologists recently have begun to examine the expression and function of Drosophila appendage genes in Crustaceans. However, cellular aspects of Crustacean limb development such as myogenesis are poorly understood in Crustaceans so that the interpretative context in which to analyse gene functions is still fragmentary. The goal of the present project was to analyse muscle development in Crustacean appendages, and to that end, monoclonal antibodies against arthropod muscle proteins were generated. One of these antibodies recognises certain isoforms of myosin heavy chain and strongly binds to muscle precursor cells in malacostracan Crustacea. We used this antibody to study myogenesis in two isopods, Porcellio scaber and Idotea balthica (Crustacea, Malacostraca, Peracarida), by immunohistochemistry. In these animals, muscles in the limbs originate from single muscle precursor cells, which subsequently grow to form multinucleated muscle precursors. The pattern of primordial muscles in the thoracic limbs was mapped, and results compared to muscle development in other Crustaceans and in insects. Electronic supplementary material The online version of this article (doi:10.1007/s00427-008-0216-1) contains supplementary material, which is available to authorized users. PMID:18443823

  8. Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype

    Energy Technology Data Exchange (ETDEWEB)

    Demaison, C.; Chastagner, P.; Theze, J.; Zouali, M. (Institut Pasteur, Paris (France))

    1994-01-18

    Monoclonal anti-DNA antibodies bearing a lupus nephritis-associated idiotype were derived from five patients with systemic lupus erythematosus (SLE). Genes encoding their heavy (H)-chain variable (V[sub H]) regions were cloned and sequenced. When compared with their closest V[sub h] germ-line gene relatives, these sequences exhibit a number of silent (S) and replacement (R) substitutions. The ratios of R/S mutations were much higher in the complementarity-determining regions (CDRs) of the antibodies than in the framework regions. Molecular amplification of genomic V[sub H] genes and Southern hybridization with somatic CDR2-specific oligonucleotide probes showed that the configuration of the V[sub H] genes corresponding to V[sub H] sequences in the nephritogenic antibodies is not present in the patient's own germ-line DNA, implying that the B-cell clones underwent somatic mutation in vivo. These findings, together with the characteristics of the diversity and junctional gene elements utilized to form the antibody, indicate that these autoantibodies have been driven through somatic selection processes reminiscent of those that govern antibody responses triggered by exogenous stimuli.

  9. Evaluation of heavy chain C-terminal deletions on productivity and product quality of monoclonal antibodies in Chinese hamster ovary (CHO) cells.

    Science.gov (United States)

    Hu, Zhilan; Tang, Danming; Misaghi, Shahram; Jiang, Guoying; Yu, Christopher; Yim, Mandy; Shaw, David; Snedecor, Brad; Laird, Michael W; Shen, Amy

    2017-05-01

    Monoclonal antibodies (mAbs) have been well established as potent therapeutic agents and are used to treat many different diseases. During cell culture production, antibody charge variants can be generated by cleavage of heavy chain (HC) C-terminal lysine and proline amidation. Differences in levels of charge variants during manufacturing process changes make it challenging to demonstrate process comparability. In order to reduce heterogeneity and achieve consistent product quality, we generated and expressed antibodies with deletion of either HC C-terminal lysine (-K) or lysine and glycine (-GK). Interestingly, clones that express antibodies lacking HC C-terminal lysine (-K) had considerably lower specific productivities compared to clones that expressed either wild type antibodies (WT) or antibodies lacking HC glycine and lysine (-GK). While no measurable differences in antibody HC and LC mRNA levels, glycosylation and secretion were observed, our analysis suggests that the lower specific productivity of clones expressing antibody lacking HC C-terminal lysine was due to slower antibody HC synthesis and faster antibody degradation. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:786-794, 2017. © 2017 American Institute of Chemical Engineers.

  10. In vivo regulation of the beta-myosin heavy chain gene in soleus muscle of suspended and weight-bearing rats

    Science.gov (United States)

    Giger, J. M.; Haddad, F.; Qin, A. X.; Baldwin, K. M.

    2000-01-01

    In the weight-bearing hindlimb soleus muscle of the rat, approximately 90% of muscle fibers express the beta-myosin heavy chain (beta-MHC) isoform protein. Hindlimb suspension (HS) causes the MHC isoform population to shift from beta toward the fast MHC isoforms. Our aim was to establish a model to test the hypothesis that this shift in expression is transcriptionally regulated through specific cis elements of the beta-MHC promoter. With the use of a direct gene transfer approach, we determined the activity of different length beta-MHC promoter fragments, linked to a firefly luciferase reporter gene, in soleus muscle of control and HS rats. In weight-bearing rats, the relative luciferase activity of the longest beta-promoter fragment (-3500 bp) was threefold higher than the shorter promoter constructs, which suggests that an enhancer sequence is present in the upstream promoter region. After 1 wk of HS, the reporter activities of the -3500-, -914-, and -408-bp promoter constructs were significantly reduced ( approximately 40%), compared with the control muscles. However, using the -215-bp construct, no differences in promoter activity were observed between HS and control muscles, which indicates that the response to HS in the rodent appears to be regulated within the -408 and -215 bp of the promoter.

  11. Amphipathic variable region heavy chain peptides derived from monoclonal human Wegener's anti-PR3 antibodies stimulate lymphocytes from patients with Wegener's granulomatosis and microscopic polyangiitis

    Science.gov (United States)

    Peen, E; Malone, C; Myers, C; Williams, R C; Peck, A B; Csernok, E; Gross, W L; Staud, R

    2001-01-01

    Amphipathic variable-region heavy chain 11-mer peptides from monoclonal human IgM antiproteinase-3 antibodies were studied for peripheral blood lymphocyte stimulation in 21 patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), connective tissue disease controls and normal control subjects. Positive T-cell activation was observed in most experiments with WG patients' lymphocytes using amphipathic VH-region peptides from four different human monoclonal anti-PR3 antibodies. Control peptides of the same length but without amphipathic characteristics along with other amphipathic peptides not derived from monoclonal anti-PR3 sequence were employed as controls. No significant lymphocyte stimulation was observed with normal controls, but positive stimulation with amphipathic VH peptides was also recorded in other connective tissue disease controls mainly patients with rheumatoid arthritis. Amphipathic peptides not derived from anti-PR3 sequence did not stimulate WG lymphocytes. Our findings indicate that lymphocyte reactivity as an element of cell-mediated immunity may be activated by amphipathic VH-region amino acid sequences of autoantibodies which are themselves associated with diseases such as WG. PMID:11529926

  12. VH Replacement Footprint Analyzer-I, a Java-Based Computer Program for Analyses of Immunoglobulin Heavy Chain Genes and Potential VH Replacement Products in Human and Mouse.

    Science.gov (United States)

    Huang, Lin; Lange, Miles D; Zhang, Zhixin

    2014-01-01

    VH replacement occurs through RAG-mediated secondary recombination between a rearranged VH gene and an upstream unrearranged VH gene. Due to the location of the cryptic recombination signal sequence (cRSS, TACTGTG) at the 3' end of VH gene coding region, a short stretch of nucleotides from the previous rearranged VH gene can be retained in the newly formed VH-DH junction as a "footprint" of VH replacement. Such footprints can be used as markers to identify Ig heavy chain (IgH) genes potentially generated through VH replacement. To explore the contribution of VH replacement products to the antibody repertoire, we developed a Java-based computer program, VH replacement footprint analyzer-I (VHRFA-I), to analyze published or newly obtained IgH genes from human or mouse. The VHRFA-1 program has multiple functional modules: it first uses service provided by the IMGT/V-QUEST program to assign potential VH, DH, and JH germline genes; then, it searches for VH replacement footprint motifs within the VH-DH junction (N1) regions of IgH gene sequences to identify potential VH replacement products; it can also analyze the frequencies of VH replacement products in correlation with publications, keywords, or VH, DH, and JH gene usages, and mutation status; it can further analyze the amino acid usages encoded by the identified VH replacement footprints. In summary, this program provides a useful computation tool for exploring the biological significance of VH replacement products in human and mouse.

  13. Unexpectedly Low Mutation Rates in Beta-Myosin Heavy Chain and Cardiac Myosin Binding Protein Genes in Italian Patients With Hypertrophic Cardiomyopathy

    Science.gov (United States)

    Roncarati, Roberta; Latronico, Michael VG; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

    2011-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. J. Cell. Physiol. 226: 2894–2900, 2011. © 2011 Wiley-Liss, Inc. PMID:21302287

  14. Worse prognosis with gene mutations of beta-myosin heavy chain than myosin-binding protein C in Chinese patients with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Wang, Shuxia; Zou, Yubao; Fu, Chunyan; Xu, Xiqi; Wang, Jizheng; Song, Lei; Wang, Hu; Chen, Jingzhou; Wang, Jianwei; Huan, Tujun; Hui, Rutai

    2008-03-01

    No data are available on survival analysis and longitudinal evolution of patients with gene mutations of beta-myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3) in Chinese. To prospectively investigate whether different gene mutations confer distinct prognosis. We performed a prospective study in 70 HCM patients and 46 genetically affected family members without HCM-phenotype with direct DNA sequencing of MYH7 and MYBPC3, clinical assessments, and 5.8 +/- 1.8 years follow-up. After follow-up, more surgical intervention (8/52 versus 0/18, p MYH7 mutations than in patients with MYBPC3 mutations (45.1 +/- 14.0 versus 73.5 +/- 7.5 years, p = 0.03). Seven of the 27 mutation carriers of MYH7 had clinical presentations of HCM, but no carriers of MYBPC3 mutations developed to HCM during follow-up. Maximal wall thickness was thicker in the patients carrying mutations in the global region of MYH7 than in those carrying mutations in the rod region of MYH7 (21.5 +/- 6.6 versus 15 +/- 6.1 mm, p MYH7 than in patients with other mutations. MYH7 mutations, especially in the global region, cause malignant clinical phenotypes.

  15. Recovery of the soleus muscle after short- and long-term disuse induced by hindlimb unloading: effects on the electrical properties and myosin heavy chain profile.

    Science.gov (United States)

    Desaphy, Jean-François; Pierno, Sabata; Liantonio, Antonella; De Luca, Annamaria; Didonna, M Paola; Frigeri, Antonio; Nicchia, G Paola; Svelto, Maria; Camerino, Claudia; Zallone, Alberta; Camerino, Diana Conte

    2005-03-01

    The hindlimb unloading (HU) rat is a model of muscle disuse characterized by atrophy and slow-to-fast phenotype transition of the postural muscles, such as the soleus. We previously found that the resting sarcolemmal chloride conductance (gCl) that is typically lower in slow-twitch myofibers than in fast ones increased in soleus fibers following 1 to 3 weeks of HU in accord with the slow-to-fast transition of myosin heavy chain (MHC) isoforms. Nevertheless, the gCl already raised after a 3-day HU, whereas no change in MHC expression was detected. The present work evaluates the ability of soleus muscle to recover on return to normal load after a short (3 days) or long (2 weeks) disuse period. The changes observed after a 2-week HU were slowly reversible, since 3-4 weeks of reloading were needed to completely recover gCl, fiber diameter, MHC expression pattern, as well as the mechanical threshold Rheobase, an index of calcium homeostasis. After 3-day HU, the gCl increased homogeneously in most of the soleus muscle fibers and gCl recovery was rapidly completed after 4-day reloading. These results suggest different induction mechanisms for gCl augmentation after the short and long HU periods, as well as a possible role for gCl in the slow muscle adaptation to disuse.

  16. Passive Repetitive Stretching for a Short Duration within a Week Increases Myogenic Regulatory Factors and Myosin Heavy Chain mRNA in Rats' Skeletal Muscles

    Directory of Open Access Journals (Sweden)

    Yurie Kamikawa

    2013-01-01

    Full Text Available Stretching is a stimulation of muscle growth. Stretching for hours or days has an effect on muscle hypertrophy. However, differences of continuous stretching and repetitive stretching to affect muscle growth are not well known. To clarify the difference of continuous and repetitive stretching within a short duration, we investigated the gene expression of muscle-related genes on stretched skeletal muscles. We used 8-week-old male Wistar rats ( for this study. Animals medial gastrocnemius muscle was stretched continuously or repetitively for 15 min daily and 4 times/week under anesthesia. After stretching, muscles were removed and total RNA was extracted. Then, reverse transcriptional quantitative real-time PCR was done to evaluate the mRNA expression of MyoD, myogenin, and embryonic myosin heavy chain (MyHC. Muscles, either stretched continuously or repetitively, increased mRNA expression of MyoD, myogenin, and embryonic MyHC more than unstretched muscles. Notably, repetitive stretching resulted in more substantial effects on embryonic MyHC gene expression than continuous stretching. In conclusion, passive stretching for a short duration within a week is effective in increasing myogenic factor expression, and repetitive stretching had more effects than continuous stretching for skeletal muscle on muscle growth. These findings are applicable in clinical muscle-strengthening therapy.

  17. Specific racemization of heavy-chain cysteine-220 in the hinge region of immunoglobulin gamma 1 as a possible cause of degradation during storage.

    Science.gov (United States)

    Amano, Masato; Hasegawa, Jun; Kobayashi, Naoki; Kishi, Naoyuki; Nakazawa, Takashi; Uchiyama, Susumu; Fukui, Kiichi

    2011-05-15

    Therapeutic antibodies often suffer from degradation due to various modifications during storage. We detected a degradation of immunoglobulin gamma 1 (IgG1) stored for 6 month at 40 °C, and identified the modification as the racemization of Cys220 in the hinge sequence S(219)CDKTHT(225) of the heavy chain by tryptic peptide mapping and tandem mass spectrometry. The rate of racemization at Cys220 was enhanced deliberately by incubating the protein at 50 °C and pH 9.0, while all the other cysteine residues were not affected. The racemization of Cys220 was confirmed by mass spectrometry in conjunction with extracted ion chromatography of the tryptic digest of IgG1 forced to degrade in D(2)O and a series of synthetic hinge fragments containing D-amino acid, as well as the detection of D-cysteine in the acid hydrolysate. To rationalize the possible relationship between the racemization of Cys220 and isopeptide formation at the neighboring residue of Asp221, we suggest a new reaction mechanism that assumes a base catalyst to initiate these reactions by activating the amide nitrogen of Lys222. Due to the highly flexible nature of the hinge region, Lys222 can participate in either the formation of a cyclic imidazoline intermediate involving the α-carbonyl carbon of Cys220 to facilitate the racemization of Cys220 or that of a succinimide structure leading to the isomerization of Asp221.

  18. Accelerated Systemic Autoimmunity in the Absence of Somatic Hypermutation in 564Igi: A Mouse Model of Systemic Lupus with Knocked-In Heavy and Light Chain Genes

    Directory of Open Access Journals (Sweden)

    Gabrielle McDonald

    2017-09-01

    Full Text Available 564Igi mice have knocked-in immunoglobulin (Ig heavy (H and light (L chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM and class switch recombination (CSR. To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (AicdaG23S, which is capable of promoting CSR but not SHM. We found that 564Igi AicdaG23S mice secreted class-switched antibodies (Abs at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi AicdaG23S mice had increased pathogenic IgG Abs and severe systemic lupus erythematosus-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance.

  19. Report of VA Medical Training Programs

    Data.gov (United States)

    Department of Veterans Affairs — The Report of VA Medical Training Programs Database is used to track medical center health services trainees and VA physicians serving as faculty. The database also...

  20. Non-VA Hospital System (NVH)

    Data.gov (United States)

    Department of Veterans Affairs — The Veterans Health Administration (VHA) pays for care provided to VA beneficiaries in non-VA hospitals through its contract hospitalization program as mandated by...

  1. Core Binding Factor β (CBFβ) and the Leukemogenic Fusion Protein CBFβ-Smooth Muscle Myosin Heavy Chain (SMMHC) Associate with Mitotic Chromosomes to Epigenetically Regulate Ribosomal Gene Expression*

    Science.gov (United States)

    Lopez-Camacho, Cesar; van Wijnen, Andre J.; Lian, Jane B.; Stein, Janet L.; Stein, Gary S.

    2014-01-01

    Mitotic bookmarking is an epigenetic control mechanism that sustains gene expression in progeny cells; it is often found in genes related to the maintenance of cellular phenotype and growth control. RUNX transcription factors regulate a broad spectrum of RNA Polymerase (Pol II) transcribed genes important for lineage commitment but also regulate RNA Polymerase I (Pol I) driven ribosomal gene expression, thus coordinating control of cellular identity and proliferation. In this study, using fluorescence microscopy and biochemical approaches we show that the principal RUNX co-factor, CBFβ, associates with nucleolar organizing regions (NORs) during mitosis to negatively regulate RUNX-dependent ribosomal gene expression. Of clinical relevance, we establish for the first time that the leukemogenic fusion protein CBFβ-SMMHC (smooth muscle myosin heavy chain) also associates with ribosomal genes in interphase chromatin and mitotic chromosomes to promote and epigenetically sustain regulation of ribosomal genes through RUNX factor interactions. Our results demonstrate that CBFβ contributes to the transcriptional regulation of ribosomal gene expression and provide further understanding of the epigenetic role of CBFβ-SMMHC in proliferation and maintenance of the leukemic phenotype. Background Runt-related transcription factors (RUNX) bookmark genes important for phenotype, but the mitotic behavior of RUNX cofactor, Core Binding Factor β (CBFβ) is unknown. Results CBFβ and leukemogenic fusion protein CBFβ-SMMHC associate with chromosomes during mitosis and regulate ribosomal genes. Conclusion CBFβ and CBFβ-SMMHC contribute to epigenetic control of ribosomal genes. Significance CBFβ-SMMHC alters regulation linking phenotypic control with cell growth, thereby promoting cancer. PMID:25079347

  2. Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis

    Science.gov (United States)

    Donelan, Matthew J.; Morfini, Gerardo; Julyan, Richard; Sommers, Scott; Hays, Lori; Kajio, Hiroshi; Briaud, Isabelle; Easom, Richard A.; Molkentin, Jeffery D.; Brady, Scott T.; hide

    2002-01-01

    The specific biochemical steps required for glucose-regulated insulin exocytosis from beta-cells are not well defined. Elevation of glucose leads to increases in cytosolic [Ca2+]i and biphasic release of insulin from both a readily releasable and a storage pool of beta-granules. The effect of elevated [Ca2+]i on phosphorylation of isolated beta-granule membrane proteins was evaluated, and the phosphorylation of four proteins was found to be altered by [Ca2+]i. One (a 18/20-kDa doublet) was a Ca2+-dependent increase in phosphorylation, and, surprisingly, three others (138, 42, and 36 kDa) were Ca2+-dependent dephosphorylations. The 138-kDa beta-granule phosphoprotein was found to be kinesin heavy chain (KHC). At low levels of [Ca2+]i KHC was phosphorylated by casein kinase 2, but KHC was rapidly dephosphorylated by protein phosphatase 2B beta (PP2Bbeta) as [Ca2+]i increased. Inhibitors of PP2B specifically reduced the second, microtubule-dependent, phase of insulin secretion, suggesting that dephosphorylation of KHC was required for transport of beta-granules from the storage pool to replenish the readily releasable pool of beta-granules. This is distinct from synaptic vesicle exocytosis, because neurotransmitter release from synaptosomes did not require a Ca2+-dependent KHC dephosphorylation. These results suggest a novel mechanism for regulating KHC function and beta-granule transport in beta-cells that is mediated by casein kinase 2 and PP2B. They also implicate a novel regulatory role for PP2B/calcineurin in the control of insulin secretion downstream of a rise in [Ca2+]i.

  3. Differential muscular myosin heavy chain expression of the pectoral and pelvic girdles during early growth in the king penguin (Aptenodytes patagonicus) chick.

    Science.gov (United States)

    Erbrech, Aude; Robin, Jean-Patrice; Guérin, Nathalie; Groscolas, René; Gilbert, Caroline; Martrette, Jean-Marc

    2011-06-01

    Continuous growth, associated with a steady parental food supply, is a general pattern in offspring development. So that young chicks can acquire their locomotor independence, this period is usually marked by a fast maturation of muscles, during which different myosin heavy chain (MyHC) isoforms are expressed. However, parental food provisioning may fluctuate seasonally, and offspring therefore face a challenge to ensure the necessary maturation of their tissues when energy is limited. To address this trade-off we investigated muscle maturation in both the pectoral and pelvic girdles of king penguin chicks. This species has an exceptionally long rearing period (1 year), which is prolonged when parental food provisioning is drastically reduced during the sub-Antarctic winter. Approximately 1 month post hatching, chicks acquire a functional pedestrian locomotion, which uses pelvic muscles, whereas swimming, which uses the pectoral muscles, only occurs 1 year later. We therefore tested the hypothesis that the MyHC content of the leg muscles reaches a mature state before those of the pectoral muscles. We found that leg muscle MyHC composition changed with the progressive acquisition of pedestrian locomotion, whereas pectoral muscle fibres reached their mature MyHC profile as early as hatching. Contrary to our predictions, the acquisition of the adult profile in pectoral muscles could be related to an early maturation of the contractile muscular proteins, presumably associated with early thermoregulatory capacities of chicks, necessary for survival in their cold environment. This differential maturation appears to reconcile both the locomotor and environmental constraints of king penguin chicks during growth.

  4. Effective myotube formation in human adipose tissue-derived stem cells expressing dystrophin and myosin heavy chain by cellular fusion with mouse C2C12 myoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Young Woo [Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Biomedical Research Institute, Lifeliver Co., Ltd., Suwon (Korea, Republic of); Lee, Jong Eun; Yang, Mal Sook; Jang, In Keun; Kim, Hyo Eun; Lee, Doo Hoon; Kim, Young Jin [Biomedical Research Institute, Lifeliver Co., Ltd., Suwon (Korea, Republic of); Park, Won Jin [Dr. Park' s Aesthetic Clinic, Seoul (Korea, Republic of); Kong, Jee Hyun; Shim, Kwang Yong [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Lee, Jong In, E-mail: oncochem@yonsei.ac.kr [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Kim, Hyun Soo, E-mail: khsmd@unitel.co.kr [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of)

    2011-04-29

    Highlights: {yields} hASCs were differentiated into skeletal muscle cells by treatment with 5-azacytidine, FGF-2, and the supernatant of cultured hASCs. {yields} Dystrophin and MyHC were expressed in late differentiation step by treatment with the supernatant of cultured hASCs. {yields} hASCs expressing dystrophin and MyHC contributed to myotube formation during co-culture with mouse myoblast C2C12 cells. -- Abstract: Stem cell therapy for muscular dystrophies requires stem cells that are able to participate in the formation of new muscle fibers. However, the differentiation steps that are the most critical for this process are not clear. We investigated the myogenic phases of human adipose tissue-derived stem cells (hASCs) step by step and the capability of myotube formation according to the differentiation phase by cellular fusion with mouse myoblast C2C12 cells. In hASCs treated with 5-azacytidine and fibroblast growth factor-2 (FGF-2) for 1 day, the early differentiation step to express MyoD and myogenin was induced by FGF-2 treatment for 6 days. Dystrophin and myosin heavy chain (MyHC) expression was induced by hASC conditioned medium in the late differentiation step. Myotubes were observed only in hASCs undergoing the late differentiation step by cellular fusion with C2C12 cells. In contrast, hASCs that were normal or in the early stage were not involved in myotube formation. Our results indicate that stem cells expressing dystrophin and MyHC are more suitable for myotube formation by co-culture with myoblasts than normal or early differentiated stem cells expressing MyoD and myogenin.

  5. CD98 Heavy Chain Is a Potent Positive Regulator of CD4+ T Cell Proliferation and Interferon-γ Production In Vivo.

    Science.gov (United States)

    Kurihara, Takeshi; Arimochi, Hideki; Bhuyan, Zaied Ahmed; Ishifune, Chieko; Tsumura, Hideki; Ito, Morihiro; Ito, Yasuhiko; Kitamura, Akiko; Maekawa, Yoichi; Yasutomo, Koji

    2015-01-01

    Upon their recognition of antigens presented by the MHC, T cell proliferation is vital for clonal expansion and the acquisition of effector functions, which are essential for mounting adaptive immune responses. The CD98 heavy chain (CD98hc, Slc3a2) plays a crucial role in the proliferation of both CD4+ and CD8+ T cells, although it is unclear if CD98hc directly regulates the T cell effector functions that are not linked with T cell proliferation in vivo. Here, we demonstrate that CD98hc is required for both CD4+ T cell proliferation and Th1 functional differentiation. T cell-specific deletion of CD98hc did not affect T cell development in the thymus. CD98hc-deficient CD4+ T cells proliferated in vivo more slowly as compared with control T cells. C57BL/6 mice lacking CD98hc in their CD4+ T cells could not control Leishmania major infections due to lowered IFN-γ production, even with massive CD4+ T cell proliferation. CD98hc-deficient CD4+ T cells exhibited lower IFN-γ production compared with wild-type T cells, even when comparing IFN-γ expression in cells that underwent the same number of cell divisions. Therefore, these data indicate that CD98hc is required for CD4+ T cell expansion and functional Th1 differentiation in vivo, and suggest that CD98hc might be a good target for treating Th1-mediated immune disorders.

  6. VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma.

    Science.gov (United States)

    Jiang, Yanwen; Nie, Kui; Redmond, David; Melnick, Ari M; Tam, Wayne; Elemento, Olivier

    2015-12-28

    Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding the clonal composition changes that occur within a tumor in response to certain micro-environment or treatments may lead to the design of more sophisticated and effective approaches to eradicate tumor cells. However, tracking tumor clonal sub-populations has been challenging due to the lack of distinguishable markers. To address this problem, a VDJ-seq protocol was created to trace the clonal evolution patterns of diffuse large B cell lymphoma (DLBCL) relapse by exploiting VDJ recombination and somatic hypermutation (SHM), two unique features of B cell lymphomas. In this protocol, Next-Generation sequencing (NGS) libraries with indexing potential were constructed from amplified rearranged immunoglobulin heavy chain (IgH) VDJ region from pairs of primary diagnosis and relapse DLBCL samples. On average more than half million VDJ sequences per sample were obtained after sequencing, which contain both VDJ rearrangement and SHM information. In addition, customized bioinformatics pipelines were developed to fully utilize sequence information for the characterization of IgH-VDJ repertoire within these samples. Furthermore, the pipeline allows the reconstruction and comparison of the clonal architecture of individual tumors, which enables the examination of the clonal heterogeneity within the diagnosis tumors and deduction of clonal evolution patterns between diagnosis and relapse tumor pairs. When applying this analysis to several diagnosis-relapse pairs, we uncovered key evidence that multiple distinctive tumor evolutionary patterns could lead to DLBCL relapse. Additionally, this approach can be expanded into other clinical aspects, such as identification of minimal residual disease, monitoring relapse progress and treatment response, and investigation of immune repertoires in non-lymphoma contexts.

  7. Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A mice that model ALS.

    Directory of Open Access Journals (Sweden)

    Ching-Hua Lu

    Full Text Available Amyotrophic lateral sclerosis (ALS is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3-5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials.In this study, using the well-established SOD1(G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1(G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials.These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1(G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS.

  8. Effect of 48-h food deprivation on the expressions of myosin heavy-chain isoforms and fiber type-related factors in rats.

    Science.gov (United States)

    Mizunoya, Wataru; Sawano, Shoko; Iwamoto, Yohei; Sato, Yusuke; Tatsumi, Ryuichi; Ikeuchi, Yoshihide

    2013-01-01

    The primary aim of this study was to examine the effects of 48-h food deprivation on rat skeletal muscle fiber type, according to myosin heavy-chain (MyHC) isoform composition and some metabolism-related factors in both slow-type dominant and fast-type dominant muscle tissues. Male Wistar rats (7 wk old) were treated with 48-h food deprivation or ad libitum feeding as control. After the treatment, the soleus muscle (slow-type dominant) and the extensor digitorum longus (EDL, fast-type dominant) were excised. We found that 48-h food deprivation did not affect MyHC composition in either the soleus or EDL, compared with fed rats by electrophoretic separation of MyHC isoforms. However, 48-h food deprivation significantly increased the mRNA expression of fast-type MyHC2B in the EDL muscle. Moreover, food deprivation increased fatty acid metabolism, as shown by elevated levels of related serum energy substrates and mRNA expression of mitochondrial uncoupling protein (UCP) 3 and lipoprotein lipase (LPL) in both the soleus and EDL. UCP3 and LPL are generally expressed at higher levels in slow-type fibers. Furthermore, we found that food deprivation significantly decreased the protein amounts of PGC1α and phosphorylated FOXO1, which are known as skeletal muscle fiber type regulators. In conclusion, 48-h food deprivation increased mRNA expression of fast-type MyHC isoform and oxidative metabolism-related factors in EDL, whereas MyHC composition at the protein level did not change in either the soleus or EDL.

  9. The saponin D39 blocks dissociation of non-muscular myosin heavy chain IIA from TNF receptor 2, suppressing tissue factor expression and venous thrombosis.

    Science.gov (United States)

    Zhai, Ke-Feng; Zheng, Jin-Rong; Tang, You-Mei; Li, Fang; Lv, Yan-Ni; Zhang, Yuan-Yuan; Gao, Zhen; Qi, Jin; Yu, Bo-Yang; Kou, Jun-Ping

    2017-09-01

    Non-muscular myosin heavy chain IIA (NMMHC IIA) plays a key role in tissue factor expression and venous thrombosis. Natural products might inhibit thrombosis through effects on NMMHC IIA. Here, we have shown that a natural saponin, D39, from Liriope muscari exerted anti-thrombotic activity in vivo, by targeting NMMHC IIA. Expression and activity of tissue factor in endothelial cells were analysed in vitro by Western blot and simplified chromogenic assays. Interactions between D39 and NMMHC IIA were assessed by serial affinity chromatography and molecular docking analysis. D39-dependent interactions between NMMHC IIA and TNF receptor 2 (TNFR2) were measured by immunofluorescence, co-immunoprecipitation and proximity ligation assays. Anti-thrombotic activity of D39 in vivo was evaluated with a model of inferior vena cava ligation injury in mice. D39 inhibited tissue factor expression and procoagulant activities in HUVECs and decreased thrombus weight in inferior vena cava-ligated mice dose-dependently. Serial affinity chromatography and molecular docking analysis suggested that D39 bound to NMMHC IIA. In HEK293T cells, D39 inhibited tissue factor expression evoked by NMMHC IIA overexpression. This effect was blocked by NMMHC IIA knockdown in HUVECs. D39 inhibited dissociation of NMMHC IIA from TNFR2, which subsequently modulated the Akt/GSK3β-NF-κB signalling pathways. D39 inhibited tissue factor expression and thrombus formation by modulating the Akt/GSK3β and NF-κB signalling pathways through NMMHC IIA. We identified a new natural product that targeted NMMHC IIA, as a potential treatment for thrombotic disorders and other vasculopathies. © 2017 The British Pharmacological Society.

  10. Discovery of a unique Ig heavy-chain (IgT) in rainbow trout: Implications for a distinctive B cell developmental pathway in teleost fish

    Science.gov (United States)

    Hansen, J.D.; Landis, E.D.; Phillips, R.B.

    2005-01-01

    During the analysis of Ig superfamily members within the available rainbow trout (Oncorhynchus mykiss) EST gene index, we identified a unique Ig heavy-chain (IgH) isotype. cDNAs encoding this isotype are composed of a typical IgH leader sequence and a VDJ rearranged segment followed by four Ig superfamily C-1 domains represented as either membrane-bound or secretory versions. Because teleost fish were previously thought to encode and express only two IgH isotypes (IgM and IgD) for their humoral immune repertoire, we isolated all three cDNA isotypes from a single homozygous trout (OSU-142) to confirm that all three are indeed independent isotypes. Bioinformatic and phylogenetic analysis indicates that this previously undescribed divergent isotype is restricted to bony fish, thus we have named this isotype "IgT" (??) for teleost fish. Genomic sequence analysis of an OSU-142 bacterial artificial chromosome (BAC) clone positive for all three IgH isotypes revealed that IgT utilizes the standard rainbow trout VH families, but surprisingly, the IgT isotype possesses its own exclusive set of DH and JH elements for the generation of diversity. The IgT D and J segments and ?? constant (C) region genes are located upstream of the D and J elements for IgM, representing a genomic IgH architecture that has not been observed in any other vertebrate class. All three isotypes are primarily expressed in the spleen and pronephros (bone marrow equivalent), and ontogenically, expression of IgT is present 4 d before hatching in developing embryos. ?? 2005 by The National Academy of Sciences of the USA.

  11. Influence of Al and the heavy metals Fe, Mn, Zn, Cu, Pb, and Cd on development and efficacy of vesicular-arbuscular mycorrhiza in tropical and subtropical plants. Einfluss von Al und den Schwermetallen Fe, Mn, Zn, Cu, Pb und Cd auf die Effizienz der VA-Mykorrhiza bei tropischen und subtropischen Pflanzen

    Energy Technology Data Exchange (ETDEWEB)

    Fabig, B.

    1982-07-08

    In greenhouse experiments the influence of Al and the heavy metals Fe, Mn, Zn, Cu, Pb, and Cd on the efficacy of VA-mycorrhizal fungi was tested with special regard to several soil pH levels and soil water regimes in different combinations. The most important results were: The inoculation led to a significantly better growth of all test plants in the presence of Al, Fe, Mn, Zn, Cu, Pb, and Cd up to a specific amount of the soil-applied element; beyond this specific limit the efficacy of the mycorrhiza was more or less inhibited depending on the element. In correlation with the growth, the nearly always better P uptake of the inoculated plants was impaired only by the highest toxic amounts of the elements. In comparison with the uninoculated plants, all the inoculated plants showed higher P and Pb concentrations. The mycorrhizal plants generally had significantly higher concentrations of the elements Al, Mn, Zn, Cu, and Cd in the roots than the uninoculated plants. Generally even toxic levels of Fe in the soil did not lead to higher Fe concentrations in the plants. Even the highest amounts of Al, Fe, Mn, Zn, and Cu did not cause microscopically visible injuries to the development of the mycorrhiza and did not impede the infection. Only the toxic levels of Pb led to a decrease of the infection rate of about 50%. Pb and Cd were the reason for morphological changes of the different developmental phases of the fungus. High amounts of Pb induced an increased formation of vesicles. The highest amounts of Cd were accompanied by the crowded occurrence of arbuscules.

  12. Origin, transfer and effects of heavy metals in a soil-plant-snail food chain in polluted ecosystems of Biesbosch National Park

    NARCIS (Netherlands)

    Notten, M.J.M.

    2005-01-01

    Emissions of heavy metals result in pollution of the soil, the atmosphere and the hydrosphere, and this pollution is a potential threat to the health of humans and ecosystems. Biesbosch National Park (the Netherlands) is exposed to chronic and diffuse pollution of heavy metals. The park is the

  13. Inter-alpha-trypsin inhibitor heavy chain 4: a novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Lee KY

    2015-04-01

    Full Text Available Kang-Yun Lee,1–3 Po-Hao Feng,1,2 Shu-Chuan Ho,4 Kai-Jen Chuang,5,6 Tzu-Tao Chen,2,3 Chien-Ling Su,2,4 Wen-Te Liu,2,4 Hsiao-Chi Chuang2,4 1Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 2Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, 3Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 4School of Respiratory Therapy, College of Medicine, Taipei Medical University, 5Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, 6School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan Abstract: Chronic obstructive pulmonary disease (COPD is a chronic inflammatory disease that is correlated with environmental stress. Particulate matter ≤10 µm (PM10 is considered to be a risk factor for COPD development; however, the effects of PM10 on the protein levels in COPD remain unclear. Fifty subjects with COPD and 15 healthy controls were recruited. Gene ontology analysis of differentially expressed proteins identified immune system process and binding as the most important biological process and molecular function, respectively, in the responses of PM10-exposed patients with COPD. Biomarkers for PM10 in COPD were identified and compared with the same in healthy controls and included proteoglycan 4 (PRG4, inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, and apolipoprotein F (APOF. PRG4 and ITIH4 were associated with a past 3-year PM10 exposure level. The receiver operating characteristic curve analysis showed that ITIH4 is a sensitive and specific biomarker for PM10 exposure (area under the curve [AUC] =0.690, P=0.015 compared with PRG4 (AUC =0.636, P=0.083, APOF (AUC =0.523, P=0.766, 8-isoprostane (AUC =0.563, P=0.405, and C-reactive protein (CRP; AUC =0.634, P=0.086. ITIH4 levels were correlated with CRP (r=0

  14. Immunogenicity and Protective Efficacy of Brugia malayi Heavy Chain Myosin as Homologous DNA, Protein and Heterologous DNA/Protein Prime Boost Vaccine in Rodent Model.

    Science.gov (United States)

    Gupta, Jyoti; Pathak, Manisha; Misra, Sweta; Misra-Bhattacharya, Shailja

    2015-01-01

    We earlier demonstrated the immunoprophylactic efficacy of recombinant heavy chain myosin (Bm-Myo) of Brugia malayi (B. malayi) in rodent models. In the current study, further attempts have been made to improve this efficacy by employing alternate approaches such as homologous DNA (pcD-Myo) and heterologous DNA/protein prime boost (pcD-Myo+Bm-Myo) in BALB/c mouse model. The gene bm-myo was cloned in a mammalian expression vector pcDNA 3.1(+) and protein expression was confirmed in mammalian Vero cell line. A significant degree of protection (79.2%±2.32) against L3 challenge in pcD-Myo+Bm-Myo immunized group was observed which was much higher than that exerted by Bm-Myo (66.6%±2.23) and pcD-Myo (41.6%±2.45). In the heterologous immunized group, the percentage of peritoneal leukocytes such as macrophages, neutrophils, B cells and T cells marginally increased and their population augmented further significantly following L3 challenge. pcD-Myo+Bm-Myo immunization elicited robust cellular and humoral immune responses as compared to pcD-Myo and Bm-Myo groups as evidenced by an increased accumulation of CD4+, CD8+ T cells and CD19+ B cells in the mouse spleen and activation of peritoneal macrophages. Though immunized animals produced antigen-specific IgG antibodies and isotypes, sera of mice receiving pcD-Myo+Bm-Myo or Bm-Myo developed much higher antibody levels than other groups and there was profound antibody-dependent cellular adhesion and cytotoxicity (ADCC) to B. malayi infective larvae (L3). pcD-Myo+Bm-Myo as well as Bm-Myo mice generated a mixed T helper cell phenotype as evidenced by the production of both pro-inflammatory (IL-2, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines. Mice receiving pcD-Myo on contrary displayed a polarized pro-inflammatory immune response. The findings suggest that the priming of animals with DNA followed by protein booster generates heightened and mixed pro- and anti-inflammatory immune responses that are capable of providing

  15. Immunogenicity and Protective Efficacy of Brugia malayi Heavy Chain Myosin as Homologous DNA, Protein and Heterologous DNA/Protein Prime Boost Vaccine in Rodent Model.

    Directory of Open Access Journals (Sweden)

    Jyoti Gupta

    Full Text Available We earlier demonstrated the immunoprophylactic efficacy of recombinant heavy chain myosin (Bm-Myo of Brugia malayi (B. malayi in rodent models. In the current study, further attempts have been made to improve this efficacy by employing alternate approaches such as homologous DNA (pcD-Myo and heterologous DNA/protein prime boost (pcD-Myo+Bm-Myo in BALB/c mouse model. The gene bm-myo was cloned in a mammalian expression vector pcDNA 3.1(+ and protein expression was confirmed in mammalian Vero cell line. A significant degree of protection (79.2%±2.32 against L3 challenge in pcD-Myo+Bm-Myo immunized group was observed which was much higher than that exerted by Bm-Myo (66.6%±2.23 and pcD-Myo (41.6%±2.45. In the heterologous immunized group, the percentage of peritoneal leukocytes such as macrophages, neutrophils, B cells and T cells marginally increased and their population augmented further significantly following L3 challenge. pcD-Myo+Bm-Myo immunization elicited robust cellular and humoral immune responses as compared to pcD-Myo and Bm-Myo groups as evidenced by an increased accumulation of CD4+, CD8+ T cells and CD19+ B cells in the mouse spleen and activation of peritoneal macrophages. Though immunized animals produced antigen-specific IgG antibodies and isotypes, sera of mice receiving pcD-Myo+Bm-Myo or Bm-Myo developed much higher antibody levels than other groups and there was profound antibody-dependent cellular adhesion and cytotoxicity (ADCC to B. malayi infective larvae (L3. pcD-Myo+Bm-Myo as well as Bm-Myo mice generated a mixed T helper cell phenotype as evidenced by the production of both pro-inflammatory (IL-2, IFN-γ and anti-inflammatory (IL-4, IL-10 cytokines. Mice receiving pcD-Myo on contrary displayed a polarized pro-inflammatory immune response. The findings suggest that the priming of animals with DNA followed by protein booster generates heightened and mixed pro- and anti-inflammatory immune responses that are capable of

  16. Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients.

    Science.gov (United States)

    García-Castro, Mónica; Reguero, Julián R; Batalla, Alberto; Díaz-Molina, Beatriz; González, Pelayo; Alvarez, Victoria; Cortina, Arturo; Cubero, Gustavo I; Coto, Eliecer

    2003-08-01

    Mutations in the cardiac beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC). Although there are no mutational hotspots, most of the mutations are located in specific exons of the MYH7 and TNNT2 genes. Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy. We sequenced exons 8, 9, 13-16, 19, 20, 22-24, and 30 of the MYH7 gene and exons 8, 9, 11, and 14-16 of the TNNT2 gene in 30 HC patients (18-60 years of age) from the region of Asturias (Northern Spain); 25 cases (80%) had a family history of the disease. Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 200 healthy controls through single-strand conformation analysis. Four of the probands had nucleotide changes absent in the healthy controls. Two cases had mutations previously described in the MYH7 gene (exon 14, Arg453Cys) or the TNNT2 gene (exon 16, Arg278Cys). Two cases had new mutations (MYH7 exon 22, Met822Val; TNNT2 exon 14, Lys247Arg) not found among the healthy controls. We found MYH7 Met822Val in a woman with a severe form of HC; the mutation was absent in her parents, indicating a de novo mutation. MYH7 R453C was present in a woman with mild HC, mother of a son who died from SCD. TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy. A patient with severe HC was carrier of TNNT2 247Arg. Mutations in the MYH7 and TNNT2 genes can be found in patients without a family history of HC. However, compared with other populations MYH7 or TNNT2 mutations were rare among our HC patients. This study illustrates the

  17. OneVA EA Vision and Strategy

    Data.gov (United States)

    Department of Veterans Affairs — The outcomes/goals supported by effective use of an EA are: Improved Service Delivery, Functional Integration, Resource Optimization and Authoritative Reference. VA...

  18. Geographic Distribution of VA Expenditures FY2012

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  19. Geographic Distribution of VA Expenditures FY2007

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  20. Geographic Distribution of VA Expenditures FY1999

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  1. Geographic Distribution of VA Expenditures FY2008

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  2. Geographic Distribution of VA Expenditures FY2004

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  3. Geographic Distribution of VA Expenditures FY2000

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  4. Geographic Distribution of VA Expenditures FY2005

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  5. Geographic Distribution of VA Expenditures FY2003

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  6. Geographic Distribution of VA Expenditures FY 2016

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  7. Geographic Distribution of VA Expenditures FY2009

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  8. Geographic Distribution of VA Expenditures FY2006

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  9. Geographic Distribution of VA Expenditures FY2011

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  10. Geographic Distribution of VA Expenditures FY2013

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  11. Geographic Distribution of VA Expenditures FY1997

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  12. Geographic Distribution of VA Expenditures FY2010

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  13. Geographic Distribution of VA Expenditures FY1996

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    Department of Veterans Affairs — This report details VA expenditures at the state, county, and Congressional District level. It includes categories such as Compensation and Pension, Construction,...

  14. COAXIAL DISK SHUNT FOR MEASURING IN THE HEAVY-CURRENT CHAIN OF HIGH-VOLTAGE GENERATOR OF STORM DISCHARGES OF IMPULSES OF CURRENT OF ARTIFICIAL LIGHTNING WITH THE INTEGRAL OF ACTION TO 15•106 J/OHM

    Directory of Open Access Journals (Sweden)

    M. I. Baranov

    2017-10-01

    Full Text Available Purpose. Description of construction and basic technical descriptions developed and created in Research & Design Institute «Molniya» National Technical University «Kharkiv Polytechnic Institute» high-voltage heavy-current coaxial disk shunt of type of SC-300M2, allowing reliably to measure the peak-temporal parameters (PTP of impulses of current of artificial lightning in wide peak and temporal ranges with the integral of their action to 15·106 J/Ohm. Methodology. Electrophysics bases of high-voltage impulsive technique, scientific and technical bases of development and creation of high-voltage heavy-current impulsive electrical equipment, including the powerful generators of current of lightning (GCL, and also measuring methods in bit chains powerful high-voltage GCL AVP large impulsive currents of micro- and millisecond temporal ranges. Results. Offered and described new construction of measuring high-voltage heavy-current shunt, containing a measuring round disk from stainless steel easily soiled a 12Х18Н10Т thickness 2 mm and external diameter 80 mm. Experimental a way impulsive active resistance of RS≈0,08 mOhm of the indicated measuring disk and on his basis a calculation coefficient transformation is found of SS of coaxial disk shunt of type of SC-300M2, numeral equal in the concerted mode of operations of his coaxial cable line (CCL SS≈2/RS≈25·103 A/V. It is rotined that it is expedient to use this value SS for measuring in the heavy-current bit chain of GCL ATP impulsive A- and repeated impulsive D- component of current of artificial lightning, and also ATP of aperiodic impulse of current of artificial lightning of temporal form 10 μc/350 μc. It is set that taking into account application in the end CCL of shunt of a co-ordinate divizor of voltage with two output coaxial sockets 1:1 (for SSA≈25·103 A/V and 1:2 (SSC≈12,5·103 A/V at measuring of ATP intermediate B-, protracted C- and shortened protracted C

  15. IgG subclass and heavy chain domains contribute to binding and protection by mAbs to the poly γ-D-glutamic acid capsular antigen of Bacillus anthracis.

    Directory of Open Access Journals (Sweden)

    Maria Hovenden

    Full Text Available Bacterial capsules are common targets for antibody-mediated immunity. The capsule of Bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-γ-d-glutamic acid (γdPGA. We previously generated murine IgG3 monoclonal antibodies (mAbs to γdPGA that were protective in a murine model of pulmonary anthrax. IgG3 antibodies are characteristic of the murine response to polysaccharide antigens. The goal of the present study was to produce subclass switch variants of the γdPGA mAbs (IgG3 → IgG1 → IgG2b → IgG2a and assess the contribution of subclass to antibody affinity and protection. Subclass switch antibodies had identical variable regions but differed in their heavy chains. The results showed that a switch from the protective IgG3 to IgG1, IgG2b or IgG2a was accompanied by i a loss of protective activity ii a change in mAb binding to the capsular matrix, and iii a loss of affinity. These results identify a role for the heavy chain constant region in mAb binding. Hybrid mAbs were constructed in which the CH1, CH2 or CH3 heavy chain constant domains from a non-protective, low binding IgG2b mAb were swapped into the protective IgG3 mAb. The IgG3 mAb that contained the CH1 domain from IgG2b showed no loss of affinity or protection. In contrast, swapping the CH2 or CH3 domains from IgG2b into IgG3 produced a reduction in affinity and a loss of protection. These studies identify a role for the constant region of IgG heavy chains in affinity and protection against an encapsulated bacterial pathogen.

  16. Triticale (XTriticosecale W.) Heavy Metal Upptake as a Possibility of Food Chain Pollution in a Long-Term Field Experiment in Hungary

    Science.gov (United States)

    László Phd, M., ,, Dr.

    2009-04-01

    mixes and crackers due to a savory, nutty flavor. Etanol plants will pay a premium for triticale over barley since it has more starch and no hull, making alcohol production more efficient. Germany, France, China, Poland and Hungary account for nearly 90 percent of world triticale production (Donald et al. 2001). Heavy metals are dangerous because they tend to bioaccumulate in food chain. Bioaccumulation means an increase in the concentration of a chemical in a biological organism over time, compared to the chemical`s concentration in they environment. Compounds accumulate in living things any time they are taken up and stored faster han they are broken down (metabolize) or extreted. Crops have ability to heavy metal accumulation from fertilizers such as Cd, Pb, Cu, Zn etc. to a different degree (Lee et al. 2001, Scholz and Ellerbrock 2004). The main purposes of this study was to determine the triticale toxic element upptake by the soil, triticale leaf+straw and grain element concentrations on acid sandy soil in a long-term field fertilization experiment at Nyirlugos, Hungary in 1998. Material and Methods: Field experiments were carried out on an acidic sandy brown forest soil at Nyírlugos in East-Hungary from 1962 to 2005. Soil geochemical parameters were as follow: humus 0.6%, pH (H2O) 5.8, pH (KCl) 4.6, total N 32.8 mg/kg, AL (ammonium lactate soluble)- P2O5 43 mg/kg, AL-K2O 52 mg/kg. The experiments involved 32 NPKCaMg treatments in 4 replications giving a total of 128 plots. N levels were 0, 50, 100, 150 kg/ha/yr, P2O5 and K2O 0, 60, 120, 180 kg/ha/yr, CaCO3 0, 250, 500, 1000 kg/ha/yr and MgCO3 doses were 0, 140, 280 kg/ha/yr. Plot brutto size was 50 m2. Composite soil samples consisting of 25 subsamples collected at before flowering time from the ploughed layer of each plot. The so-called "mobile" fraction was extracted by ammonium-acetate+EDTA (AAc+EDTA, Lakanen and Ervio 1971) and the heavy metal determination by ICP-AES technic. Plant leaf+straw and seed

  17. Technology Reference Model (TRM) Reports: VA Category Framework Count Report

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    Department of Veterans Affairs — The One VA Enterprise Architecture (OneVA EA) is a comprehensive picture of the Department of Veterans Affairs' (VA) operations, capabilities and services and the...

  18. Technology Reference Model (TRM) Reports: VA Category Mapping Report

    Data.gov (United States)

    Department of Veterans Affairs — The One VA Enterprise Architecture (OneVA EA) is a comprehensive picture of the Department of Veterans Affairs' (VA) operations, capabilities and services and the...

  19. Geographic Distribution of VA Expenditures Report FY2015

    Data.gov (United States)

    Department of Veterans Affairs — Geographic Distribution of VA Expenditures Report (GDX) located on the Expenditures page in the Expenditure Tables category. This report details VA expenditures at...

  20. VA Personal Health Record Sample Data

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    Department of Veterans Affairs — My HealtheVet (www.myhealth.va.gov) is a Personal Health Record portal designed to improve the delivery of health care services to Veterans, to promote health and...

  1. Genetics Home Reference: carbonic anhydrase VA deficiency

    Science.gov (United States)

    ... bicarbonate. Bicarbonate is necessary to maintain the proper acid-base balance in the body, which is necessary for most biological reactions to proceed properly. The carbonic anhydrase VA enzyme ...

  2. A failure of oversight at the VA

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-09-01

    Full Text Available No abstract available. Article truncated at 150 words. On September 8, 2014 the Washington Examiner reported that the Central Office of the VA was allowed to change language in the VA Office of Inspector General (VAOIG report on delays in patient care at the Phoenix VA Medical Center (1. Crucial language that the VAOIG could not “conclusively” prove that delays in care caused patient deaths at a Phoenix hospital was added to its final report after a draft version was sent to agency administrators for comment. Rep. Jeff Miller, chairman of the House veterans' committee, said "there are significant differences between the final IG report and the draft version ...". The following day Richard Griffin, the acting VAOIG, vigorously defended the independence of his office and bristled at the allegations that the VA was allowed to alter his office's report. However, his denials and indignance seem disingenuous. To understand why, we need to go back a few years. ...

  3. 78 FR 32126 - VA Dental Insurance Program

    Science.gov (United States)

    2013-05-29

    ... misinterpretations of eligibility for VA dental benefits, because these misinterpretations seemed to also create... communication channels to notify all eligible persons of their right to voluntarily enroll in VADIP. The...

  4. Generation of induced pluripotent stem cells (iPSCs from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7 gene

    Directory of Open Access Journals (Sweden)

    Samantha Barratt Ross

    2017-04-01

    Full Text Available Induced pluripotent stem cells (iPSCs were generated from peripheral blood mononuclear cells (PBMCs isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7. Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p.Val698Ala, have a normal karyotype and no longer carry the episomal reprogramming vector. This line is useful for studying the link between variants in MYH7 and the pathogenesis of HCM.

  5. Generation of induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7) gene.

    Science.gov (United States)

    Ross, Samantha Barratt; Fraser, Stuart T; Nowak, Natalie; Semsarian, Christopher

    2017-04-01

    Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM) who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7). Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p.Val698Ala, have a normal karyotype and no longer carry the episomal reprogramming vector. This line is useful for studying the link between variants in MYH7 and the pathogenesis of HCM. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

    DEFF Research Database (Denmark)

    Claësson, M H; Nissen, Mogens Holst

    1994-01-01

    A variety of murine tumor cell lines was studied for its binding of exogeneously added human beta 2-microglobulin (h beta 2m). Three T lymphomas and one IL-2-dependent T-cell line (HT-1) bound substantial amounts of h beta 2m, whereas P815 mastocytoma cells, an Abelson virus-infected pre-B cell....... EL4 cells which had bound h beta 2m decreased their rate of constitutive IL-2 secretion and became resistant to activated natural killer (NK) cell killing. The present data suggest the binding of h beta 2m to mouse T cells leads to conformational changes of MHC-I heavy chains which influence both...

  7. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men

    DEFF Research Database (Denmark)

    Lange, Kai Henrik Wiborg; Andersen, Jesper Løvind; Beyer, Nina

    2002-01-01

    ) quadriceps muscle power; 3) quadriceps muscle fiber type, size, and myosin heavy chain (MHC) composition; 4) quadriceps cross-sectional area (CSA) [nuclear magnetic resonance imaging (NMRI)]; 5) body composition (dual-energy x-ray absorptiometry scanning); and 6) GH-related serum markers were performed...... at baseline and after 12 wk. The final GH dose was 1.77 +/- 0.18 IU x d(-1) (approximately 7.2 +/- 0.8 microg x kg(-1) x d(-1)). GH alone had no effect on isokinetic quadriceps muscle strength, power, CSA, or fiber size. However, a substantial increase in MHC 2X isoform was observed with GH administration...... alone, and this may be regarded as a change into a more youthful MHC composition, possibly induced by the rejuvenating of systemic IGF-I levels. RT + placebo caused substantial increases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvements were not further augmented...

  8. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men

    DEFF Research Database (Denmark)

    Lange, Kai Henrik Wiborg; Andersen, Jesper Løvind; Beyer, Nina

    2002-01-01

    GH administration, either alone or combined with resistance exercise training (RT), has attracted interest as a means of increasing muscle mass and strength in the elderly. In the present study, 31 healthy, elderly men [age, 74 +/- 1 yr (mean +/- SEM)] were assigned to either RT [3 sessions/wk, 3......-5 sets of 8-12 repetition maximum (RM)/session] + placebo (n = 8), RT + GH (n = 8), GH (n = 8), or placebo (n = 7) in a randomized, placebo-controlled, double-blinded (RT + placebo and RT + GH) or single-blinded (GH or placebo) design. Measurements of: 1) isokinetic quadriceps muscle strength; 2......) quadriceps muscle power; 3) quadriceps muscle fiber type, size, and myosin heavy chain (MHC) composition; 4) quadriceps cross-sectional area (CSA) [nuclear magnetic resonance imaging (NMRI)]; 5) body composition (dual-energy x-ray absorptiometry scanning); and 6) GH-related serum markers were performed...

  9. Apical hypertrophic cardiomyopathy due to a de novo mutation Arg719Trp of the beta-myosin heavy chain gene and cardiac arrest in childhood. A case report and family study.

    Science.gov (United States)

    Döhlemann, C; Hebe, J; Meitinger, T; Vosberg, H P

    2000-07-01

    Hypertrophic cardiomyopathy (HCM) is a myocardial disease with variable phenotpye and genotype. To demonstrate that the mutation Arg719Trp in the cardiac beta-myosin heavy chain (beta MHC) gene is a high risk factor for sudden death and can be associated with an unusual apical non-obstructive HCM, we report the case of a 6 1/2 year old boy, who suffered cardiac arrest. The proband had a de novo mutation of the beta MHC gene (Arg719Trp) on the paternal beta MHC allele and a second maternally transmitted mutation (Met349Thr), as was shown previously (Jeschke et al. 1998 (11)). Here we report the clinical phenotype of the proband and of his relatives in detail. The proband had a marked apical and midventricular hypertrophy of the left and right ventricle without obstruction. There was an abnormal relaxation of both ventricles. Holter monitoring detected no arrhythmia. Ventricular fibrillation was inducible only by aggressive programmed stimulation. The boy died 3 1/2 years later after another cardiac arrest due to arrhythmia. Five carriers of the Met349Thr mutation in the family were asymptomatic and had no echocardiographic changes in the heart, suggesting a neutral inherited polymorphism or a recessive mutation. It is concluded that there is an association of the mutation Arg719Trp in the beta-myosin heavy chain with sudden cardiac death in a young child. Disease history in conjunction with the genetic analysis suggests that the implantation of a defibrillator converter would have been a beneficial and probably life saving measure.

  10. Static stretch promotes MEF2A nuclear translocation and expression of neonatal myosin heavy chain in C2C12 myocytes in a calcineurin- and p38-dependent manner.

    Science.gov (United States)

    Rauch, Cyril; Loughna, Paul T

    2005-03-01

    Although the effects of mechanical stimuli have been studied extensively in fully differentiated skeletal muscle and have been shown to promote changes in phenotype, including altered myosin heavy chain isoform expression, the effects of a change in mechanical environment have been poorly studied at earlier stages of skeletal muscle differentiation. In particular, the early events elicited by mechanical stimuli upon differentiating myocytes have not been investigated. In the present study, the effect of static stretch on the activation of transcriptional factors MEF2A and NFATc1, which have been shown to be involved in the differentiation and phenotype regulation of skeletal muscle, have been examined. Furthermore, putative second messenger signaling pathways that could be involved in the dephosphorylation and hence activation of these factors were also examined. We have demonstrated that static stretch application produces a robust increase in p38 phosphorylation preceding MEF2A, but not NFATc1, nuclear translocation as well as deactivation of GSK-3beta via its phosphorylation. Using SB-203580 and cyclosporine A drugs to inhibit both p38- or/and calcineurin-dependent signals, respectively, we have shown that MEF2A phosphorylation and subsequent nuclear translocation are regulated by p38 and calcineurin in a biphasic, time-dependent manner. Moreover, we also present evidence for another kinase that is involved in the stretch-related signal triggering MEF2A hyperphosphorylation, impairing its nuclear translocation, and that is related to p38. Finally, we have shown that static stretch application overnight promotes neonatal myosin heavy chain expression, which is inhibited by an inactivation of both p38 and calcineurin.

  11. Plasma vitamin D-binding protein (GC) factors, immunoglobulin G heavy chain (GM) allotypes and immunoglobulin kappa light chain (KM1) allotype in patients with sarcoidosis and in healthy control subjects

    DEFF Research Database (Denmark)

    Milman, Nils; Thymann, Mariann; Graudal, Niels

    2002-01-01

    and immunoglobulin kappa light chain (KM) allotype differed significantly from the distribution in healthy subjects. METHODS: GC 1S, 1F, 2 allotypes, GM 1, 2, 5 allotypes, and KM1 allotype were assessed in 44 patients with sarcoidosis and in healthy control subjects. RESULTS: There were no significant differences...... between the frequencies of the GC, GM and KM allotypes in sarcoidosis patients and in control subjects. Furthermore, there was no relationship between the presentation or course of the sarcoid disease and GC, GM or KM allotypes. CONCLUSIONS: GC, GM and KMI allotypes do not appear to play any major role...

  12. Impact of substrate contamination with mycotoxins, heavy metals and pesticides on the growth performance and composition of black soldier fly larvae (Hermetia illucens) for use in the feed and food value chain.

    Science.gov (United States)

    Purschke, Benedict; Scheibelberger, Rafaela; Axmann, Sonja; Adler, Andreas; Jäger, Henry

    2017-08-01

    Edible insects have emerged as an alternative and sustainable source of high-quality, animal-derived protein and fat for livestock production or direct human nutrition. During the production of insects, substrate quality is a key parameter to assure optimal insect biomass gain as well as the safety of feed and food derived from commercially reared insects. Therefore, the influence of a realistic substrate contamination scenario on growth performance and accumulation behaviour of black soldier fly larvae (BSFL; Hermetia illucens L.) was investigated. Newly hatched larvae were fed on a corn-based substrate spiked with heavy metals (As, Cd, Cr, Hg, Ni, Pb), mycotoxins (aflatoxins B1/B2/G2, deoxynivalenol, ochratoxin A, zearalenone) and pesticides (chlorpyrifos, chlorpyrifos-methyl, pirimiphos-methyl) under defined breeding conditions (10 days, 28°C, 67% relative humidity). The extent of contaminants' bioaccumulation in the larval tissue as well as the effect on growing determinants were examined. The applied heavy metal substrate contamination was shown to impair larval growing indicated by significantly lower post-trial larval mass and feed conversion ratio (FCR). Cd and Pb accumulation factors of 9 and 2, respectively, were determined, while the concentrations of other heavy metals in the larvae remained below the initial substrate concentration. In contrast, mycotoxins and pesticides have neither been accumulated in the larval tissue nor significantly affected the growing determinants in comparison with the control. The use of BSFL as livestock feed requires contaminant monitoring - especially for Cd and Pb - in the substrates as well as in feedstuff containing BSFL to ensure feed and food safety along the value chain.

  13. VaST: A variability search toolkit

    Science.gov (United States)

    Sokolovsky, K. V.; Lebedev, A. A.

    2018-01-01

    Variability Search Toolkit (VaST) is a software package designed to find variable objects in a series of sky images. It can be run from a script or interactively using its graphical interface. VaST relies on source list matching as opposed to image subtraction. SExtractor is used to generate source lists and perform aperture or PSF-fitting photometry (with PSFEx). Variability indices that characterize scatter and smoothness of a lightcurve are computed for all objects. Candidate variables are identified as objects having high variability index values compared to other objects of similar brightness. The two distinguishing features of VaST are its ability to perform accurate aperture photometry of images obtained with non-linear detectors and handle complex image distortions. The software has been successfully applied to images obtained with telescopes ranging from 0.08 to 2.5 m in diameter equipped with a variety of detectors including CCD, CMOS, MIC and photographic plates. About 1800 variable stars have been discovered with VaST. It is used as a transient detection engine in the New Milky Way (NMW) nova patrol. The code is written in C and can be easily compiled on the majority of UNIX-like systems. VaST is free software available at http://scan.sai.msu.ru/vast/.

  14. 75 FR 26160 - Drug and Drug-Related Supply Promotion by Pharmaceutical Company Sales Representatives at VA...

    Science.gov (United States)

    2010-05-11

    ... compliance with standards of ethical conduct. Pharmaceutical sales representatives have heavy interaction... gifts above the de minimis value set forth in the standards of ethical conduct for Federal employees..., describes general behavior that is prohibited on the grounds of VA property. Proposed Sec. 1.220, would...

  15. The mechanism of vinylacetylene (VA) hydrochlorination

    Energy Technology Data Exchange (ETDEWEB)

    Shestakov, G.K.; Belskii, F.I.; Airyan, S.M.; Temkin, O.N.

    1978-03-01

    The mechanism of vinylacetylene (VA) hydrochlorination in a cupric chloride solution was studied at 50/sup 0/C in a gradientless flow reactor, and chromatographic analysis identified 2- and 1-chloro-1,3-butadienes as the main products. Analysis of the reaction kinetics showed that CuCl catalyzed both 1,4 and 1,2 (Markovnikov and anti-Markovnikov types) addition of HCl to VA and that no VA conversion occurred without CuCl. The formation of both products occurred via similar many-route mechanisms, with at least one of the routes involving formation and isomerization of 4-chloro-1,2-butadiene (''allene''). Based on the results of this study together with published data on hydrochlorination and hydration of acetylene and methylacetylene, some conclusions on the effect of substituents on the mechanism of hydrochlorination of acetylene compounds were reached. Tables, graphs, and 15 references.

  16. Side-chain selective and covalent labelling of proteins by organometallic complexes of heavy transition metals--possible application in radio-crystallography of proteins.

    Science.gov (United States)

    Salmain, M; Gorfti, A; Jaouen, G

    1998-11-15

    Organo-rhenium and organo-tungsten N-succinimidyl and N-sulfosuccinimidyl esters react at amino groups of proteins to form stable amide bonds between the protein and the heavy transition metal complexes. We show here that factors such as pH of the reaction medium and nature of the reagent (coordinating metal, surrounding ligands, type of ester) had a marked influence on the final number of coupled organometallic groups per protein molecule, defined as the coupling ratio. By operating with stoichiometric quantities of reagent with respect to the number of aqino groups, up to 30 organometallic groups were introduced into the model protein, bovine serum albumin (BSA). BSA conjugates were characterized by gel electrophoresis in non-denaturating conditions. Hen egg-white lysozyme organo-tungsten conjugates were prepared in the same manner and the peptides resulting from their tryptic hydrolysis were analyzed by reverse-phase HPLC. A tentative assignment of the preferential amino sites of conjugation is suggested from the latter results.

  17. Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy.

    Science.gov (United States)

    Petropoulou, Evmorfia; Soltani, Mohammadhossein; Firoozabadi, Ali Dehghani; Namayandeh, Seyedeh Mahdieh; Crockford, Jade; Maroofian, Reza; Jamshidi, Yalda

    2017-09-01

    Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. 76 FR 75509 - Autopsies at VA Expense

    Science.gov (United States)

    2011-12-02

    ... Facilities; 64.007, Blind Rehabilitation Centers; 64.008, Veterans Domiciliary Care; 64.009, Veterans Medical Care Benefits; 64.010, Veterans Nursing Home Care; 64.014, Veterans State Domiciliary Care; 64.015...-reference to VA regulations that authorize certain outpatient and ambulatory care. The proposed rule would...

  19. A configurational and conformational study of aframodial and its diasteriomers via experimental and theoretical VA and VCD spectroscopies

    DEFF Research Database (Denmark)

    Jalkanen, Karl J.; Gale, J.D.; Lassen, Peter Rygaard

    2008-01-01

    In this work we present the experimental and theoretical vibrational absorption (VA) and the theoretical vibrational circular dichroism (VCD) spectra for aframodial. In addition, we present the theoretical VA and VCD spectra for the diasteriomers of aframodial. Aframodial has four chiral centers...... in the molecule, since one has two contributions; one due to the inherent chirality at the four chiral centers, and one due to the chirality of the side chain groups in specific conformers, that is, its helicity. Theoretical simulations for various levels of theory are compared to the experimental VA recorded...... of this molecule, even though the chiral part of the molecule is very rigid and has four chiral centers. In addition to VCD and Raman measurements, Raman optical activity (ROA) measurements would be very enlightening, as in many cases bands which are weak in both the VA and VCD, may be large in the Raman and...

  20. Analysis of VA-1 and VA4 RIA tests with FRAPTRAN and SCANAIR codes

    Energy Technology Data Exchange (ETDEWEB)

    Sagrado, I. C.; Vallejo, I.; Herranz, L. E.

    2012-07-01

    This paper summarizes the CIEMAT results of VA-1 and VA-3 RIA tests modeling with the FRAPTRAN 1.4 (PNNL) and SCANAIR 7.1 (IRSN) codes. This work is framed within the international OECD-CABRI project in which a RIA code benchmarking has been set up with a broad international participation, Both experiments were conducted in the Japanese NSRR experimental reactor.

  1. Accessing VA Healthcare During Large-Scale Natural Disasters.

    Science.gov (United States)

    Der-Martirosian, Claudia; Pinnock, Laura; Dobalian, Aram

    2017-01-01

    Natural disasters can lead to the closure of medical facilities including the Veterans Affairs (VA), thus impacting access to healthcare for U.S. military veteran VA users. We examined the characteristics of VA patients who reported having difficulty accessing care if their usual source of VA care was closed because of natural disasters. A total of 2,264 veteran VA users living in the U.S. northeast region participated in a 2015 cross-sectional representative survey. The study used VA administrative data in a complex stratified survey design with a multimode approach. A total of 36% of veteran VA users reported having difficulty accessing care elsewhere, negatively impacting the functionally impaired and lower income VA patients.

  2. Stimulatory and inhibitory mechanisms of slow muscle-specific myosin heavy chain gene expression in fish: transient and transgenic analysis of torafugu MYH(M86-2) promoter in zebrafish embryos.

    Science.gov (United States)

    Asaduzzaman, Md; Kinoshita, Shigeharu; Bhuiyan, Sharmin Siddique; Asakawa, Shuichi; Watabe, Shugo

    2013-04-01

    The myosin heavy chain gene, MYHM86-2, exhibited restricted expression in slow muscle fibers of torafugu embryos and larvae, suggesting its functional roles for embryonic and larval muscle development. However, the transcriptional mechanisms involved in its expression are still ambiguous. The present study is the first extensive analysis of slow muscle-specific MYHM86-2 promoter in fish for identifying the cis-elements that are crucial for its expression. Combining both transient transfection and transgenic approaches, we demonstrated that the 2614bp 5'-flanking sequences of MYHM86-2 contain a sufficient promoter activity to drive gene expression specific to superficial slow muscle fibers. By cyclopamine treatment, we also demonstrated that the differentiation of such superficial slow muscle fibers depends on hedgehog signaling activity. The deletion analyses defined an upstream fragment necessary for repressing ectopic MYHM86-2 expression in the fast muscle fibers. The transcriptional mechanism that prevents MYHM86-2 expression in the fast muscle fibers is mediated through Sox6 binding elements. We also demonstrated that Sox6 may function as a transcriptional repressor of MYHM86-2 expression. We further discovered that nuclear factor of activated T cells (NFAT) binding elements plays a key role and myocyte enhancer factor-2 (MEF2) binding elements participate in the transcriptional regulation of MYHM86-2 expression. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis.

    Science.gov (United States)

    Li, Aihong; Rue, Montse; Zhou, Jianbiao; Wang, Hongjun; Goldwasser, Meredith A; Neuberg, Donna; Dalton, Virginia; Zuckerman, David; Lyons, Cheryl; Silverman, Lewis B; Sallan, Stephen E; Gribben, John G

    2004-06-15

    Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the V(H) locus is involved in preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H) segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL.

  4. Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Weissler-Snir, Adaya; Hindieh, Waseem; Gruner, Christiane; Fourey, Dana; Appelbaum, Evan; Rowin, Ethan; Care, Melanie; Lesser, John R; Haas, Tammy S; Udelson, James E; Manning, Warren J; Olivotto, Iacopo; Tomberli, Benedetta; Maron, Barry J; Maron, Martin S; Crean, Andrew M; Rakowski, Harry; Chan, Raymond H

    2017-02-01

    The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (β-myosin heavy chain) and MYBPC3 (β-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se. © 2017 American Heart Association, Inc.

  5. A PCR-based integrated protocol for the structural analysis of the 13th exon of the human beta-myosin heavy chain gene (MYH7): development of a diagnostic tool for HCM disease.

    Science.gov (United States)

    Stravopodis, Dimitrios J; Zapheiropoulos, Athanassios Z; Voutsinas, Gerassimos; Margaritis, Lukas H; Papassideri, Issidora S

    2008-06-01

    Familial Hypertrophic Cardiomyopathy (FHC) constitutes a genetic disease of the sarcomere characterized by a Mendelian pattern of inheritance. A variety of different mutations affecting the at least eight sarcomeric gene products has been identified and the majority of them appear to function through a dominant negative mechanism. Family history analysis and genetic counseling have been widely adopted as integral tools for the evaluation and management of individuals with Hypertrophic Cardiomyopathy (HCM). Genetic testing of the disease has been progressively released into the clinical mainstream, thus rendering the development of novel and potent molecular diagnostic protocols an inevitable task. To this direction, we have evolved an integrated PCR-based molecular protocol, which through the utilization of novel "exonic" primers allows, among others, the structural analysis of the 13th exon of the human beta-myosin heavy chain gene locus (MYH7) mainly characterized by the critical for HCM Arginine residue 403 (R(403)). Interestingly, through a DNA sequencing approach, a single nucleotide substitution from "G" to "T" was detected in the adjacent 13th intron, thus divulging the versatile potential of the present molecular protocol to clinical practice.

  6. 38 CFR 74.27 - How will VA store information?

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false How will VA store... (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.27 How will VA store information? VA... electronically on the Department's secure servers. CVE personnel will compare information provided concerning...

  7. Troubles continue for the Phoenix VA

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-10-01

    Full Text Available No abstract available. Article truncated after 150 words. According to the Joint Commission on the Accreditation of Healthcare Organizations (Joint Commission, JCAHO, an independent organization that reviews hospitals, the Phoenix VA does not comply with U.S. standards for safety, patient care and management (1. The hospital was at the epicenter of the national scandal over the quality of care being afforded to the nation's veterans where the now notorious practice of double-booking patient appointments was first exposed. The hospital's indifferent management provoked congressional investigations that uncovered still more system-wide abuses leading to the removal of the hospital director and the resignation of then VA secretary, Eric Shinseki. The hospital maintains its accreditation but with a follow-up survey in 1-6 months where it must show that it has successfully addressed the 13 identified problems (1. Inspectors who conducted the review in July found that VA employees were unable to report concerns "without retaliatory action from the hospital." Other alarming ...

  8. Influence of PVP/VA copolymer composition on drug-polymer solubility.

    Science.gov (United States)

    Rask, Malte Bille; Knopp, Matthias Manne; Olesen, Niels Erik; Holm, René; Rades, Thomas

    2016-03-31

    In this study, the influence of copolymer composition on drug-polymer solubility was investigated. The solubility of the model drug celecoxib (CCX) in various polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w) and the pure homopolymers polyvinylpyrrolidone (PVP) and polyvinyl acetate (PVA) was predicted at 25 °C using a thermal analysis method based on the recrystallization of a supersaturated amorphous dispersion (recrystallization method). These solubilities were compared with a prediction based on the solubility of CCX in the liquid monomeric precursors of PVP/VA, N-vinylpyrrolidone (NVP) and vinyl acetate (VA), using the Flory-Huggins lattice theory (liquid monomer solubility approach). The solubilities predicted from the liquid monomer solubility approach increased linearly with increasing VP/VA ratio from 0.03-0.60 w/w. Even though the solubilities predicted from the recrystallization method also increased with increasing VP/VA ratio from 0.02-0.40 w/w, the predicted solubility seemed to approach a plateau at high VP/VA ratios. Increasing positive deviations from the Gordon-Taylor equation with increasing VP/VA ratio indicated strong interactions between CCX and the VP repeat unit, which was in accordance with the relatively high solubilities predicted using both methods. As the solubility plateau may be a consequence of steric hindrance caused by the size differences between CCX and the VP repeat units, it is likely that a CCX molecule interacting with a VP repeat unit hinders another CCX molecule from binding to the neighboring repeat units in the polymer chain. Therefore, it is possible that replacing these neighboring hygroscopic VP repeat units with hydrophobic VA repeat units, could increase the physical stability of an amorphous solid dispersion without compromising the drug-polymer solubility. This knowledge could be used advantageously in future development of amorphous drug delivery systems as

  9. The Glycosylphosphatidylinositol-Anchored Variable Region of Llama Heavy Chain-Only Antibody JM4 Efficiently Blocks both Cell-Free and T Cell-T Cell Transmission of Human Immunodeficiency Virus Type 1.

    Science.gov (United States)

    Liu, Lihong; Wang, Weiming; Matz, Julie; Ye, Chaobaihui; Bracq, Lucie; Delon, Jerome; Kimata, Jason T; Chen, Zhiwei; Benichou, Serge; Zhou, Paul

    2016-12-01

    The variable regions (VHHs) of two heavy chain-only antibodies, JM2 and JM4, from llamas that have been immunized with a trimeric gp140 bound to a CD4 mimic have been recently isolated (here referred to as VHH JM2 and VHH JM4, respectively). JM2 binds the CD4-binding site of gp120 and neutralizes HIV-1 strains from subtypes B, C, and G. JM4 binds gp120 and neutralizes HIV-1 strains from subtypes A, B, C, A/E, and G in a CD4-dependent manner. In the present study, we constructed glycosylphosphatidylinositol (GPI)-anchored VHH JM2 and JM4 along with an E4 control and transduced them into human CD4+ cell lines and primary CD4 T cells. We report that by genetically linking the VHHs with a GPI attachment signal, VHHs are targeted to the lipid rafts of the plasma membranes. Expression of GPI-VHH JM4, but not GPI-VHH E4 and JM2, on the surface of transduced TZM.bl cells potently neutralizes multiple subtypes of HIV-1 isolates, including tier 2 or 3 strains, transmitted founders, quasispecies, and soluble single domain antibody (sdAb) JM4-resistant viruses. Moreover, transduction of CEMss-CCR5 cells with GPI-VHH JM4, but not with GPI-VHH E4, confers resistance to both cell-free and T cell-T cell transmission of HIV-1 and HIV-1 envelope-mediated fusion. Finally, GPI-VHH JM4-transduced human primary CD4 T cells efficiently resist both cell-free and T cell-T cell transmission of HIV-1. Thus, we conclude that VHH JM4, when targeted to the lipid rafts of the plasma membrane, efficiently neutralizes HIV-1 infection via both cell-free and T cell-T cell transmission. Our findings should have important implications for GPI-anchored antibody-based therapy against HIV-1. Lipid rafts are specialized dynamic microdomains of the plasma membrane and have been shown to be gateways for HIV-1 budding as well as entry into T cells and macrophages. In nature, many glycosylphosphatidylinositol (GPI)-anchored proteins localize in the lipid rafts. In the present study, we developed GPI

  10. Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington's Disease.

    Science.gov (United States)

    Hering, Tanja; Braubach, Peter; Landwehrmeyer, G Bernhard; Lindenberg, Katrin S; Melzer, Werner

    2016-01-01

    Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene. We investigated alterations in the extensor digitorum longus (EDL), a typical fast-twitch muscle, and the soleus (SOL), a slow-twitch muscle. We focussed on mechanographic measurements of excised muscles using single and repetitive electrical stimulation and on the expression of the various myosin isoforms (heavy and light chains) using dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole muscle and single fiber preparations. In EDL of R6/2, the functional tests showed a left shift of the force-frequency relation and decrease in specific force. Moreover, the estimated relative contribution of the fastest myosin isoform MyHC IIb decreased, whereas the contribution of the slower MyHC IIx isoform increased. An additional change occurred in the alkali MyLC forms showing a decrease in 3f and an increase in 1f level. In SOL, a shift from fast MyHC IIa to the slow isoform I was detectable in male R6/2 mice only, and there was no evidence of isoform interconversion in the MyLC pattern. These alterations point to a partial remodeling of the contractile apparatus of R6/2 mice towards a slower contractile phenotype, predominantly in fast glycolytic fibers.

  11. A heterodimer of a VHH (variable domains of camelid heavy chain-only) antibody that inhibits anthrax toxin cell binding linked to a VHH antibody that blocks oligomer formation is highly protective in an anthrax spore challenge model.

    Science.gov (United States)

    Moayeri, Mahtab; Leysath, Clinton E; Tremblay, Jacqueline M; Vrentas, Catherine; Crown, Devorah; Leppla, Stephen H; Shoemaker, Charles B

    2015-03-06

    Anthrax disease is caused by a toxin consisting of protective antigen (PA), lethal factor, and edema factor. Antibodies against PA have been shown to be protective against the disease. Variable domains of camelid heavy chain-only antibodies (VHHs) with affinity for PA were obtained from immunized alpacas and screened for anthrax neutralizing activity in macrophage toxicity assays. Two classes of neutralizing VHHs were identified recognizing distinct, non-overlapping epitopes. One class recognizes domain 4 of PA at a well characterized neutralizing site through which PA binds to its cellular receptor. A second neutralizing VHH (JKH-C7) recognizes a novel epitope. This antibody inhibits conversion of the PA oligomer from "pre-pore" to its SDS and heat-resistant "pore" conformation while not preventing cleavage of full-length 83-kDa PA (PA83) by cell surface proteases to its oligomer-competent 63-kDa form (PA63). The antibody prevents endocytosis of the cell surface-generated PA63 subunit but not preformed PA63 oligomers formed in solution. JKH-C7 and the receptor-blocking VHH class (JIK-B8) were expressed as a heterodimeric VHH-based neutralizing agent (VNA2-PA). This VNA displayed improved neutralizing potency in cell assays and protected mice from anthrax toxin challenge with much better efficacy than the separate component VHHs. The VNA protected virtually all mice when separately administered at a 1:1 ratio to toxin and protected mice against Bacillus anthracis spore infection. Thus, our studies show the potential of VNAs as anthrax therapeutics. Due to their simple and stable nature, VNAs should be amenable to genetic delivery or administration via respiratory routes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. A Novel Alpha Cardiac Actin (ACTC1 Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects.

    Directory of Open Access Journals (Sweden)

    Céline Augière

    Full Text Available A Lebanese Maronite family presented with 13 relatives affected by various congenital heart defects (mainly atrial septal defects, conduction tissue anomalies and midline defects. No mutations were found in GATA4 and NKX2-5.A set of 399 poly(AC markers was used to perform a linkage analysis which peaked at a 2.98 lod score on the long arm of chromosome 15. The haplotype analysis delineated a 7.7 meganucleotides genomic interval which included the alpha-cardiac actin gene (ACTC1 among 36 other protein coding genes. A heterozygous missense mutation was found (c.251T>C, p.(Met84Thr in the ACTC1 gene which changed a methionine residue conserved up to yeast. This mutation was absent from 1000 genomes and exome variant server database but segregated perfectly in this family with the affection status. This mutation and 2 other ACTC1 mutations (p.(Glu101Lys and p.(Met125Val which result also in congenital heart defects are located in a region in close apposition to a myosin heavy chain head region by contrast to 3 other alpha-cardiac actin mutations (p.(Ala297Ser,p.(Asp313His and p.(Arg314His which result in diverse cardiomyopathies and are located in a totally different interaction surface.Alpha-cardiac actin mutations lead to congenital heart defects, cardiomyopathies and eventually midline defects. The consequence of an ACTC1 mutation may in part be dependent on the interaction surface between actin and myosin.

  13. Increased cardiac alpha-myosin heavy chain in left atria and decreased myocardial insulin-like growth factor (Igf-I) expression accompany low heart rate in hibernating grizzly bears.

    Science.gov (United States)

    Barrows, N D; Nelson, O L; Robbins, C T; Rourke, B C

    2011-01-01

    Grizzly bears (Ursus arctos horribilis) tolerate extended periods of extremely low heart rate during hibernation without developing congestive heart failure or cardiac chamber dilation. Left ventricular atrophy and decreased left ventricular compliance have been reported in this species during hibernation. We evaluated the myocardial response to significantly reduced heart rate during hibernation by measuring relative myosin heavy-chain (MyHC) isoform expression and expression of a set of genes important to muscle plasticity and mass regulation in the left atria and left ventricles of active and hibernating bears. We supplemented these data with measurements of systolic and diastolic function via echocardiography in unanesthetized grizzly bears. Atrial strain imaging revealed decreased atrial contractility, decreased expansion/reservoir function (increased atrial stiffness), and decreased passive-filling function (increased ventricular stiffness) in hibernating bears. Relative MyHC-α protein expression increased significantly in the atrium during hibernation. The left ventricle expressed 100% MyHC-β protein in both groups. Insulin-like growth factor (IGF-I) mRNA expression was reduced by ∼50% in both chambers during hibernation, consistent with the ventricular atrophy observed in these bears. Interestingly, mRNA expression of the atrophy-related ubiquitin ligases Muscle Atrophy F-box (MAFBx) and Muscle Ring Finger 1 did not increase, nor did expression of myostatin or hypoxia-inducible factor 1α (HIF-1α). We report atrium-specific decreases of 40% and 50%, respectively, in MAFBx and creatine kinase mRNA expression during hibernation. Decreased creatine kinase expression is consistent with lowered energy requirements and could relate to reduced atrial emptying function during hibernation. Taken together with our hemodynamic assessment, these data suggest a potential downregulation of atrial chamber function during hibernation to prevent fatigue and dilation

  14. 48 CFR 853.215-70 - VA Form 10-1170, Application for Furnishing Nursing Home Care to Beneficiaries of VA.

    Science.gov (United States)

    2010-10-01

    ..., Application for Furnishing Nursing Home Care to Beneficiaries of VA. 853.215-70 Section 853.215-70 Federal... 853.215-70 VA Form 10-1170, Application for Furnishing Nursing Home Care to Beneficiaries of VA. VA Form 10-1170, Application for Furnishing Nursing Home Care to Beneficiaries of VA, will be used for...

  15. Gangrenous cholecystitis in an urban VA hospital.

    Science.gov (United States)

    Wilson, A K; Kozol, R A; Salwen, W A; Manov, L J; Tennenberg, S D

    1994-05-01

    Gangrenous cholecystitis is an advanced form of acute cholecystitis associated with increased morbidity and mortality. We sought to determine the incidence of gangrenous cholecystitis in an urban VA hospital patient population and identify any distinguishing characteristics that may aid in its preoperative diagnosis. We retrospectively reviewed all urgent admissions that underwent cholecystectomy (n = 65) over the past 7 years at the Allen Park VAMC. Using histologic criteria, 17 (26%) of these patients had gangrenous cholecystitis. As a group compared to patients with nongangrenous cholecystitis, patients with gangrenous cholecystitis were statistically older (64 vs 54) and had an elevated WBC (15.4 vs 11.5) and increased serum glucose levels (203 vs 141). Preoperative imaging studies (ultrasound and cholescintigraphy) correctly identified only 31% of the gangrenous cholecystitis patients. We conclude that in an urban VA hospital patient population, the diagnosis of gangrenous cholecystitis cannot be accurately made or ruled out among urgent admissions with acute biliary disease. Considering the high incidence (26%) and difficulty confirming the diagnosis of gangrenous cholecystitis in this setting, we recommend early surgical intervention for this and similar patient populations.

  16. Visionary leadership and the future of VA health system.

    Science.gov (United States)

    Bezold, C; Mayer, E; Dighe, A

    1997-01-01

    As the U.S. Department of Veterans Affairs (VA) makes the change over to Veterans Integrated Service Network (VISNs) the need for new and better leadership is warranted if VA wants to not only survive, but thrive in the emerging twenty-first century healthcare system. VA can prepare for the future and meet the challenges facing them by adopting a system of visionary leadership. The use of scenarios and vision techniques are explained as they relate to VA's efforts to move toward their new system of VISNs. The four scenarios provide snapshots of possible futures for the U.S. healthcare system as well as the possible future role and mission of VA--from VA disappearing to its becoming a premier virtual organization.

  17. VA/DoD Joint Executive Council Fiscal Year 2010

    Science.gov (United States)

    2010-01-01

    Medical Department (AMEDD) Center and School and the Military Departments to provide training to additional personnel. Joint VA/DoD training in TBI...Capital Region, VA initiated a “ paperless ” program for processing all DES claims electronically. VA worked with the MTFs in the National Capital...Management System for paperless claims processing. On March 29, 2010, DoD implemented a policy entitled “Cross-Service Support and Service Organization

  18. Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not.

    Science.gov (United States)

    Castorena, Carlos M; Mackrell, James G; Bogan, Jonathan S; Kanzaki, Makoto; Cartee, Gregory D

    2011-10-01

    Skeletal muscle is a heterogeneous tissue. To further elucidate this heterogeneity, we probed relationships between myosin heavy chain (MHC) isoform composition and abundance of GLUT4 and four other proteins that are established or putative GLUT4 regulators [Akt substrate of 160 kDa (AS160), Tre-2/Bub2/Cdc 16-domain member 1 (TBC1D1), Tethering protein containing an UBX-domain for GLUT4 (TUG), and RuvB-like protein two (RUVBL2)] in 12 skeletal muscles or muscle regions from Wistar rats [adductor longus, extensor digitorum longus, epitrochlearis, gastrocnemius (mixed, red, and white), plantaris, soleus, tibialis anterior (red and white), tensor fasciae latae, and white vastus lateralis]. Key results were 1) significant differences found among the muscles (range of muscle expression values) for GLUT4 (2.5-fold), TUG (1.7-fold), RUVBL2 (2.0-fold), and TBC1D1 (2.7-fold), but not AS160; 2) significant positive correlations for pairs of proteins: GLUT4 vs. TUG (R = 0.699), GLUT4 vs. RUVBL2 (R = 0.613), TUG vs. RUVBL2 (R = 0.564), AS160 vs. TBC1D1 (R = 0.293), and AS160 vs. TUG (R = 0.246); 3) significant positive correlations for %MHC-I: GLUT4 (R = 0.460), TUG (R = 0.538), and RUVBL2 (R = 0.511); 4) significant positive correlations for %MHC-IIa: GLUT4 (R = 0.293) and RUVBL2 (R = 0.204); 5) significant negative correlations for %MHC-IIb vs. GLUT4 (R = -0.642), TUG (R = -0.626), and RUVBL2 (R = -0.692); and 6) neither AS160 nor TBC1D1 significantly correlated with MHC isoforms. In 12 rat muscles, GLUT4 abundance tracked with TUG and RUVBL2 and correlated with MHC isoform expression, but was unrelated to AS160 or TBC1D1. Our working hypothesis is that some of the mechanisms that regulate GLUT4 abundance in rat skeletal muscle also influence TUG and RUVBL2 abundance.

  19. Stimulatory and inhibitory mechanisms of slow muscle-specific myosin heavy chain gene expression in fish: Transient and transgenic analysis of torafugu MYH{sub M86-2} promoter in zebrafish embryos

    Energy Technology Data Exchange (ETDEWEB)

    Asaduzzaman, Md. [Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo 113-8657 (Japan); Kinoshita, Shigeharu, E-mail: akino@mail.ecc.u-tokyo.ac.jp [Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo 113-8657 (Japan); Bhuiyan, Sharmin Siddique; Asakawa, Shuichi [Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo 113-8657 (Japan); Watabe, Shugo [Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo 113-8657 (Japan); School of Marine Biosciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 (Japan)

    2013-04-01

    The myosin heavy chain gene, MYH{sub M86-2}, exhibited restricted expression in slow muscle fibers of torafugu embryos and larvae, suggesting its functional roles for embryonic and larval muscle development. However, the transcriptional mechanisms involved in its expression are still ambiguous. The present study is the first extensive analysis of slow muscle-specific MYH{sub M86-2} promoter in fish for identifying the cis-elements that are crucial for its expression. Combining both transient transfection and transgenic approaches, we demonstrated that the 2614 bp 5′-flanking sequences of MYH{sub M86-2} contain a sufficient promoter activity to drive gene expression specific to superficial slow muscle fibers. By cyclopamine treatment, we also demonstrated that the differentiation of such superficial slow muscle fibers depends on hedgehog signaling activity. The deletion analyses defined an upstream fragment necessary for repressing ectopic MYH{sub M86-2} expression in the fast muscle fibers. The transcriptional mechanism that prevents MYH{sub M86-2} expression in the fast muscle fibers is mediated through Sox6 binding elements. We also demonstrated that Sox6 may function as a transcriptional repressor of MYH{sub M86-2} expression. We further discovered that nuclear factor of activated T cells (NFAT) binding elements plays a key role and myocyte enhancer factor-2 (MEF2) binding elements participate in the transcriptional regulation of MYH{sub M86-2} expression. - Highlights: ► MYH{sub M86-2} is highly expressed in slow muscle fibers of torafugu embryos and larvae. ► MYH{sub M86-2} promoter activity depends on the hedgehog signaling. ► Sox6 binding elements inhibits MYH{sub M86-2} expression in fast muscle fibers. ► Sox6 elements function as transcriptional repressor of MYH{sub M86-2} promoter activity. ► NFAT and MEF2 binding elements play a key role for directing MYH{sub M86-2} expression.

  20. Dystrophin deficiency in canine X-linked muscular dystrophy in Japan (CXMDJ alters myosin heavy chain expression profiles in the diaphragm more markedly than in the tibialis cranialis muscle

    Directory of Open Access Journals (Sweden)

    Hijikata Takao

    2008-01-01

    Full Text Available Abstract Background Skeletal muscles are composed of heterogeneous collections of muscle fiber types, the arrangement of which contributes to a variety of functional capabilities in many muscle types. Furthermore, skeletal muscles can adapt individual myofibers under various circumstances, such as disease and exercise, by changing fiber types. This study was performed to examine the influence of dystrophin deficiency on fiber type composition of skeletal muscles in canine X-linked muscular dystrophy in Japan (CXMDJ, a large animal model for Duchenne muscular dystrophy. Methods We used tibialis cranialis (TC muscles and diaphragms of normal dogs and those with CXMDJ at various ages from 1 month to 3 years old. For classification of fiber types, muscle sections were immunostained with antibodies against fast, slow, or developmental myosin heavy chain (MHC, and the number and size of these fibers were analyzed. In addition, MHC isoforms were detected by gel electrophoresis. Results In comparison with TC muscles of CXMDJ, the number of fibers expressing slow MHC increased markedly and the number of fibers expressing fast MHC decreased with growth in the affected diaphragm. In populations of muscle fibers expressing fast and/or slow MHC(s but not developmental MHC of CXMDJ muscles, slow MHC fibers were predominant in number and showed selective enlargement. Especially, in CXMDJ diaphragms, the proportions of slow MHC fibers were significantly larger in populations of myofibers with non-expression of developmental MHC. Analyses of MHC isoforms also indicated a marked increase of type I and decrease of type IIA isoforms in the affected diaphragm at ages over 6 months. In addition, expression of developmental (embryonic and/or neonatal MHC decreased in the CXMDJ diaphragm in adults, in contrast to continuous high-level expression in affected TC muscle. Conclusion The CXMDJ diaphragm showed marked changes in fiber type composition unlike TC muscles

  1. Myosin heavy chain expression pattern as a marker for anabolic potency: desoxymethyltestosterone (madol), norandrostenedione and testosterone repress MHC-IIb expression and stimulate MHC-IId/x expression in orchiectomized rat gastrocnemius muscle.

    Science.gov (United States)

    Frese, S; Velders, M; Schleipen, B; Schänzer, W; Bloch, W; Diel, P

    2011-06-01

    Both 19-norandrostenedione (estr-4-ene-3,17-dione, NOR) and desoxymethyltestosterone (17alpha-methyl-5alpha-androst-2-en-17beta-ol, DMT or "madol") are 'designer steroids' misused for doping purposes in the bodybuilding scene. We have previously characterized the pharmacological profile of madol and identified potential adverse side effects. The aim of this study was to investigate the anabolic potency of NOR, madol and the reference substance testosterone propionate (TP). Besides wet weight of the M.levator ani (LA), we examined the effects on muscle fiber type composition and myosin heavy chain (MHC) expression in the M.gastrocnemius (Gas) muscle as additional markers for anabolic potency. A Hershberger assay was performed, where orchiectomized (orchi) male Wistar rats were treated subcutaneously with NOR, madol, TP or vehicle control (all 1 mg/kg BW/day) for 12 days. Wet weights of the Gas, LA, prostate and seminal vesicle were examined to determine anabolic and androgenic effects. Fiber type composition of the Gas muscle was analyzed using ATPase staining, and MHC protein profiles were determined by silver stain and Western blot analysis. NOR and madol exhibited strong anabolic and weak androgenic potency by stimulating growth of the LA but not the prostate and seminal vesicle. Skeletal muscle fiber type composition characterized by ATPase staining was not significantly altered between the treatment groups, although there was a tendency toward lower levels of type IIB and increased type IIA fibers in all treatment groups relative to orchi. MHC protein expression determined by Western blot and silver stain analysis revealed that MHC IId/x was significantly up-regulated, while MHC IIb was significantly down-regulated in NOR, madol and TP groups relative to orchi. There were no significant differences for MHC IIa and MHC I expression between groups. Results suggest that the observed MHC expression shift could serve as a molecular marker to determine anabolic

  2. VA office of inspector general releases scathing report of Phoenix VA

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-08-01

    Full Text Available No abstract available. Article truncated at 150 words. The long-awaited Office of Inspector General’s (OIG report on the Phoenix VA Health Care System (PVAHCS was released on August 27, 2014 (1. The report was scathing in its evaluation of VA practices and leadership. Five questions were investigated: 1.Were there clinically significant delays in care? 2. Did PVAHCS omit the names of veterans waiting for care from its Electronic Wait List (EWL? 3. Were PVAHCS personnel not following established scheduling procedures? 4. Did the PVAHCS culture emphasize goals at the expense of patient care? 5. Are scheduling deficiencies systemic throughout the VA? In each case, the OIG found that the allegations were true. Despite initial denials, the OIG report showed that former PVAHCS director Sharon Helman, associate director Lance Robinson, hospital administration director Brad Curry, chief of staff Darren Deering and other senior executives were aware of delays in care and unofficial wait lists. Perhaps most disturbing is ...

  3. Effect of common dead space on VA/Q distribution in the dog.

    Science.gov (United States)

    Tsukimoto, K; Arcos, J P; Schaffartzik, W; Wagner, P D; West, J B

    1990-06-01

    Several previous studies have shown worsening ventilation-perfusion (VA/Q) relationships in humans during heavy exercise at sea level. However, the mechanism of this deterioration remains unclear because of the correlation with ventilatory and circulatory variables. Our hypothesis was that the decrease in the series dead space-to-tidal volume ratio during exercise might be partly responsible because mixing in the common dead space can reduce apparent inequality. We tested this notion in 10 resting anesthetized normocapnic dogs passively hyperventilated by increase tidal volume and a) inspired CO2 or b) external dead space. We predicted less apparent VA/Q inequality in condition b because of mixing in the added dead space. After base-line measurements, conditions a and b were randomly assigned, and after a second set of base-line measurements they were repeated in the reverse order in each dog. VA/Q inequality was measured by the multiple inert gas elimination technique. Comparison of conditions a and b demonstrated that additional external dead space improved (P less than 0.001) the blood flow distributions as hypothesized [log standard deviation of perfusion = 0.49 +/- 0.02 (SE) in condition b and 0.61 +/- 0.03 in condition a with respect to 0.52 +/- 0.03 at base line]. This study suggests that the increased tidal volume during exercise could uncover VA/Q inequality not evident at rest because of the higher ratio of common dead space to tidal volume at rest.

  4. 76 FR 52230 - Establishment of Class E Airspace; Forest, VA

    Science.gov (United States)

    2011-08-22

    ... Federal Aviation Administration 14 CFR Part 71 Establishment of Class E Airspace; Forest, VA AGENCY... Airspace at Forest, VA, to accommodate the new Area Navigation (RNAV) Global Positioning System (GPS... published in the Federal Register a notice of proposed rulemaking to establish Class E airspace at Forest...

  5. 77 FR 70967 - Authorization for Non-VA Medical Services

    Science.gov (United States)

    2012-11-28

    ..., Mental health programs, Nursing homes, Reporting and recordkeeping requirements, Veterans. Dated... may use this authority to provide needed non- VA care using community resources, such as private physicians or community hospitals. Care provided under VA's authority in 38 U.S.C. 1703 is usually referred...

  6. D-Va category phenotype and genotype in Japanese families

    NARCIS (Netherlands)

    Legler, TJ; Wiemann, [No Value; Ohto, H; Matuda, [No Value; Obara, T; Uchikawa, M; Kohler, M

    2000-01-01

    Background and Objectives: The genetic background of the D-Va category phenotype has been described in two Caucasian individuals. We were interested in the RHD sequence of 7 Japanese D-Va individuals and their families. Materials and Methods: With SSP-PCR we tested exons 4, 5 and 7 of the RHD gene

  7. Microcirculatory assessment of patients under VA-ECMO

    NARCIS (Netherlands)

    Kara, Atila; Akin, Sakir; Dos Reis Miranda, Dinis; Struijs, Ard; Caliskan, Kadir; van Thiel, Robert J.; Dubois, Eric A.; de Wilde, Wouter; Zijlstra, Felix; Gommers, Diederik; Ince, Can

    2016-01-01

    Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an effective technique for providing emergency mechanical circulatory support for patients with cardiogenic shock. VA-ECMO enables a rapid restoration of global systemic organ perfusion, but it has not been found to always show a

  8. Microcirculatory assessment of patients under VA-ECMO

    NARCIS (Netherlands)

    A. Kara (Atila); S. Akin (Sakir); D. dos Reis Miranda (Dinis); A. Struijs (Ard); K. Caliskan (Kadir); R.J. van Thiel (Robert); E.A. Dubois; de Wilde, W. (Wouter); F. Zijlstra (Felix); D.A.M.P.J. Gommers (Diederik); C. Ince (Can)

    2016-01-01

    textabstractBackground: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an effective technique for providing emergency mechanical circulatory support for patients with cardiogenic shock. VA-ECMO enables a rapid restoration of global systemic organ perfusion, but it has not been found

  9. VaR Methodology Application for Banking Currency Portfolios

    Directory of Open Access Journals (Sweden)

    Daniel Armeanu

    2007-02-01

    Full Text Available VaR has become the standard measure that financial analysts use to quantify market risk. VaR measures can have many applications, such as in risk management, to evaluate the performance of risk takers and for regulatory requirements, and hence it is very important to develop methodologies that provide accurate estimates. In particular, the Basel Committee on Banking Supervision at the Bank for International Settlements imposes to financial institutions such as banks and investment firms to meet capital requirements based on VaR estimates. In this paper we determine VaR for a banking currency portfolio and respect rules of National Bank of Romania regarding VaR report.

  10. Trade in Value Added (TiVA in EU New Member States (EU NMS

    Directory of Open Access Journals (Sweden)

    Ines Kersan-Škabić

    2017-01-01

    Full Text Available Contemporary trade analysis indicates the necessity of calculating trade in value added (TiVA which is created through global value chains (GVCs. This paper aims to determine the characteristics and importance of GVC trade in the EU new member states (EU NMS with special emphasis placed on the industry level. The results demonstrate different levels of GVC participation of the EU NMS, where Hungary is the most integrated country and Croatia the least integrated. Regional GVCs exist because a huge part of value added (VA comes from EU member states, as in gross export as well as in final demand (Europe as a hub. The most important source countries are Germany and Italy and there is also evidence of geographical and historical relations between the countries. The domination of backward participation has been found in the analysis made on the industrial level, i.e. the EU NMS are highly dependent on the import of intermediates for the production and export of final products. Strong interconnections between imports of intermediate products and exports of final products have been found in the manufacture of computers, electronics and optical products; manufacture of wood, paper, printing and reproduction. This research has contributed to the scarce literature concerning GVC (TiVA in EU NMS and has opened up new possibilities for further research and analysis.

  11. 76 FR 40453 - Agency Information Collection (Application for VA Education Benefits) Activity Under OMB Review

    Science.gov (United States)

    2011-07-08

    ... AFFAIRS Agency Information Collection (Application for VA Education Benefits) Activity Under OMB Review... INFORMATION: Titles: a. Application for VA Education Benefits, VA Form 22-1990. b. Application for Family Member to Use Transferred Benefits, VA Form 22-1990E. ] c. Application for VA Education Benefits Under...

  12. Direct observation of the myosin Va recovery stroke that contributes to unidirectional stepping along actin.

    Directory of Open Access Journals (Sweden)

    Katsuyuki Shiroguchi

    2011-04-01

    Full Text Available Myosins are ATP-driven linear molecular motors that work as cellular force generators, transporters, and force sensors. These functions are driven by large-scale nucleotide-dependent conformational changes, termed "strokes"; the "power stroke" is the force-generating swinging of the myosin light chain-binding "neck" domain relative to the motor domain "head" while bound to actin; the "recovery stroke" is the necessary initial motion that primes, or "cocks," myosin while detached from actin. Myosin Va is a processive dimer that steps unidirectionally along actin following a "hand over hand" mechanism in which the trailing head detaches and steps forward ∼72 nm. Despite large rotational Brownian motion of the detached head about a free joint adjoining the two necks, unidirectional stepping is achieved, in part by the power stroke of the attached head that moves the joint forward. However, the power stroke alone cannot fully account for preferential forward site binding since the orientation and angle stability of the detached head, which is determined by the properties of the recovery stroke, dictate actin binding site accessibility. Here, we directly observe the recovery stroke dynamics and fluctuations of myosin Va using a novel, transient caged ATP-controlling system that maintains constant ATP levels through stepwise UV-pulse sequences of varying intensity. We immobilized the neck of monomeric myosin Va on a surface and observed real time motions of bead(s attached site-specifically to the head. ATP induces a transient swing of the neck to the post-recovery stroke conformation, where it remains for ∼40 s, until ATP hydrolysis products are released. Angle distributions indicate that the post-recovery stroke conformation is stabilized by ≥ 5 k(BT of energy. The high kinetic and energetic stability of the post-recovery stroke conformation favors preferential binding of the detached head to a forward site 72 nm away. Thus, the recovery

  13. Time for the VA to clean up its act

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2015-06-01

    Full Text Available No abstract available. Article truncated after 150 words. One year after a Veterans Affairs (VA scandal was ignited here in Phoenix, the number of veterans on wait lists is 50 percent higher than at the same time last year, according to VA data (1. The VA is also facing a nearly $3 billion budget shortfall. VA Secretary Bob McDonald has asked for “flexibility” to reallocate billions of dollars in clinical funds to cover the shortfall. Since the scandal broke last year, VA providers have increased their workloads, adding 2.7 million more appointments than the previous year. However, the VA has played "games" with patient eligibility for years. When money was plentiful VA administrators would open the doors to patients since the following years' budgets were based on the number of patients seen. However, when money was tight, the doors would be slammed shut leaving many patients in the lurch scrambling to obtain health care elsewhere. Now it appears ...

  14. VA INFORMATION SYSTEMS: Computer Security Weaknesses Persist at the Veterans Health Administration

    National Research Council Canada - National Science Library

    2000-01-01

    .... To determine the status of computer security within VHA, we (1) evaluated information system general controls at the VA Maryland Health Cafe System, the New Mexico VA Health Care System, and the VA North Texas Health Care System and (2...

  15. Heavy metal

    African Journals Online (AJOL)

    niloticus after exposure to sublethal concentrations of heavy metals such as copper, lead and zinc for a 12-week period, using static renewable toxicity tests. The concentrations of the metals accumulated in the tissue of exposed fish were about 3-5 times higher than the concentrations detected in control fish.

  16. Menorrhagia (Heavy Menstrual Bleeding)

    Science.gov (United States)

    Menorrhagia (heavy menstrual bleeding) Overview Menorrhagia is the medical term for menstrual periods with abnormally heavy or prolonged bleeding. Although heavy menstrual bleeding is a common concern, ...

  17. Effects of a traditional Chinese medicine formula and its extraction on muscle fiber characteristics in finishing pigs, porcine cell proliferation and isoforms of myosin heavy chain gene expression in myocytes

    Directory of Open Access Journals (Sweden)

    Qin Ping Yu

    2017-11-01

    Full Text Available Objective This study evaluated the effects of a traditional Chinese medicine formula (TCMF on muscle fiber characteristics in finishing pigs and the effects of the formula’s extract (distilled water, ethyl acetate and petroleum ether extraction on porcine cell proliferation and isoforms of myosin heavy chain (MyHC gene expression in myocytes. Methods In a completely randomized design, ninety pigs were assigned to three diets with five replications per treatment and six pigs per pen. The diets included the basal diet (control group, TCMF1 (basal diet+2.5 g/kg TCMF and TCMF2 (basal diet+5 g/kg TCMF. The psoas major muscle was obtained from pigs at the end of the experiment. Muscle fiber characteristics in the psoas major muscle were analyzed using myosin ATPase staining. Cell proliferation was measured using 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT dye and cytometry. Isoforms of MyHC gene expression were detected by real-time quantitative polymerase chain reaction. Results The final body weight and carcass weight of finishing pigs were increased by TCMF1 (p<0.05, while the psoas major muscle cross-sectional area was increased by TCMF (p<0.05. The cross-sectional area and diameter of psoas major muscle fiber I, IIA, and IIB were increased by TCMF2 (p<0.05. The cross-sectional area and fiber diameter of psoas major muscle fiber IIA and IIB were increased by diet supplementation with TCMF1 (p<0.05. Psoas major muscle fiber IIA and IIB fiber density from the pigs fed the TCMF1 diet and the type IIB fiber density from the pigs fed the TCMF2 diet were lower compared to pigs fed the control diet (p<0.05. Pigs fed TCMF2 had a higher composition of type I fiber and a lower percentage of type IIB fiber in the psoas major muscle (p<0.05. The expression levels of MyHC I, MyHC IIa, and MyHC IIx mRNA increased and the amount of MyHC IIb mRNA decreased in the psoas major muscle from TCMF2, whereas MyHC I and MyHC IIx mRNA increased

  18. SlaVaComp: Konvertierungstool (= SlaVaComp Fonts Converter

    Directory of Open Access Journals (Sweden)

    Simon Skilevic

    2013-12-01

    Full Text Available Der vorliegende Beitrag informiert über ein Tool, das im Rahmen eines Freiburger Projekts zur historischen Korpuslinguistik entwickelt wurde und dazu dient, kirchenslavische Texte, die ohne Einsatz von Unicode digitalisiert wurden, ohne Verlust von Information bzw. Formatierung ins Unicode-Format zu überführen. Das Tool heißt SlaVaComp-Konvertierer. Es eignet sich für die Konvertierung aller idiosynkratischen Fonts und kann somit nicht nur in der Paläoslavistik, sondern in allen historisch arbeitenden Philologien eingesetzt werden. ____________________ This paper presents a fonts converter that was developed as a part of the Freiburg project on historical corpus linguistics. The tool named SlaVaComp-Konvertierer converts Church Slavonic texts digitized with non-Unicode fonts into the Unicode format without any loss of information contained in the original file and without damage to the original formatting. It is suitable for the conversion of all idiosyncratic fonts—not only Church Slavonic—and therefore can be used not only in Palaeoslavistic, but also in all historical and philological studies.

  19. VA Enterprise Design Patters - 2.5 (Enterprise Architecture)

    Data.gov (United States)

    Department of Veterans Affairs — Enterprise architectural guidelines and constraints that provide references to the use of enterprise capabilities that will enable the VA to access and exchange data...

  20. 78 FR 62441 - VA Dental Insurance Program-Federalism

    Science.gov (United States)

    2013-10-22

    ... and their corresponding regulatory paragraphs. Subsection of Paragraph of Sec. Topic section 510 17.... Administrative Procedure Act VA believes this regulatory amendment is non-controversial and anticipates that this...

  1. VA Facilities by Congressional District (FY2011): Overview

    Data.gov (United States)

    Department of Veterans Affairs — Maps are organized by state and depict the Veteran population using VetPop2011 data as of 9/30/2013 and VA facilities using Veteran Affairs Site Tracking (VAST) data...

  2. VA Enterprise Design Patterns - 5.1 (Mobility) Mobile

    Data.gov (United States)

    Department of Veterans Affairs — First of a set of guidance documents that establish the architectural foundation for mobile computing in the VA. This document outlines the enterprise capabilities...

  3. Service Utilization of Veterans Dually Eligible for VA...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Service Utilization of Veterans Dually Eligible for VA and Medicare Fee-For-Service, 1999-2004 According to findings in Service Utilization of Veterans Dually...

  4. A VA medical center's PTSD residential recovery program.

    Science.gov (United States)

    Devaney, Donald E

    2010-01-01

    With the influx of military veterans with Post Traumatic Stress Disorder (PTSD) increasingly affecting all healthcare facilities, including acute care and long term, learning from the experience of VA hospitals in treating those with PTSD may prove valuable. In this article, Tripler/VA Provost Marshal Donald E. Delaney describes a program that has been in operation since 1994. He may be contacted for further in formation at (808) 433-4465 or Donald.devaney@amedd.army .mil

  5. Inpatient Mental Health Recaptre using Dod/VA Sharing

    Science.gov (United States)

    2009-10-03

    Center. Although no diagnostic categories are excluded, common diagnosis include, adjustment disorders, mood disorders, anxiety disorders, psychoses ... definition of acute psychiatry. Staffing The Waco VA has nurse managers who determine the number of RN’s and other support staff based on patient...Enrollment Priority Groups Priority Group Definition 1 • Veterans with VA-rated service-connected disabilities 50% or more disabling • Veterans

  6. Whistle-blower accuses VA inspector general of a "whitewash"

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-09-01

    Full Text Available No abstract available. Article truncated after 150 words. Yesterday, Dr. Sam Foote, the initial whistle-blower at the Phoenix VA, criticized the Department of Veterans Affairs inspector general's (VAOIG report on delays in healthcare at the Phoenix VA at a hearing before the House Committee of Veterans Affairs (1,2. Foote accused the VAOIG of minimizing bad patient outcomes and deliberately confusing readers, downplaying the impact of delayed health care at Phoenix VA facilities. "At its best, this report is a whitewash. At its worst, it is a feeble attempt at a cover-up," said Foote. Foote earlier this year revealed that as many as 40 Phoenix patients died while awaiting care and that the Phoenix VA maintained secret waiting lists while under-reporting patient wait times for appointments. His disclosures triggered the national VA scandal. Richard Griffin, the acting VAOIG, said that nearly 300 patients died while on backlogged wait lists in the Phoenix VA Health Care System, a much higher ...

  7. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.

    Science.gov (United States)

    van Karnebeek, Clara D; Sly, William S; Ross, Colin J; Salvarinova, Ramona; Yaplito-Lee, Joy; Santra, Saikat; Shyr, Casper; Horvath, Gabriella A; Eydoux, Patrice; Lehman, Anna M; Bernard, Virginie; Newlove, Theresa; Ukpeh, Henry; Chakrapani, Anupam; Preece, Mary Anne; Ball, Sarah; Pitt, James; Vallance, Hilary D; Coulter-Mackie, Marion; Nguyen, Hien; Zhang, Lin-Hua; Bhavsar, Amit P; Sinclair, Graham; Waheed, Abdul; Wasserman, Wyeth W; Stockler-Ipsiroglu, Sylvia

    2014-03-06

    Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. VA Health Care: Further Action Needed to Address Weaknesses in Management and Oversight of Non-VA Medical Care

    Science.gov (United States)

    2014-06-18

    medical care when a VA facility is unable to provide certain specialty care services, such as cardiology or orthopedics, or when a veteran would have...needing treatment in several specialties—including audiology, cardiology , and ophthalmology—were referred to non-VA providers for this reason...Government Accountability Office, the audit, evaluation, and investigative arm of Congress , exists to support Congress in meeting its constitutional

  9. Markov chains

    CERN Document Server

    Revuz, D

    1984-01-01

    This is the revised and augmented edition of a now classic book which is an introduction to sub-Markovian kernels on general measurable spaces and their associated homogeneous Markov chains. The first part, an expository text on the foundations of the subject, is intended for post-graduate students. A study of potential theory, the basic classification of chains according to their asymptotic behaviour and the celebrated Chacon-Ornstein theorem are examined in detail. The second part of the book is at a more advanced level and includes a treatment of random walks on general locally compact abelian groups. Further chapters develop renewal theory, an introduction to Martin boundary and the study of chains recurrent in the Harris sense. Finally, the last chapter deals with the construction of chains starting from a kernel satisfying some kind of maximum principle.

  10. Heavy-tailed value-at-risk analysis for Malaysian stock exchange

    Science.gov (United States)

    Chin, Wen Cheong

    2008-07-01

    This article investigates the comparison of power-law value-at-risk (VaR) evaluation with quantile and non-linear time-varying volatility approaches. A simple Pareto distribution is proposed to account the heavy-tailed property in the empirical distribution of returns. Alternative VaR measurement such as non-parametric quantile estimate is implemented using interpolation method. In addition, we also used the well-known two components ARCH modelling technique under the assumptions of normality and heavy-tailed (student- t distribution) for the innovations. Our results evidenced that the predicted VaR under the Pareto distribution exhibited similar results with the symmetric heavy-tailed long-memory ARCH model. However, it is found that only the Pareto distribution is able to provide a convenient framework for asymmetric properties in both the lower and upper tails.

  11. Multiclonal methicillin-resistant Staphylococcus aureus (MRSA) outbreak and its control after use of the Veterans Affairs (VA) MRSA bundle in a VA long-term care facility, 2004-2014.

    Science.gov (United States)

    Webb, Risa M; Denton, Carmelita; Spruill, Emily; Henson, Gay; Bruce, Lisa; Woods, Gail L; Swiatlo, Andrea; Walker, Erica D; Peel, Chere; Sullivan, Donna

    2016-06-01

    A multiclonal methicillin-resistant Staphylococcus aureus (MRSA) outbreak with 91 infections occurred in our Veterans Affairs (VA) community living center over 46 months. Both similar and unique strains were shown by repetitive polymerase chain reaction to contribute to the outbreak, including 1 strain causing infections over a 33-month period. Most infections were soft tissue infections (67%). For 21 months after the initiation of the VA MRSA bundle, no infections were identified, and low rates of infection have been sustained an additional 4 years. The average annual rate of MRSA infection decreased by 62% (P < .001) from 0.6 per 1,000 resident days for 4 years prior to the bundle implementation to 0.09 per 1,000 resident days for 4 years after the bundle implementation. Published by Elsevier Inc.

  12. 76 FR 24570 - Proposed Information Collection (Application for VA Education Benefits) Activity; Comment Request

    Science.gov (United States)

    2011-05-02

    ... AFFAIRS Proposed Information Collection (Application for VA Education Benefits) Activity; Comment Request.... Titles: a. Application for VA Education Benefits, VA Form 22-1990. b. Application for Transfer of Entitlement (TOE), Basic Educational Assistance Under the Montgomery GI Bill, VA Form 22-1990E. c. Application...

  13. 78 FR 76412 - Agency Information Collection (VA National Rehabilitation Special Events, Event Registration...

    Science.gov (United States)

    2013-12-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS... Application, VA Form 0924t. e. National Veterans Wheelchair Games Event Application, VA Form 0925b. f. Voluntary Service Application, VA Form 0925d. g. National Veteran Golden Age Games Application, VA Form 0926...

  14. A Role for Myosin Va in Human Cytomegalovirus Nuclear Egress.

    Science.gov (United States)

    Wilkie, Adrian R; Sharma, Mayuri; Pesola, Jean M; Ericsson, Maria; Fernandez, Rosio; Coen, Donald M

    2018-03-15

    Herpesviruses replicate and package their genomes into capsids in replication compartments within the nuclear interior. Capsids then move to the inner nuclear membrane for envelopment and release into the cytoplasm in a process called nuclear egress. We previously found that nuclear F-actin is induced upon infection with the betaherpesvirus human cytomegalovirus (HCMV) and is important for nuclear egress and capsid localization away from replication compartment-like inclusions toward the nuclear rim. Despite these and related findings, it has not been shown that any specific motor protein is involved in herpesvirus nuclear egress. In this study, we have investigated whether the host motor protein, myosin Va, could be fulfilling this role. Using immunofluorescence microscopy and coimmunoprecipitation, we observed associations between a nuclear population of myosin Va and the viral major capsid protein, with both concentrating at the periphery of replication compartments. Immunoelectron microscopy showed that nearly 40% of assembled nuclear capsids associate with myosin Va. We also found that myosin Va and major capsid protein colocalize with nuclear F-actin. Importantly, antagonism of myosin Va with RNA interference or a dominant negative mutant revealed that myosin Va is important for the efficient production of infectious virus, capsid accumulation in the cytoplasm, and capsid localization away from replication compartment-like inclusions toward the nuclear rim. Our results lead us to suggest a working model whereby human cytomegalovirus capsids associate with myosin Va for movement from replication compartments to the nuclear periphery during nuclear egress. IMPORTANCE Little is known regarding how newly assembled and packaged herpesvirus capsids move from the nuclear interior to the periphery during nuclear egress. While it has been proposed that an actomyosin-based mechanism facilitates intranuclear movement of alphaherpesvirus capsids, a functional role for

  15. Patient deaths blamed on long waits at the Phoenix VA

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2014-04-01

    Full Text Available No abstract available. Article truncated at 150 words. This morning the lead article in the Arizona Republic was a report blaming as many as 40 deaths at the Phoenix VA on long waits (1. Yesterday, Rep. Jeff Miller, the chairman of the House Committee on Veterans Affairs, held a hearing titled “A Continued Assessment of Delays in VA Medical Care and Preventable Veteran Deaths.” “It appears as though there could be as many as 40 veterans whose deaths could be related to delays in care,” Miller announced to a stunned audience. The committee has spent months investigating patient-care scandals and allegations at VA facilities in Pittsburgh, Atlanta, Miami and other cities. said that dozens of VA hospital patients in Phoenix may have died while awaiting medical care. He went on to say that staff investigators have evidence that the Phoenix VA Health Care System keeps two sets of records to conceal prolonged waits that patients must endure for ...

  16. A direct thrombin inhibitor suppresses protein C activation and factor Va degradation in human plasma: Possible mechanisms of paradoxical enhancement of thrombin generation.

    Science.gov (United States)

    Kamisato, Chikako; Furugohri, Taketoshi; Morishima, Yoshiyuki

    2016-05-01

    We have demonstrated that antithrombin (AT)-independent thrombin inhibitors paradoxically increase thrombin generation (TG) in human plasma in a thrombomodulin (TM)- and protein C (PC)-dependent manner. We determined the effects of AT-independent thrombin inhibitors on the negative-feedback system, activation of PC and production and degradation of factor Va (FVa), as possible mechanisms underlying the paradoxical enhancement of TG. TG in human plasma containing 10nM TM was assayed by means of the calibrated automated thrombography. As an index of PC activation, plasma concentration of activated PC-PC inhibitor complex (aPC-PCI) was measured. The amounts of FVa heavy chain and its degradation product (FVa(307-506)) were examined by western blotting. AT-independent thrombin inhibitors, melagatran and dabigatran (both at 25-600nM) and 3-30μg/ml active site-blocked thrombin (IIai), increased peak levels of TG. Melagatran, dabigatran and IIai significantly decreased plasma concentration of aPC-PCI complex at 25nM or more, 75nM or more, and 10 and 30μg/ml, respectively. Melagatran (300nM) significantly increased FVa and decreased FVa(307-506). In contrast, a direct factor Xa inhibitor edoxaban preferentially inhibited thrombin generation (≥25nM), and higher concentrations were required to inhibit PC activation (≥150nM) and FVa degradation (300nM). The present study suggests that the inhibitions of protein C activation and subsequent degradation of FVa and increase in FVa by antithrombin-independent thrombin inhibitors may contribute to the paradoxical TG enhancement, and edoxaban may inhibit PC activation and FVa degradation as a result of TG suppression. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. REACH VA: Moving from Translation to System Implementation.

    Science.gov (United States)

    Nichols, Linda O; Martindale-Adams, Jennifer; Burns, Robert; Zuber, Jeffrey; Graney, Marshall J

    2016-02-01

    Resources for Enhancing All Caregivers Health in the Department of Veterans Affairs (REACH VA) has been implemented in the VA system as a national program for caregivers. We describe the trajectory of REACH VA from national randomized clinical trial through translation to national implementation. The implementation is examined through the six stages of the Fixsen and Blasé implementation process model: exploration and adoption, program installation, initial implementation, full operation, innovation, and sustainability. Different drivers that move the implementation process forward are important at each stage, including staff selection, staff training, consultation and coaching, staff evaluation, administrative support, program evaluation/fidelity, and systems interventions. Caregivers in the REACH VA 4 session intervention currently implemented in the VA had similar outcomes to longer REACH interventions, including Resources for Enhancing Alzheimer's Caregivers Health (REACH II). Caregivers experienced significant decreases in burden, depression, anxiety, number of troubling patient behaviors reported, caregiving frustrations, stress symptoms (feeling overwhelmed, feeling like crying, being frustrated as a result of caregiving, being lonely), and general stress. Effect sizes (Cohen's d) for these significant variables were between small and medium ranging from .24 to .46. The implementation of REACH VA provides a road map for implementation of other behavioral interventions in health care delivery settings. Lessons learned include the importance of implementing a proven, needed intervention, support from both leadership and clinical staff, willingness to respond to staff and organization needs and modify the intervention while preserving its integrity, and fitting the intervention into ongoing routines and practices. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

  18. Stratigraphic-structural characteristics of Mačva basin

    Directory of Open Access Journals (Sweden)

    Carević Ivana

    2009-01-01

    Full Text Available The analysis of stratigraphic-structural features of Mačva basin had been conducted in this paper on the basis of data obtained with deep exploratory boring performed for the needs of hydrogeothermal research project for the purpose of identifying the reserves of geothermal energy of Mačva. The research has been carried out with the aim of finding out the relation between the Tertiary and its Triassic bedrock (Ladinian and Carnian stages in which process the considerable realistic image of paleorelief (the bedrock of Tertiary deposits was obtained.

  19. Poisoning of domestic animals with heavy metals

    Directory of Open Access Journals (Sweden)

    Velev Romel

    2009-01-01

    Full Text Available The term heavy metal refers to a metal that has a relatively high density and is toxic for animal and human organism at low concentrations. Heavy metals are natural components of the Earth's crust. They cannot be degraded or destroyed. To a small extent they enter animal organism via food, drinking water and air. Some heavy metals (e.g cooper, iron, chromium, zinc are essential in very low concentrations for the survival of all forms of life. These are described as essential trace elements. However, when they are present in greater quantities, like the heavy metals lead, cadmium and mercury which are already toxic in very low concentrations, they can cause metabolic anomalies or poisoning. Heavy metal poisoning of domestic animals could result, for instance, from drinking-water contamination, high ambient air concentrations near emission sources, or intake via the food chain. Heavy metals are dangerous because they tend to bioaccumulate in a biological organism over time. Manifestation of toxicity of individual heavy metals varies considerably, depending on dose and time of exposure, species, gender and environmental and nutritional factors. Large differences exist between the effects of a single exposure to a high concentration, and chronic exposures to lower doses. The aim of this work is to present the source of poisoning and toxicity of some heavy metals (lead, mercury, cadmium, thallium, arsenic, as well as new data about effects of those heavy metals on the health of domestic animals. .

  20. VA-INPC: Linking Department of Veterans Affairs (VA) and Indiana Network for Patient Care (INPC) data to assess surveillance testing among veterans with colorectal cancer.

    Science.gov (United States)

    Haggstrom, David A; Rosenman, Marc; Myers, Laura J; Teal, Evgenia; Doebbeling, Bradley N

    2010-11-13

    The goal of this project was to provide empiric evidence about the benefit to US veterans and the VA of capturing data from a citywide clinical informatics network (INPC) to assess care received outside the VA. We identified 468 veterans diagnosed with colorectal cancer from 2000-2007 in the Indianapolis VA cancer registry. Electronic VA healthcare data were linked with electronic health records from the regional health information organization (RHIO) INPC; 341 matches were found. Both the VA and INPC systems were queried regarding receipt of surveillance tests. The proportion with additional data from INPC varied by test: colonoscopy (3%), CT scan/abdomen (13%), CT scan/chest (79%), carcinoembryonic antigen test (8%), and other laboratory tests (25%-53%). An incremental benefit of linking VA and INPC data was present and may increase when expanded beyond patients with a single condition. New, important information about care outside the VA is obtained through RHIO data linkage.

  1. 76 FR 77270 - Board Meeting; January 9, 2012, Arlington, VA

    Science.gov (United States)

    2011-12-12

    ... at the Ritz- Carlton Hotel, 1250 South Hayes Street, Arlington, Virginia 22202; (Tel) (703) 415-5000... From the Federal Register Online via the Government Publishing Office NUCLEAR WASTE TECHNICAL REVIEW BOARD Board Meeting; January 9, 2012, Arlington, VA The U.S. Nuclear Waste Technical Review Board...

  2. Military and VA General Dentistry Training: A National Resource.

    Science.gov (United States)

    Atchison, Kathryn A.; Bachand, William; Buchanan, C. Richard; Lefever, Karen H.; Lin, Sylvia; Engelhardt, Rita

    2002-01-01

    Compared the program characteristics of the postgraduate general dentistry (PGD) training programs sponsored by the military and the Veterans Health Administration (VA). Gathered information on program infrastructure and emphasis, resident preparation prior to entering the program, and patients served and types of services provided. Programs…

  3. 77 FR 70893 - Authorization for Non-VA Medical Services

    Science.gov (United States)

    2012-11-28

    ..., Mental health programs, Nursing homes, Reporting and recordkeeping requirements, Veterans. Dated... authority to provide needed non- VA care using community resources, such as private physicians or community... such medical services for a veteran who has been furnished hospital care, nursing home care...

  4. 77 FR 67063 - VA Directive 0005 on Scientific Integrity

    Science.gov (United States)

    2012-11-08

    ... interest to strengthen disclosure of and reduce conflict of interest among, employees, and reviewers. Conflict of interest policies should apply to research staff as well as research investigators. VA Response... developing conflict of interest requirements specifically applicable to research. Consequently, no changes...

  5. Heavy flavour in ALICE

    CERN Document Server

    Pillot, Philippe

    2008-01-01

    Open heavy flavours and heavy quarkonium states are expected to provide essential informa- tion on the properties of the strongly interacting system fo rmed in the early stages of heavy-ion collisions at very high energy density. Such probes are espe cially promising at LHC energies where heavy quarks (both c and b) are copiously produced. The ALICE detector shall measure the production of open heavy flavours and heavy quarkonium st ates in both proton-proton and heavy-ion collisions at the LHC. The expected performances of ALICE for heavy flavour physics is discussed based on the results of simulation studies on a s election of benchmark channels

  6. 76 FR 71920 - Payment for Home Health Services and Hospice Care by Non-VA Providers

    Science.gov (United States)

    2011-11-21

    ...The Department of Veterans Affairs (VA) proposes to amend its regulation and internal policy documents concerning the billing methodology for non-VA providers of home health services and hospice care. The proposed rulemaking would include home health services and hospice care under the VA regulation governing payment for other non-VA health care providers. Because the newly applicable methodology cannot supersede rates for which VA has specifically contracted, this rulemaking will only affect providers who do not have existing negotiated contracts with VA. The proposed rule would also rescind internal guidance documents that could be interpreted as conflicting with the proposed rule.

  7. EPA, W. Va. DEP File Settlement with Justice Companies to Restore and Protect Monroe Co., W. Va. Waterways

    Science.gov (United States)

    CHARLESTON, W.Va. (Dec. 10, 2015) Today, the U.S. Environmental Protection Agency and the West Virginia Department of Environmental Protection filed a settlement with James C. Justice II, the James C. Justice Companies, Inc. and High Mountain Living

  8. 75 FR 33216 - Payment or Reimbursement for Emergency Treatment Furnished by Non-VA Providers in Non-VA...

    Science.gov (United States)

    2010-06-11

    ... grammatical errors and updating obsolete citations. DATES: Comments must be received by VA on or before August... amendments made to 38 U.S.C. 1725 and 1728, and would make technical changes such as correcting grammatical errors and updating obsolete regulatory citations: 38 CFR 17.120, 17.121, 17.1002, 17.1005, 17.1006, and...

  9. Business process modelling in demand-driven agri-food supply chains : a reference framework

    OpenAIRE

    Verdouw, C.N.

    2010-01-01

    Keywords: Business process models; Supply chain management; Information systems; Reference information models; Market orientation; Mass customisation; Configuration; Coordination; Control; SCOR; Pot plants; Fruit industry Abstract The increasing volatility and diversity of demand urge agri-food supply chains to become more demand driven, i.e. sensitive and responsive to demand information of the ultimate consumer. Companies that participate in demand-driven supply chains must manage a high va...

  10. Heavy metals in the environment; uncertainty and sensitivity analysis of spatial predictions of heavy metals in wheat

    NARCIS (Netherlands)

    Brus, D.J.; Jansen, M.J.W.

    2004-01-01

    Heavy metals seriously threaten the health of human beings when they enter the food chain. Therefore, policymakers require precise predictions of heavy metal concentrations in agricultural crops. In this paper we quantify the uncertainty of regression predictions of Cd and Pb in wheat (Triticum

  11. VA-Index: Quantifying Assortativity Patterns in Networks with Multidimensional Nodal Attributes (Open Access)

    Science.gov (United States)

    2016-01-27

    comparison. In this work we introduce a novel network metric, which we call VA-index, for quantify- ing the multi-dimensional assortativity. In a nutshell ...network randomization with statistical hypothesis testing. In a nutshell , the intuition of our approach is based on comparing the pairwise average...1)), we would need to normalize the VA-index with the maximum possible average similarity that Fig 2. The computation of VA-index in a nutshell . VA

  12. 78 FR 26250 - Payment for Home Health Services and Hospice Care to Non-VA Providers

    Science.gov (United States)

    2013-05-06

    ...The Department of Veterans Affairs (VA) amends its regulations concerning the billing methodology for non-VA providers of home health services and hospice care. Because the newly applicable methodology cannot supersede rates for which VA has specifically contracted, this rulemaking will only affect home health and hospice care providers who do not have existing negotiated contracts with VA. This rule also rescinds internal guidance documents that could be interpreted as conflicting with this final rule.

  13. VaR: Exchange Rate Risk and Jump Risk

    Directory of Open Access Journals (Sweden)

    Fen-Ying Chen

    2010-01-01

    Full Text Available Incorporating the Poisson jumps and exchange rate risk, this paper provides an analytical VaR to manage market risk of international portfolios over the subprime mortgage crisis. There are some properties in the model. First, different from past studies in portfolios valued only in one currency, this model considers portfolios not only with jumps but also with exchange rate risk, that is vital for investors in highly integrated global financial markets. Second, in general, the analytical VaR solution is more accurate than historical simulations in terms of backtesting and Christoffersen's independence test (1998 for small portfolios and large portfolios. In other words, the proposed model is reliable not only for a portfolio on specific stocks but also for a large portfolio. Third, the model can be regarded as the extension of that of Kupiec (1999 and Chen and Liao (2009.

  14. Implementation of online suicide-specific training for VA providers.

    Science.gov (United States)

    Marshall, Elizabeth; York, Janet; Magruder, Kathryn; Yeager, Derik; Knapp, Rebecca; De Santis, Mark L; Burriss, Louisa; Mauldin, Mary; Sulkowski, Stan; Pope, Charlene; Jobes, David A

    2014-10-01

    Due to the gap in suicide-specific intervention training for mental health students and professionals, e-learning is one solution to improving provider skills in the Veterans Affairs (VA) health system. This study focused on the development and evaluation of an equivalent e-learning alternative to the Collaborative Assessment and Management of Suicidality (CAMS) in-person training approach at a Veteran Health Affairs medical center. The study used a multicenter, randomized, cluster, and three group design. the development of e-CAMS was an iterative process and included pilot testing. Eligible and consenting mental health providers, who completed a CAMS pre-survey, were randomized. Provider satisfaction was assessed using the standard VA evaluation of training consisting of 20 items. Two post training focus groups, divided by learning conditions, were conducted to assess practice adoption using a protocol focused on experiences with training and delivery of CAMS. A total of 215 providers in five sites were randomized to three conditions: 69 to e-learning, 70 to in-person, 76 to the control. The providers were primarily female, Caucasian, midlife providers. Based on frequency scores of satisfaction items, both learning groups rated the trainings positively. In focus groups representing divided by learning conditions, participants described positive reactions to CAMS training and similar individual and institutional barriers to full implementation of CAMS. This is the first evaluation study of a suicide-specific e-learning training within the VA. The e-CAMS appears equivalent to the in-person CAMS in terms of provider satisfaction with training and practice adoption, consistent with other comparisons of training deliveries across specialty areas. Additional evaluation of provider confidence and adoption and patient outcomes is in progress. The e-CAMS has the potential to provide ongoing training for VA and military mental health providers and serve as a tutorial for

  15. Addressing the Health Concerns of VA Women with Sexual Trauma

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0368 TITLE: Addressing the Health Concerns of VA Women with Sexual Trauma PRINCIPAL INVESTIGATOR: Caron Zlotnick, PhD...develop and assess a computer-delivered intervention (Safety and Health Experiences Program; SHE) that will provide a screening and brief behavior...intervention for women veterans with any lifetime ST. More specifically, the intervention, SHE, will address interrelated health concerns for women

  16. Determination of heavy metals in the ambient atmosphere.

    Science.gov (United States)

    Suvarapu, Lakshmi Narayana; Baek, Sung-Ok

    2017-01-01

    Heavy metal determination in ambient air is an important task for environmental researchers because of their toxicity to human beings. Some heavy metals (hexavalent chromium (Cr), arsenic (As), cadmium (Cd) and nickel (Ni)) have been listed as carcinogens. Furthermore, heavy metals in the atmosphere can accumulate in various plants and animals and enter humans through the food chain. This article reviews the determination of heavy metals in the atmosphere in different areas of the world since 2006. The results showed that most researchers concentrated on toxic metals, such as Cr, Cd, Ni, As and lead. A few studies used plant materials as bio-monitors for the atmospheric levels of heavy metals. Some researchers found higher concentrations of heavy metals surrounding industrial areas compared with residential and/or commercial areas. Most studies reported the major sources of the particulate matter and heavy metals in the atmosphere to be industrial emissions, vehicular emissions and secondary aerosols.

  17. 75 FR 3541 - Agency Information Collection (Verification of VA Benefits) Activity Under OMB Review

    Science.gov (United States)

    2010-01-21

    ... AFFAIRS Agency Information Collection (Verification of VA Benefits) Activity Under OMB Review AGENCY... INFORMATION: Title: Verification of VA Benefits, VA Form 26-8937. OMB Control Number: 2900-0406. Type of... Veterans Benefits Administration, Department of Veterans Affairs will submit the collection of information...

  18. 77 FR 64383 - Proposed Information Collection (Verification of VA Benefits) Activity: Comment Request

    Science.gov (United States)

    2012-10-19

    ... AFFAIRS Proposed Information Collection (Verification of VA Benefits) Activity: Comment Request AGENCY... techniques or the use of other forms of information technology. Title: Verification of VA Benefits, VA Form... comment on the proposed collection of certain information by the agency. Under the Paperwork Reduction Act...

  19. Use of VA and Medicare services by dually eligible veterans with psychiatric problems.

    Science.gov (United States)

    Carey, Kathleen; Montez-Rath, Maria E; Rosen, Amy K; Christiansen, Cindy L; Loveland, Susan; Ettner, Susan L

    2008-08-01

    To examine how service accessibility measured by geographic distance affects service sector choices for veterans who are dually eligible for veterans affairs (VA) and Medicare services and who are diagnosed with mental health and/or substance abuse (MH/SA) disorders. Primary VA data sources were the Patient Treatment (acute care), Extended Care (long-term care), and Outpatient Clinic files. VA cost data were obtained from (1) inpatient and outpatient cost files developed by the VA Health Economics and Resource Center and (2) outpatient VA Decision Support System files. Medicare data sources were the denominator, Medicare Provider Analysis Review (MEDPAR), Provider-of-Service, Outpatient Standard Analytic and Physician/Supplier Standard Analytic files. Additional sources included the Area Resource File and Census Bureau data. We identified dually eligible veterans who had either an inpatient or outpatient MH/SA diagnosis in the VA system during fiscal year (FY)'99. We then estimated one- and two-part regression models to explain the effects of geographic distance on both VA and Medicare total and MH/SA costs. Results provide evidence for substitution between the VA and Medicare, demonstrating that poorer geographic access to VA inpatient and outpatient clinics decreased VA expenditures but increased Medicare expenditures, while poorer access to Medicare-certified general and psychiatric hospitals decreased Medicare expenditures but increased VA expenditures. As geographic distance to VA medical facility increases, Medicare plays an increasingly important role in providing mental health services to veterans.

  20. The Impact of VA's Geriatric Research, Education and Clinical Centers on Academic Affiliates

    Science.gov (United States)

    Bragg, Elizabeth J.; Meganathan, Karthikeyan; Shay, Kenneth; Gilman, Stuart C.; Zeiss, Robert A.; Hettler, Debbie L.

    2011-01-01

    The education mission of the Department of Veterans Affairs (VA) is to train health professionals to benefit VA and the United States. One approach for achieving that mission, along with VA's research and clinical missions, was the establishment of Geriatric Research, Education and Clinical Centers (GRECCs) in 1975. These were developed at VA…

  1. 77 FR 12697 - VA Homeless Providers Grant and Per Diem Program

    Science.gov (United States)

    2012-03-01

    ... applicant takes measures to protect the capital securing VA's grant investment. We would remove the... would reduce the redundancy of current application requirements, provide an improved picture of overall... consist primarily of VA clinicians and VA homeless specialists, the current regulation could better...

  2. 78 FR 56271 - FY 2014-2020 Draft VA Strategic Plan

    Science.gov (United States)

    2013-09-12

    ... AFFAIRS FY 2014-2020 Draft VA Strategic Plan AGENCY: Department of Veterans Affairs. ACTION: Notice of... availability of the FY 2014-2020 Draft VA Strategic Plan (Strategic Plan) for public review and comment, as..., and leadership to meet our clients' needs and expectations. DATES: Comments must be received by VA on...

  3. Validation of KENO V.a Comparison with Critical Experiments

    Energy Technology Data Exchange (ETDEWEB)

    Jordan, W.C.

    1999-01-01

    Section 1 of this report documents the validation of KENO V.a against 258 critical experiments. Experiments considered were primarily high or low enriched uranium systems. The results indicate that the KENO V.a Monte Carlo Criticality Program accurately calculates a broad range of critical experiments. A substantial number of the calculations showed a positive or negative bias in excess of 1 1/2% in k-effective (k{sub eff}). Classes of criticals which show a bias include 3% enriched green blocks, highly enriched uranyl fluoride slab arrays, and highly enriched uranyl nitrate arrays. If these biases are properly taken into account, the KENO V.a code can be used with confidence for the design and criticality safety analysis of uranium-containing systems. Section 2 of this report documents the results of investigation into the cause of the bias observed in Sect. 1. The results of this study indicate that the bias seen in Sect. 1 is caused by code bias, cross-section bias, reporting bias, and modeling bias. There is evidence that many of the experiments used in this validation and in previous validations are not adequately documented. The uncertainty in the experimental parameters overshadows bias caused by the code and cross sections and prohibits code validation to better than about 1% in k{sub eff}.

  4. Natural Hazards and Supply Chain Disruptions

    Science.gov (United States)

    Haraguchi, M.

    2016-12-01

    Natural hazards distress the global economy through disruptions in supply chain networks. Moreover, despite increasing investment to infrastructure for disaster risk management, economic damages and losses caused by natural hazards are increasing. Manufacturing companies today have reduced inventories and streamlined logistics in order to maximize economic competitiveness. As a result, today's supply chains are profoundly susceptible to systemic risks, which are the risk of collapse of an entire network caused by a few node of the network. For instance, the prolonged floods in Thailand in 2011 caused supply chain disruptions in their primary industries, i.e. electronic and automotive industries, harming not only the Thai economy but also the global economy. Similar problems occurred after the Great East Japan Earthquake and Tsunami in 2011, the Mississippi River floods and droughts during 2011 - 2013, and the Earthquake in Kumamoto Japan in 2016. This study attempts to discover what kind of effective measures are available for private companies to manage supply chain disruptions caused by floods. It also proposes a method to estimate potential risks using a Bayesian network. The study uses a Bayesian network to create synthetic networks that include variables associated with the magnitude and duration of floods, major components of supply chains such as logistics, multiple layers of suppliers, warehouses, and consumer markets. Considering situations across different times, our study shows desirable data requirements for the analysis and effective measures to improve Value at Risk (VaR) for private enterprises and supply chains.

  5. Structural repertoire of immunoglobulin λ light chains

    KAUST Repository

    Chailyan, Anna

    2011-03-01

    The immunoglobulin λ isotype is present in nearly all vertebrates and plays an important role in the human immune system. Despite its importance, few systematic studies have been performed to analyze the structural conformation of its variable regions, contrary to what is the case for κ and heavy chains. We show here that an analysis of the structures of λ chains allows the definition of a discrete set of recurring conformations (canonical structures) of their hypervariable loops and, most importantly, the identification of sequence constraints that can be used to predict their structure. We also show that the structural repertoire of λ chains is different and more varied than that of the κ chains, consistently with the current view of the involvement of the two major light-chain families in complementary strategies of the immune system to ensure a fine tuning between diversity and stability in antigen recognition. © 2011 Wiley-Liss, Inc.

  6. Single chain Fab (scFab fragment

    Directory of Open Access Journals (Sweden)

    Brenneis Mariam

    2007-03-01

    Full Text Available Abstract Background The connection of the variable part of the heavy chain (VH and and the variable part of the light chain (VL by a peptide linker to form a consecutive polypeptide chain (single chain antibody, scFv was a breakthrough for the functional production of antibody fragments in Escherichia coli. Being double the size of fragment variable (Fv fragments and requiring assembly of two independent polypeptide chains, functional Fab fragments are usually produced with significantly lower yields in E. coli. An antibody design combining stability and assay compatibility of the fragment antigen binding (Fab with high level bacterial expression of single chain Fv fragments would be desirable. The desired antibody fragment should be both suitable for expression as soluble antibody in E. coli and antibody phage display. Results Here, we demonstrate that the introduction of a polypeptide linker between the fragment difficult (Fd and the light chain (LC, resulting in the formation of a single chain Fab fragment (scFab, can lead to improved production of functional molecules. We tested the impact of various linker designs and modifications of the constant regions on both phage display efficiency and the yield of soluble antibody fragments. A scFab variant without cysteins (scFabΔC connecting the constant part 1 of the heavy chain (CH1 and the constant part of the light chain (CL were best suited for phage display and production of soluble antibody fragments. Beside the expression system E. coli, the new antibody format was also expressed in Pichia pastoris. Monovalent and divalent fragments (DiFabodies as well as multimers were characterised. Conclusion A new antibody design offers the generation of bivalent Fab derivates for antibody phage display and production of soluble antibody fragments. This antibody format is of particular value for high throughput proteome binder generation projects, due to the avidity effect and the possible use of

  7. A heavy load for heavy ions

    CERN Multimedia

    2003-01-01

    On 25 September, the two large coils for the dipole magnet of ALICE, the LHC experiment dedicated to heavy ions, arrived at Point 2 on two heavy load trucks after a 1200 km journey from their assembly in Vannes, France.

  8. Heavy Menstrual Bleeding

    Science.gov (United States)

    ... can cause heavy bleeding. • Medications—Blood thinners and aspirin can cause heavy menstrual bleeding. The copper intrauterine ... on the ovaries, fallopian tubes, and other pelvic structures. Endometrium: The lining of the uterus. Fibroids: Growths, ...

  9. Noncoherent detection of DQPSK in OFDM systems using predictive VA

    Science.gov (United States)

    Veludandi, Vineel K.; Vasudevan, K.

    2017-01-01

    Noncoherent detection of differential quaternary phase shift keying (DQPSK) signals in OFDM systems is efficiently implemented using a predictive Viterbi algorithm (VA) operating on a trellis with just S T = MP-1 states instead of M P states, where M denotes an M-ary PSK constellation and P denotes the order of the prediction filter. The prediction filter coefficients are generated based on the channel DFT alone making a high SNR approximation, since the estimation of the noise-variance using training symbols results in loss of throughput.

  10. The VA Maryland Health Care System's telemental health program.

    Science.gov (United States)

    Koch, Edward F

    2012-05-01

    The VA Maryland Health Care System introduced videoconferencing technology to provide psychiatry, evidenced-based psychotherapy, case management, and patient education at rural clinics where it was difficult to recruit providers. Telemental health services enable rural clinics to offer additional services, such as case management and patient education. Services have been expanded to urban outpatient clinics where a limited number of mental health clinic hours are available. This technology expands the availability of mental health providers and services, allowing patients to receive services from providers located at distant medical centers.

  11. Use of alcoholic beverages in VA medical centers

    Directory of Open Access Journals (Sweden)

    Qadri S Faiz

    2006-10-01

    Full Text Available Abstract Background Benzodiazepines are the first-line choice for the treatment of alcohol withdrawal syndrome. However, several hospitals continue to provide alcoholic beverages through their formulary for the treatment of alcohol withdrawal. While there are data on the prevalence of this practice in academic medical centers, there are no data on the availability of alcoholic beverages at the formularies of the hospitals operated by the department of Veteran's Affairs. Methods In this study, we surveyed the Pharmacy managers at 112 Veterans' Affairs Medical Centers (VAMCs to ascertain the availability of alcohol on the VAMC formularies, and presence or lack of a policy on the use of alcoholic beverages in their VA Medical Center. Results Of the pharmacy directors contacted, 81 responded. 8 did not allow their use, while 20 allowed their use. There was a lack of a consistent policy across the VA medical centers on availability and use of alcoholic beverages for the treatment of alcohol withdrawal syndrome. Conclusion There is lack of uniform policy on the availability of alcoholic beverages across the VAMCs, which may create potential problems with difference in the standards of care.

  12. V-A hadronic tau decays : a QCD laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Narison, Stephan E-mail: narison@lpm.univ-montp2.fr

    2001-04-01

    Recent ALEPH/OPAL data on the V-A spectral functions from hadronic {tau} decays are used for fixing the QCD continuum threshold at which the first and second Weinberg sum rules should be satisfied in the chiral limit, and for predicting the values of the low-energy constants f{sub {pi}}, m{sub {pi}{sup +}} - m{sub {pi}{sup 0}} and L{sub 10}. Some DMO-like sum rules and the {tau}-total hadronic widths R{sub {tau}}{sub ,V-A} are also used for extracting the values of the D = 6, 8 QCD vacuum condensates and the corresponding (in the chiral limit) electroweak kaon penguin matrix elements {sub 2{pi}}, where a deviation from the vacuum saturation estimate has been obtained. Combining these results with the one of the QCD penguin matrix element {sub 2{pi}} obtained from a (maximal) q-barq-gluonium mixing scheme from the scalar meson sum rules, we deduce, in the Electroweak Standard Model (ESM), the conservative upper bound for the CP-violating ratio: {epsilon}'/{epsilon} {<=} (22 {+-} 9)10{sup -4}, in agreement with the present measurements.

  13. V.A. Gorodtsov and Kazan: tour 1920

    Directory of Open Access Journals (Sweden)

    Kuzminykh Sergey V.

    2014-12-01

    Full Text Available A fragment of an archival document is published, that is connected to the September 8-12, 1920, stay in Kazan of V.A. Gorodtsov, who headed the Archaeological Subdepartment with the Museum Department of the RSFSR People’s Commissariat for Education, in the framework of his inspecting tour around the towns of the Volga and Urals region. The document is a diary, and its entries reflect information about the tour and its results that had not been exhaustively reflected in official documentation. It narrates about meetings, polemic exchanges, Gorodtsov’s addresses to scientists and the public, his impressions of the archaeological investigations in the regions, and the state of the museums and collections. V.A. Gorodtsov’s encounters and personal contacts with B.F. Adler, N.F. Katanov, M.G. Hudyakov and other researchers had played a positive role in archaeology development in the Volga-Kama region during the hardest times after the revolution.

  14. Cost-Effectiveness of Treatments for Genotype 1 Hepatitis C Virus Infection in Non-VA and VA Populations

    Directory of Open Access Journals (Sweden)

    Shan Liu PhD

    2016-09-01

    Full Text Available Background: Chronic hepatitis C viral (HCV infection affects millions of Americans. Health care systems face complex choices between highly efficacious, costly treatments. This study assessed the cost-effectiveness of treatments for chronic, genotype 1 HCV monoinfected, treatment-naïve individuals in the Department of Veterans Affairs (VA and general US health care systems. Methods: The study used a decision-analytic Markov model, employing appropriate payer perspectives and time horizons, and discounting benefits and costs at 3% annually. Interventions included the following: sofosbuvir/ledipasvir (SOF-LDV; ombitasvir/paritaprevir/ritonavir/dasabuvir (3D; sofosbuvir/simeprevir (SOF-SMV; sofosbuvir/pegylated interferon/ribavirin (SOF-RBV-PEG; boceprevir/pegylated interferon/ribavirin (BOC-RBV-PEG; and pegylated interferon/ribavirin (PEG-RBV. Outcomes were sustained virologic response (SVR, advanced liver disease, costs, quality adjusted life years (QALYs, and incremental cost-effectiveness. Results: SOF-LDV and 3D achieve high SVR rates, reducing advanced liver disease (>20% relative to no treatment, and increasing QALYs by >2 years per person. For the non-VA population, at current prices ($5040 per week for SOF-LDV; $4796 per week for 3D, SOF-LDV’s lifetime cost ($293,370 is $18,000 lower than 3D’s because of its shorter duration in subgroups. SOF-LDV costs $17,100 per QALY gained relative to no treatment. 3D costs $208,000 per QALY gained relative to SOF-LDV. Both dominate other treatments and are even more cost-effective for the VA, though VA aggregate treatment costs still exceed $4 billion at SOF-LDV prices of $3308 per week. Drug prices strongly determine relative cost-effectiveness for SOF-LDV and 3D; with price reductions of 20% to 30% depending on health system, 3D could be cost-effective relative to SOF-LDV. We currently lack head-to-head regimen effectiveness trials. Conclusions: New HCV treatments are cost-effective in multiple

  15. Marginal AMP chain graphs

    OpenAIRE

    Pena, Jose M.

    2014-01-01

    We present a new family of models that is based on graphs that may have undirected, directed and bidirected edges. We name these new models marginal AMP (MAMP) chain graphs because each of them is Markov equivalent to some AMP chain graph under marginalization of some of its nodes. However, MAMP chain graphs do not only subsume AMP chain graphs but also multivariate regression chain graphs. We describe global and pairwise Markov properties for MAMP chain graphs and prove their equivalence for...

  16. Influence of PVP/VA copolymer composition on drug-polymer solubility

    DEFF Research Database (Denmark)

    Rask, Malte Bille; Knopp, Matthias Manne; Olesen, Niels Erik

    2016-01-01

    polyvinylpyrrolidone (PVP) and polyvinyl acetate (PVA) was predicted at 25 °C using a thermal analysis method based on the recrystallization of a supersaturated amorphous dispersion (recrystallization method). These solubilities were compared with a prediction based on the solubility of CCX in the liquid monomeric...... precursors of PVP/VA, N-vinylpyrrolidone (NVP) and vinyl acetate (VA), using the Flory-Huggins lattice theory (liquid monomer solubility approach). The solubilities predicted from the liquid monomer solubility approach increased linearly with increasing VP/VA ratio from 0.03-0.60 w/w. Even though...... the solubilities predicted from the recrystallization method also increased with increasing VP/VA ratio from 0.02-0.40 w/w, the predicted solubility seemed to approach a plateau at high VP/VA ratios. Increasing positive deviations from the Gordon-Taylor equation with increasing VP/VA ratio indicated strong...

  17. KENO V.a Primer: A Primer for Criticality Calculations with SCALE/KENO V.a Using CSPAN for Input

    Energy Technology Data Exchange (ETDEWEB)

    Busch, R.D.

    2003-01-17

    The SCALE (Standardized Computer Analyses for Licensing Evaluation) computer software system developed at Oak Ridge National Laboratory (ORNL) is widely used and accepted around the world for criticality safety analyses. The well-known KENO V.a three-dimensional Monte Carlo criticality computer code is the primary criticality safety analysis tool in SCALE. The KENO V.a primer is designed to help a new user understand and use the SCALE/KENO V.a Monte Carlo code for nuclear criticality safety analyses. It assumes that the user has a college education in a technical field. There is no assumption of familiarity with Monte Carlo codes in general or with SCALE/KENO V.a in particular. The primer is designed to teach by example, with each example illustrating two or three features of SCALE/KENO V.a that are useful in criticality analyses. The primer is based on SCALE 4.4a, which includes the Criticality Safety Processor for Analysis (CSPAN) input processor for Windows personal computers (PCs). A second edition of the primer, which uses the new KENO Visual Editor, is currently under development at ORNL and is planned for publication in late 2003. Each example in this first edition of the primer uses CSPAN to provide the framework for data input. Starting with a Quickstart section, the primer gives an overview of the basic requirements for SCALE/KENO V.a input and allows the user to quickly run a simple criticality problem with SCALE/KENO V.a. The sections that follow Quickstart include a list of basic objectives at the beginning that identifies the goal of the section and the individual SCALE/KENO V.a features which are covered in detail in the example problems in that section. Upon completion of the primer, a new user should be comfortable using CSPAN to set up criticality problems in SCALE/KENO V.a.

  18. Food Safety Risk Assessment in Whole Food Supply Chain Based on Catastrophe Model

    OpenAIRE

    Shangmei Zhao; Xuemei Yang

    2013-01-01

    The objective of this study was to develop a food safety-risk assessment model for the whole food supply chain. In order to assess whole risk of food safety, this study designed the evaluation index system from the perspective of the food chain, which considered agricultural production, food processing and food consumption three stages. Based on catastrophe model and stability theory, the risk of agricultural production, food processing and food consumption is evaluated. This study got the va...

  19. Penn/VA center for studies of addiction.

    Science.gov (United States)

    O'Brien, Charles P; McLellan, A Thomas; Childress, Anna Rose; Woody, George E

    2009-01-01

    The Penn/VA Center was founded in 1971 because of great concern over the number of Vietnam veterans returning home addicted to heroin. At that time little was known about the science of addiction, so our program from the very beginning was designed to gather data about the nature of addiction and measure the effects of available treatments. In other words, the goals were always a combination of treatment and research. This combination has continued to the present day. A human laboratory for the study of addiction phenomena such as conditioned responses was also founded in 1971. The key clinician investigators in this group have remained in the Center since the 1970s with most of the research staff continuing to work together. Important new investigators have been added over the years. Treatment was empirically based with randomized, controlled clinical trials as the gold standard for determining evidence-based treatment. The patients coming to treatment do not distinguish between abuse of alcohol and other drugs, so the treatment and research programs have always focused on all drugs including ethyl alcohol and the combination of ethyl alcohol with other drugs such as cocaine and opioids. Most of the patients coming for treatment also suffered from additional psychiatric disorders such as depression, anxiety, bipolar disorder or schizophrenia. Thus, the addiction treatment program in 1980 absorbed the rest of the VA Psychiatry Service into the Substance Abuse Program forming a new Behavioral Health Service with responsibility for over 9000 patients. The integration of substance abuse treatment with overall mental health care was the most efficient way to handle patients with complicated combinations of disorders. While this continues to be the best way to treat patients, it has proven difficult in practice. The main reason for this difficulty is that most mental health therapists whether they are psychiatrists, psychologists or social workers feel very inadequate

  20. Helman defends decision to pull VA sponsorship of Veterans day parade

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2013-04-01

    Full Text Available No abstract available. Article truncated after 150 words. Sharon Helman, Phoenix VA Director, defended her decision to cancel VA sponsorship of the annual Phoenix Veterans Day Parade in a 4/10/13 email to VA employees. Helman said that VA sponsorship was cancelled because of “…priorities in the organization (specifically access, and heightened awareness over liability concerns which VA Legal Counsel brought forward”. She concluded her letter by warning “… that all media inquiries should be forwarded to Paul Coupaud, Acting Public Affairs Officer”. VA officials initially said fear of litigation prompted the review of VA support. Last year, a float carrying wounded Veterans in a Midland, Texas, parade collided with a freight train, killing four and injuring 17. Crash victims and their families filed lawsuits in Texas against Union Pacific Railroad and the float owner. The VA was not a defendant, and the VA has not issued any national directives on liability as a result of the tragedy.In…

  1. Differential patterns of myosin Va expression during the ontogenesis of the rat hippocampus

    Directory of Open Access Journals (Sweden)

    L.S. Brinn

    2010-09-01

    Full Text Available Myosin Va is an actin-based, processive molecular motor protein highly enriched in the nervous tissue of vertebrates. It has been associated with processes of cellular motility, which include organelle transport and neurite outgrowth. The in vivo expression of myosin Va protein in the developing nervous system of mammals has not yet been reported. We describe here the immunolocalization of myosin Va in the developing rat hippocampus. Coronal sections of the embryonic and postnatal rat hippocampus were probed with an affinity-purified, polyclonal anti-myosin Va antibody. Myosin Va was localized in the cytoplasm of granule cells in the dentate gyrus and of pyramidal cells in Ammon's horn formation. Myosin Va expression changed during development, being higher in differentiating rather than already differentiated granule and pyramidal cells. Some of these cells presented a typical migratory profile, while others resembled neurons that were in the process of differentiation. Myosin Va was also transiently expressed in fibers present in the fimbria. Myosin Va was not detected in germinative matrices of the hippocampus proper or of the dentate gyrus. In conclusion, myosin Va expression in both granule and pyramidal cells showed both position and time dependency during hippocampal development, indicating that this motor protein is under developmental regulation.

  2. Binge-drinking and non-partner aggression are associated with gambling among Veterans with recent substance use in VA outpatient treatment.

    Science.gov (United States)

    Davis, Alan K; Bonar, Erin E; Goldstick, Jason E; Walton, Maureen A; Winters, Jamie; Chermack, Stephen T

    2017-11-01

    Gambling is relatively under-assessed in Veterans Affairs (VA) substance use disorder (SUD) treatment settings, yet shared characteristics with substance addiction suggest the importance of understanding how gambling behaviors present in Veterans seeking SUD care. We evaluated substance use, mental health, and violence-related correlates of past 30-day gambling among 833 Veterans (93% male, M age 48years, 72% Caucasian) seeking treatment in VA outpatient mental health and SUD clinics who completed screening for a randomized clinical trial. A total of 288 (35%) Veterans reported past 30-day gambling. Among those who gambled, 79% had cravings/urges to gamble, whereas between 20%-27% of gamblers reported perceived relationship, legal, and daily life problems related to gambling, as well as difficulty controlling gambling. A logistic regression analysis revealed that age, recent binge-drinking, and non-partner physical aggression were associated with recent gambling. Gambling was associated with binge-drinking and non-partner physical aggression, supporting potential shared characteristics among these behaviors such as impulsivity and risk-taking, which may complicate SUD treatment engagement and effectiveness. Findings support the need to screen for gambling in the VA, and to adapt treatments to include gambling as a potential behavioral target or relapse trigger, particularly among heavy drinking patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Periodic Traveling Waves in Diatomic Granular Chains

    Science.gov (United States)

    Betti, Matthew; Pelinovsky, Dmitry E.

    2013-10-01

    We study bifurcations of periodic traveling waves in diatomic granular chains from the anti-continuum limit, when the mass ratio between the light and heavy beads is zero. We show that every limiting periodic wave is uniquely continued with respect to the mass ratio parameter, and the periodic waves with a wavelength larger than a certain critical value are spectrally stable. Numerical computations are developed to study how this solution family is continued to the limit of equal mass ratio between the beads, where periodic traveling waves of homogeneous granular chains exist.

  4. Fireworks algorithm for mean-VaR/CVaR models

    Science.gov (United States)

    Zhang, Tingting; Liu, Zhifeng

    2017-10-01

    Intelligent algorithms have been widely applied to portfolio optimization problems. In this paper, we introduce a novel intelligent algorithm, named fireworks algorithm, to solve the mean-VaR/CVaR model for the first time. The results show that, compared with the classical genetic algorithm, fireworks algorithm not only improves the optimization accuracy and the optimization speed, but also makes the optimal solution more stable. We repeat our experiments at different confidence levels and different degrees of risk aversion, and the results are robust. It suggests that fireworks algorithm has more advantages than genetic algorithm in solving the portfolio optimization problem, and it is feasible and promising to apply it into this field.

  5. Factor Va alternative conformation reconstruction using atomic force microscopy.

    Science.gov (United States)

    Chaves, R C; Dahmane, S; Odorico, M; Nicolaes, G A F; Pellequer, J-L

    2014-12-01

    Protein conformational variability (or dynamics) for large macromolecules and its implication for their biological function attracts more and more attention. Collective motions of domains increase the ability of a protein to bind to partner molecules. Using atomic force microscopy (AFM) topographic images, it is possible to take snapshots of large multi-component macromolecules at the single molecule level and to reconstruct complete molecular conformations. Here, we report the application of a reconstruction protocol, named AFM-assembly, to characterise the conformational variability of the two C domains of human coagulation factor Va (FVa). Using AFM topographic surfaces obtained in liquid environment, it is shown that the angle between C1 and C2 domains of FVa can vary between 40° and 166°. Such dynamical variation in C1 and C2 domain arrangement may have important implications regarding the binding of FVa to phospholipid membranes.

  6. Archetypal Analysis of "Almalek and Albrahmh” from Kalila va Demna

    Directory of Open Access Journals (Sweden)

    Ali Noori

    2016-12-01

    Full Text Available Archetype Theory, has been raised from Carl Gustav Young’s Psychoanalytical School. Young knows mental images and Sediments and Hereditary information which there are in the collective unconscious as Archetype. In other word, archetype is general type of repeated experiences and behaviors of human forefathers which rooted in collective unconscious. the most important Archetypes are "Anima"," Animus", "old wise man", "shadow", "mask", "rebirth" ,and "self" and "individuality". Kalila va Demna is the book which is full of allegorical stories, which because of their mythical aspect, are researchable from Archetypal Analytic criticism. One of this stories which Archetypal color is Dominant in it, is "Almalek and Albrahmh” from 16th chapter of Kalila va Demna. In this study, some archetypes such as "shadow", "Anima", "mask", "old wise man", " self " and "individuality" in the story of "Almalek and Albrahmh" from sixteenth chapter of book, has been analyzed. Since either this tale because of being legendary, and consisting of series of dreams – which have given it mythical, symbolic and interpretable nature – has capacity for archetypal analysis, or archetypal approach has high capacity and power to analyze such narrations. The story was investigated on mentioned view, and it was found that king Heblar which has stricken to a kind of Psychosis, Finds its way into the subconscious through dreams and After a confrontation with his anima, under guidance of old wise meets his self (true self and reach to his individuality and Is rescued from distress. It can be said that the king starts his path of the individual process with a dream.  He, in the bigining of the story, with the help of Iran Dokht and at the end of the story, with the help of minister is released of grief and psychosis.

  7. A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice.

    Science.gov (United States)

    Sayeed, Md Abu; Bufano, Meagan Kelly; Xu, Peng; Eckhoff, Grace; Charles, Richelle C; Alam, Mohammad Murshid; Sultana, Tania; Rashu, Md Rasheduzzaman; Berger, Amanda; Gonzalez-Escobedo, Geoffrey; Mandlik, Anjali; Bhuiyan, Taufiqur Rahman; Leung, Daniel T; LaRocque, Regina C; Harris, Jason B; Calderwood, Stephen B; Qadri, Firdausi; Vann, W F; Kováč, Pavol; Ryan, Edward T

    2015-01-01

    Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS). Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc). We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 μg), vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1), effect of an adjuvant, and route of immunization. Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 μg). We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model. We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

  8. A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice.

    Directory of Open Access Journals (Sweden)

    Md Abu Sayeed

    Full Text Available Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP component of lipopolysaccharide (LPS.Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc. We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 μg, vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1, effect of an adjuvant, and route of immunization.Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 μg. We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model.We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

  9. Heavy quark masses

    Science.gov (United States)

    Testa, Massimo

    1990-01-01

    In the large quark mass limit, an argument which identifies the mass of the heavy-light pseudoscalar or scalar bound state with the renormalized mass of the heavy quark is given. The following equation is discussed: m(sub Q) = m(sub B), where m(sub Q) and m(sub B) are respectively the mass of the heavy quark and the mass of the pseudoscalar bound state.

  10. Myosin Heavy Chain Composition of the Human Genioglossus Muscle

    Science.gov (United States)

    Daugherty, Megan; Luo, Qingwei; Sokoloff, Alan J.

    2012-01-01

    Background: The human tongue muscle genioglossus (GG) is active in speech, swallowing, respiration, and oral transport, behaviors encompassing a wide range of tongue shapes and movement speeds. Studies demonstrate substantial diversity in patterns of human GG motor unit activation, but whether this is accompanied by complex expression of muscle…

  11. Generation of heavy-chain-only antibodies in mice.

    NARCIS (Netherlands)

    R. Janssens (Rick); S. Dekker (Sylvia); R.W. Hendriks (Rudi); G. Panayotou (George); A. van Remoortere (Alexandra); J.K. San (John Kong-a); F.G. Grosveld (Frank); D.D. Drabek (Dubravka)

    2006-01-01

    textabstractWe have generated transgenic mice containing hybrid llama/human antibody loci that contain two llama variable regions and the human D, J, and Cmu and/or Cgamma constant regions. Such loci rearrange productively and rescue B cell development efficiently without LC rearrangement.

  12. Ferritin heavy chain in triple negative breast cancer

    DEFF Research Database (Denmark)

    Liu, Ning Qing; De Marchi, Tommaso; Timmermans, Annemieke M

    2014-01-01

    of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells...

  13. Logistic chain modelling

    NARCIS (Netherlands)

    Slats, P.A.; Bhola, B.; Evers, J.J.M.; Dijkhuizen, G.

    1995-01-01

    Logistic chain modelling is very important in improving the overall performance of the total logistic chain. Logistic models provide support for a large range of applications, such as analysing bottlenecks, improving customer service, configuring new logistic chains and adapting existing chains to

  14. Health supply chain management.

    Science.gov (United States)

    Zimmerman, Rolf; Gallagher, Pat

    2010-01-01

    This chapter gives an educational overview of: * The actual application of supply chain practice and disciplines required for service delivery improvement within the current health environment. * A rationale for the application of Supply Chain Management (SCM) approaches to the Health sector. * The tools and methods available for supply chain analysis and benchmarking. * Key supply chain success factors.

  15. Chains and identity

    NARCIS (Netherlands)

    Grijpink, J.H.A.M.

    2012-01-01

    This article is available in English and DutchGuidelines are presented to cope with identity problems in chains. A chain is a collaboration of a great number of autonomous organisations and professionals to tackle a dominant chain problem. In many chains identity fraud is an aspect of the dominant

  16. Silicone chain extender

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to a silicone chain extender, more particularly a chain extender for silicone polymers and copolymers, to a chain extended silicone polymer or copolymer and to a functionalized chain extended silicone polymer or copolymer, to a method for the preparation thereof...

  17. Production of heavy water

    Energy Technology Data Exchange (ETDEWEB)

    Spencer, Larry S.; Brown, Sam W.; Phillips, Michael R.

    2017-06-06

    Disclosed are methods and apparatuses for producing heavy water. In one embodiment, a catalyst is treated with high purity air or a mixture of gaseous nitrogen and oxygen with gaseous deuterium all together flowing over the catalyst to produce the heavy water. In an alternate embodiment, the deuterium is combusted to form the heavy water. In an alternate embodiment, gaseous deuterium and gaseous oxygen is flowed into a fuel cell to produce the heavy water. In various embodiments, the deuterium may be produced by a thermal decomposition and distillation process that involves heating solid lithium deuteride to form liquid lithium deuteride and then extracting the gaseous deuterium from the liquid lithium deuteride.

  18. Growth and Shape of a Chain Fountain

    CERN Document Server

    Biggins, John S

    2014-01-01

    If a long chain is held in a pot elevated a distance h_1 above the floor, and the end of the chain is then dragged over the rim of the pot and released, the chain flows under gravity down into a pile on the floor. Not only does the chain flow out of the pot, it also leaps above the pot in a "chain-fountain". I predict and observe that if the pot is held at an angle to the vertical the steady state shape of the fountain is an inverted catenary, and discuss how to apply boundary conditions to this solution. In the case of a level pot, the fountain shape is completely vertical. In this case I predict and observe both how fast the fountain grows to its steady state hight, and how it grows quadratically in time if there is no floor. The fountain is driven by an anomalous push force from the pot that acts on the link of chain about to come into motion. I confirm this by designing two new chains, one consisting of hollow cylinders threaded on a string and one consisting of heavy beads separated by long flexible thre...

  19. Comparing the health status of VA and non-VA ambulatory patients: the veterans' health and medical outcomes studies.

    Science.gov (United States)

    Rogers, William H; Kazis, Lewis E; Miller, Donald R; Skinner, Katherine M; Clark, Jack A; Spiro, Avron; Fincke, R Graeme

    2004-01-01

    The purpose of this study was to compare health status and disease profiles of ambulatory patients in specific Veterans Administration (VA) and civilian healthcare settings. A random sample of 2425 male veterans seeking care at 4 Boston-area VA outpatient clinics, who took part in the Veterans Health Study (VHS) in 1993-1995, were compared to 1318 male patients seeking civilian outpatient care in 3 major metropolitan areas covered in the Medical Outcomes Study (MOS) in 1986. The MOS sampled patients who had 1 of 5 conditions--hypertension, noninsulin-dependent diabetes, recent myocardial infarction, congestive heart failure, or depression. These 2 samples were age adjusted and compared in terms of the SF-36 Health Status/Quality of Life measures, and a list of 100 clinical variables (diagnostic, symptom, and medical event reports) collected with comparable instruments by a trained clinical observer. Individual odds ratios (VHS to MOS) were calculated for each measure and clinical variables. SF-36 measures of patient health in the VHS were lower than those in the MOS by more than one half of a standard deviation (SD) on 4 of 8 scales, by more than one quarter of a SD on the other 4, by 58% of a SD on the physical health summary scale, and by 37% of a SD on the mental health summary scale (P illness burden than did patients in the MOS. Current economic condition and service-connected disability explain most, if not all, of the differences. The differences were clinically and socially meaningful and would be consistent with substantially higher expected healthcare use.

  20. Systems innovation model: an integrated interdisciplinary team approach pre- and post-bariatric surgery at a veterans affairs (VA) medical center.

    Science.gov (United States)

    Eisenberg, Dan; Lohnberg, Jessica A; Kubat, Eric P; Bates, Cheryl C; Greenberg, Lauren M; Frayne, Susan M

    2017-04-01

    Provision of bariatric surgery in the Veterans Health Administration must account for obese veterans' co-morbidity burden and the geographically dispersed location of patients relative to Veterans Affairs (VA) bariatric centers. To evaluate a collaborative, integrated, interdisciplinary bariatric team of surgeons, bariatricians, psychologists, dieticians, and physical therapists working in a hub-and-spokes care model, for pre- and post-bariatric surgery assessment and management. This is a description of an interdisciplinary clinic and bariatric program at a VA healthcare system and a report on program evaluation findings. Retrospective data of a prospective database was abstracted. For program evaluation, we abstracted charts to characterize patient data and conducted a patient survey. Since 2009, 181 veterans have undergone bariatric surgery. Referrals came from 7 western U.S. states. Mean preoperative body mass index was 46 kg/m2 (maximum 71). Mean age was 53 years, with 33% aged>60 years; 79% were male. Medical co-morbidity included diabetes (70%), hypertension (85%), and lower back or extremity joint pain (84%). A psychiatric diagnosis was present in 58%. At 12 months, follow-up was 81% and percent excess body mass index loss was 50.5%. Among 54 sequential clinic patients completing anonymous surveys, overall satisfaction with the interdisciplinary team approach and improved quality of life were high (98% and 94%, respectively). The integrated, interdisciplinary team approach using a hub-and-spokes model is well suited to the VA bariatric surgery population, with its heavy burden of medical and mental health co-morbidity and its system of geographically dispersed patients receiving treatment at specialty centers. As the VA seeks to expand the use of bariatric surgery as an option for obese veterans, interdisciplinary models crafted to address case complexity, care coordination, and long-term outcomes should be part of policy planning efforts. Published by

  1. 75 FR 6098 - VA Veteran-Owned Small Business Verification Guidelines

    Science.gov (United States)

    2010-02-08

    ... verification are brand new and have not yet applied for any Federal or VA contracts. Also VA finds that... of his/her time to managing the concern.'' This commenter further recommended ``permitting the..., environmental, public health and safety, and other advantages; distributive impacts; and equity). The Executive...

  2. Homeless Veterans: Management Improvements Could Help VA Better Identify Supportive Housing Projects

    Science.gov (United States)

    2016-12-01

    HOMELESS VETERANS Management Improvements Could Help VA Better Identify Supportive-Housing Projects Report to...VETERANS Management Improvements Could Help VA Better Identify Supportive-Housing Projects What GAO Found As of September 2016, for veterans who...disabled veterans. These supportive-housing EULs receive project -based HUD-VASH vouchers, which provide housing subsidies, on-site case management

  3. 78 FR 28949 - Fund Availability Under VA's Homeless Providers Grant and Per Diem Program (Rehabilitation)

    Science.gov (United States)

    2013-05-16

    ... Homeless Providers Grant and Per Diem Program, Department of Veterans Affairs, 10770 North 46th Street... AFFAIRS Fund Availability Under VA's Homeless Providers Grant and Per Diem Program (Rehabilitation) AGENCY... grantee facilities originally funded under VA's Homeless Providers Grant and Per Diem Program (see funding...

  4. 77 FR 56709 - Proposed Information Collection (VA Subcontracting Report for Service Disabled Veteran-Owned...

    Science.gov (United States)

    2012-09-13

    ... Information Collection (VA Subcontracting Report for Service Disabled Veteran-Owned Small Business and Veteran... needed to collect information from subcontractors to compare information obtained from subcontracting... collection techniques or the use of other forms of information technology. Title: VA Subcontracting Report...

  5. 77 FR 70210 - Agency Information Collection (VA Subcontracting Report for Service Disabled Veteran-owned Small...

    Science.gov (United States)

    2012-11-23

    ... AFFAIRS Agency Information Collection (VA Subcontracting Report for Service Disabled Veteran-owned Small....'' SUPPLEMENTARY INFORMATION: Title: VA Subcontracting Report for Service Disabled Veteran-owned Small Business and... from subcontractors to compare information obtained from subcontracting plans submitted by prime...

  6. 38 CFR 58.16 - VA Form 10-0144-Certification Regarding Lobbying.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false VA Form 10-0144-Certification Regarding Lobbying. 58.16 Section 58.16 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) FORMS § 58.16 VA Form 10-0144—Certification Regarding Lobbying. ER06JA00.013 ...

  7. PSO-based optimization of PI regulator and VA loading of a SRF ...

    African Journals Online (AJOL)

    DR OKE

    results show that the proposed PSO technique causes minimum error and minimum VA loading angle by optimally choosing parameters of PI and minimum VA angle as compared to GA technique. Keywords: Active power filter (APF), synchronous reference frame (SRF), Genetic algorithm (GA), Particle Swarm. Optimization ...

  8. 75 FR 25321 - Agency Information Collection (VA National Rehabilitation Special Events, Event Registration...

    Science.gov (United States)

    2010-05-07

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS... Wheelchair Games Application, VA Form 0925a series. c. National Veterans Golden Age Games Application, VA... therapeutic rehabilitation programs such as the National Veterans Wheelchair Games, National Veterans Golden...

  9. 75 FR 9277 - Proposed Information Collection (VA National Rehabilitation Special Events, Event Registration...

    Science.gov (United States)

    2010-03-01

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS... period, comments may be viewed online through FDMS. FOR FURTHER INFORMATION CONTACT: Matt Bristol at (202... Sports Clinic Application, VA Form 0924--233 hours. b. National Veterans Wheelchair Games Application, VA...

  10. 78 FR 55777 - Proposed Information Collection (VA, National Veterans Sports Programs and Special Events, Event...

    Science.gov (United States)

    2013-09-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS... correspondence. During the comment period, comments may be viewed online through FDMS. FOR FURTHER INFORMATION... Wheelchair Games Event Application, VA Form 0925b. f. Voluntary Service Application, VA Form 0925d. g...

  11. 78 FR 48543 - Veterans Health Administration Fund Availability Under the VA's Homeless Providers Grant and Per...

    Science.gov (United States)

    2013-08-08

    ... AFFAIRS Veterans Health Administration Fund Availability Under the VA's Homeless Providers Grant and Per... continue to deliver services to the homeless Special Need veteran population as outlined in their FY 2009.... Quarles, Director, VA's Homeless Providers GPD Program, Department of Veterans Affairs, 10770 N. 46th...

  12. 48 CFR 853.236-70 - VA Form 10-6298, Architect-Engineer Fee Proposal.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false VA Form 10-6298, Architect-Engineer Fee Proposal. 853.236-70 Section 853.236-70 Federal Acquisition Regulations System DEPARTMENT OF...-Engineer Fee Proposal. VA Form 10-6298, Architect-Engineer Fee Proposal, shall be used as prescribed in 836...

  13. Comparing VA and private sector healthcare costs for end-stage renal disease.

    Science.gov (United States)

    Hynes, Denise M; Stroupe, Kevin T; Fischer, Michael J; Reda, Domenic J; Manning, Willard; Browning, Margaret M; Huo, Zhiping; Saban, Karen; Kaufman, James S

    2012-02-01

    Healthcare for end-stage renal disease (ESRD) is intensive, expensive, and provided in both the public and private sector. Using a societal perspective, we examined healthcare costs and health outcomes for Department of Veterans Affairs (VA) ESRD patients comparing those who received hemodialysis care at VA versus private sector facilities. Dialysis patients were recruited from 8 VA medical centers from 2001 through 2003 and followed for 12 months in a prospective cohort study. Patient demographics, clinical characteristics, quality of life, healthcare use, and cost data were collected. Healthcare data included utilization (VA), claims (Medicare), and patient self-report. Costs included VA calculated costs, Medicare dialysis facility reports and reimbursement rates, and patient self-report. Multivariable regression was used to compare costs between patients receiving dialysis at VA versus private sector facilities. The cohort comprised 334 patients: 170 patients in the VA dialysis group and 164 patients in the private sector group. The VA dialysis group had more comorbidities at baseline, outpatient and emergency visits, prescriptions, and longer hospital stays; they also had more conservative anemia management and lower baseline urea reduction ratio (67% vs. 72%; Pprivate sector dialysis group (Pprivate sector settings is critical in informing health policy options for patients with complex chronic illnesses such as ESRD.

  14. 78 FR 77204 - Proposed Information Collection (VA National Veterans Sports Programs and Special Event Surveys...

    Science.gov (United States)

    2013-12-20

    ... AFFAIRS Proposed Information Collection (VA National Veterans Sports Programs and Special Event Surveys... solicits comments on the information needed to evaluate the National Veterans Sports Programs and Special... ``OMB Control No. 2900-NEW (VA National Veterans Sports Programs and Special Event Surveys)'' in any...

  15. 76 FR 44288 - Establishment of Class E Airspace; New Market, VA

    Science.gov (United States)

    2011-07-25

    ... Federal Aviation Administration 14 CFR Part 71 Establishment of Class E Airspace; New Market, VA AGENCY... action proposes to establish Class E Airspace at New Market, VA, to accommodate the additional airspace needed for the Standard Instrument Approach Procedures developed for New Market Airport. This action...

  16. 77 FR 75918 - VA Health Professional Scholarship and Visual Impairment and Orientation and Mobility...

    Science.gov (United States)

    2012-12-26

    ... AFFAIRS 38 CFR Part 17 RIN 2900-AO34 VA Health Professional Scholarship and Visual Impairment and Orientation and Mobility Professional Scholarship Programs AGENCY: Department of Veterans Affairs. ACTION... Professional Scholarship Program (HPSP) regulations. VA also proposes to establish regulations for a new...

  17. 78 FR 51067 - VA Health Professional Scholarship and Visual Impairment and Orientation and Mobility...

    Science.gov (United States)

    2013-08-20

    ... AFFAIRS 38 CFR Part 17 RIN 2900-AO34 VA Health Professional Scholarship and Visual Impairment and Orientation and Mobility Professional Scholarship Programs AGENCY: Department of Veterans Affairs. ACTION... Scholarship Program (HPSP) regulations. VA is also establishing regulations for a new program, the Visual...

  18. 38 CFR 17.96 - Medication prescribed by non-VA physicians.

    Science.gov (United States)

    2010-07-01

    ... AFFAIRS MEDICAL Outpatient Treatment § 17.96 Medication prescribed by non-VA physicians. Any prescription... of osteopathy duly licensed to practice in the jurisdiction where the prescription is written, shall... contract with VA for filling prescriptions for patients in state homes, provided: (a) The prescription is...

  19. 48 CFR 852.219-9 - VA Small business subcontracting plan minimum requirements.

    Science.gov (United States)

    2010-10-01

    ... Provisions and Clauses 852.219-9 VA Small business subcontracting plan minimum requirements. As prescribed in subpart 819.709, insert the following clause: VA Small Business Subcontracting Plan Minimum Requirements... plan, the minimum goals for award of subcontracts to service-disabled veteran-owned small business...

  20. 75 FR 60171 - Proposed Information Collection (Credit Underwriting Standards and Procedures for Processing VA...

    Science.gov (United States)

    2010-09-29

    ... AFFAIRS Proposed Information Collection (Credit Underwriting Standards and Procedures for Processing VA... Affairs (VA), is announcing an opportunity for public comment on the proposed collection of certain... publish notice in the Federal Register concerning each proposed collection of information, including each...

  1. 78 FR 60379 - Proposed Information Collection (Credit Underwriting Standards and Procedures for Processing VA...

    Science.gov (United States)

    2013-10-01

    ... AFFAIRS Proposed Information Collection (Credit Underwriting Standards and Procedures for Processing VA... Affairs (VA), is announcing an opportunity for public comment on the proposed collection of certain... publish notice in the Federal Register concerning each proposed collection of information, including each...

  2. Sustainable Supply Chain Design

    DEFF Research Database (Denmark)

    Bals, Lydia; Tate, Wendy

    A significant conceptual and practical challenge is how to integrate triple bottom line (TBL; including economic, social and environmental) sustainability into global supply chains. Although this integration is necessary to slow down global resource depletion, understanding is limited of how...... to implement TBL goals across the supply chain. In supply chain design, the classic economic perspective still dominates, although the idea of the TBL is more widely disseminated. The purpose of this research is to add to the sustainable supply chain management literature (SSCM) research agenda...... by incorporating the physical chain, and the (information and financial) support chains into supply chain design. This manuscript tackles issues of what the chains are designed for and how they are designed structurally. Four sustainable businesses are used as illustrative case examples of innovative supply chain...

  3. Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII.

    Science.gov (United States)

    Schmidbauer, Stefan; Witzel, Reinhild; Robbel, Lars; Sebastian, Petra; Grammel, Nicolas; Metzner, Hubert J; Schulte, Stefan

    2015-08-01

    rVIII-SingleChain is a novel recombinant single-chain factor VIII (FVIII) construct, comprising covalently bonded heavy and light chains. Post-translational modifications of FVIII affect physicochemical parameters, including hydrophobicity and charge. The most relevant post-translational modifications of FVIII products are N-glycosylation of asparagine residues and tyrosine sulphations. Here, the physicochemical properties, thrombin cleavage products and post-translational modifications of rVIII-SingleChain were investigated and compared against commercially available recombinant FVIII (rFVIII) products with a predominant two-chain structure (B-domain deleted rFVIII and full-length rFVIII). rVIII-SingleChain was expressed in Chinese hamster ovary (CHO) cells and purified by chromatographic methods. Physicochemical properties of rVIII-SingleChain or thrombin-derived cleavage products were assessed using size-exclusion chromatography, reversed-phase chromatography and sodium dodecyl sulphate polyacrylamide gel electrophoresis. Analysis of the respective carbohydrate structures was performed after release of N-glycans by PNGase F followed by fluorescence labelling and high-performance liquid chromatography. Proteolysis by trypsin generated the corresponding peptides, which were analysed for sulphated tyrosines by liquid chromatography-electrospray ionisation time of flight-mass spectrometry. rVIII-SingleChain was shown to be of high purity and homogeneity, and presented a well-defined single-chain molecule with predominant β-sheet conformation. The coagulation-relevant thrombin-activation products of rVIII-SingleChain were comparable with those obtained by activation of commercially available rFVIII products. rVIII-SingleChain post-translational modifications were similar to other CHO cell-derived rFVIII products for N-glycopattern and tyrosine sulphation. In conclusion, rVIII-SingleChain is of high homogeneity and purity, and provides an expected cleavage pattern on

  4. MODEL NON LINIER GARCH (NGARCH UNTUK MENGESTIMASI NILAI VALUE at RISK (VaR PADA IHSG

    Directory of Open Access Journals (Sweden)

    I KOMANG TRY BAYU MAHENDRA

    2015-06-01

    Full Text Available In investment, risk measurement is important. One of risk measure is Value at Risk (VaR. There are many methods that can be used to estimate risk based on VaR framework. One of them Non Linier GARCH (NGARCH model. In this research, determination of VaR used NGARCH model. NGARCH model allowed for asymetric behaviour in the volatility such that “good news” or positive return and “bad news” or negative return. Based on calculations of VaR, the higher of the confidence level and the longer the investment period, the risk was greater. Determination of VaR using NGARCH model was less than GARCH model.

  5. Empirical analysis on future-cash arbitrage risk with portfolio VaR

    Science.gov (United States)

    Chen, Rongda; Li, Cong; Wang, Weijin; Wang, Ze

    2014-03-01

    This paper constructs the positive arbitrage position by alternating the spot index with Chinese Exchange Traded Fund (ETF) portfolio and estimating the arbitrage-free interval of futures with the latest trade data. Then, an improved Delta-normal method was used, which replaces the simple linear correlation coefficient with tail dependence correlation coefficient, to measure VaR (Value-at-risk) of the arbitrage position. Analysis of VaR implies that the risk of future-cash arbitrage is less than that of investing completely in either futures or spot market. Then according to the compositional VaR and the marginal VaR, we should increase the futures position and decrease the spot position appropriately to minimize the VaR, which can minimize risk subject to certain revenues.

  6. VA Health Professional Scholarship and Visual Impairment and Orientation and Mobility Professional Scholarship Programs. Final rule.

    Science.gov (United States)

    2013-08-20

    The Department of Veterans Affairs (VA) is amending its VA Health Professional Scholarship Program (HPSP) regulations. VA is also establishing regulations for a new program, the Visual Impairment and Orientation and Mobility Professional Scholarship Program (VIOMPSP). These regulations comply with and implement sections 302 and 603 of the Caregivers and Veterans Omnibus Health Services Act of 2010 (the 2010 Act). Section 302 of the 2010 Act established the VIOMPSP, which authorizes VA to provide financial assistance to certain students seeking a degree in visual impairment or orientation or mobility, in order to increase the supply of qualified blind rehabilitation specialists for VA and the United States. Section 603 of the 2010 Act reauthorized and modified HPSP, a program that provides scholarships for education or training in certain health care occupations.

  7. L'Agnese va a morire (novela, fragmento

    Directory of Open Access Journals (Sweden)

    Renata Viganò

    2013-07-01

    Full Text Available RENATA VIGANÒ (Bologna, 1900 - 1976, iniciada en la poesía desde muy pequeña, la mala situación económica familiar y la llegada del fascismo la obligaron a dejar temporalmente sus dos grandes pasiones, la medicina y la literatura, para volcarse, en calidad de correo, enlace y enfermera, a la causa partisana, una verdadera “scuola di partito” a la que llegó de la mano del que sería su compañero por el resto de su vida, Antonio Meluschi. Su experiencia entre los partisanos, primero en la zona de Romagna y luego en el valle de Comacchio, le sirvió de materia para su obra maestra, L’Agnese va a morire, de la que ofrecemos la traducción de su capítulo IV. La obra está considerada una de las novelas más significativas de la posguerra italiana y precursora, en ciertos aspectos, del neorrealismo. Escrita en 1949, la novela le valió ese mismo año el premio Viareggio. Aunque el mismo tema es parte ineludible de otras narraciones como Donne nella Resistenza (1955 o Matrimonio in brigata (1976, todas ellas con un importante transfondo autobiográfico, Renata Viganò sigue siendo hoy en día especialmente recordada por su Agnese va a morire, de la que en 1976 Giuliano Montaldo realizó una exitosa adaptación con la actriz Ingrid Thullin en el papel de Agnese. El fragmento seleccionado, con traducción de Sara Garrote Gutiérrez, se encuentra al inicio de la novela: Agnese acaba de perder a su marido, Palita, muerto en una prisión nazi a la que ha ido a parar tras la denuncia de una vecina que vio cómo escondía a un desertor, y, poco a poco, empieza a colaborar con los grupos partisanos de la zona.

  8. Identifying Homelessness among Veterans Using VA Administrative Data: Opportunities to Expand Detection Criteria

    Science.gov (United States)

    Peterson, Rachel; Gundlapalli, Adi V.; Metraux, Stephen; Carter, Marjorie E.; Palmer, Miland; Redd, Andrew; Samore, Matthew H.; Fargo, Jamison D.

    2015-01-01

    Researchers at the U.S. Department of Veterans Affairs (VA) have used administrative criteria to identify homelessness among U.S. Veterans. Our objective was to explore the use of these codes in VA health care facilities. We examined VA health records (2002-2012) of Veterans recently separated from the military and identified as homeless using VA conventional identification criteria (ICD-9-CM code V60.0, VA specific codes for homeless services), plus closely allied V60 codes indicating housing instability. Logistic regression analyses examined differences between Veterans who received these codes. Health care services and co-morbidities were analyzed in the 90 days post-identification of homelessness. VA conventional criteria identified 21,021 homeless Veterans from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (rate 2.5%). Adding allied V60 codes increased that to 31,260 (rate 3.3%). While certain demographic differences were noted, Veterans identified as homeless using conventional or allied codes were similar with regards to utilization of homeless, mental health, and substance abuse services, as well as co-morbidities. Differences were noted in the pattern of usage of homelessness-related diagnostic codes in VA facilities nation-wide. Creating an official VA case definition for homelessness, which would include additional ICD-9-CM and other administrative codes for VA homeless services, would likely allow improved identification of homeless and at-risk Veterans. This also presents an opportunity for encouraging uniformity in applying these codes in VA facilities nationwide as well as in other large health care organizations. PMID:26172386

  9. Identifying Homelessness among Veterans Using VA Administrative Data: Opportunities to Expand Detection Criteria.

    Directory of Open Access Journals (Sweden)

    Rachel Peterson

    Full Text Available Researchers at the U.S. Department of Veterans Affairs (VA have used administrative criteria to identify homelessness among U.S. Veterans. Our objective was to explore the use of these codes in VA health care facilities. We examined VA health records (2002-2012 of Veterans recently separated from the military and identified as homeless using VA conventional identification criteria (ICD-9-CM code V60.0, VA specific codes for homeless services, plus closely allied V60 codes indicating housing instability. Logistic regression analyses examined differences between Veterans who received these codes. Health care services and co-morbidities were analyzed in the 90 days post-identification of homelessness. VA conventional criteria identified 21,021 homeless Veterans from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (rate 2.5%. Adding allied V60 codes increased that to 31,260 (rate 3.3%. While certain demographic differences were noted, Veterans identified as homeless using conventional or allied codes were similar with regards to utilization of homeless, mental health, and substance abuse services, as well as co-morbidities. Differences were noted in the pattern of usage of homelessness-related diagnostic codes in VA facilities nation-wide. Creating an official VA case definition for homelessness, which would include additional ICD-9-CM and other administrative codes for VA homeless services, would likely allow improved identification of homeless and at-risk Veterans. This also presents an opportunity for encouraging uniformity in applying these codes in VA facilities nationwide as well as in other large health care organizations.

  10. The use of VA Disability Compensation and Social Security Disability Insurance among working-aged veterans.

    Science.gov (United States)

    Wilmoth, Janet M; London, Andrew S; Heflin, Colleen M

    2015-07-01

    Although there is substantial disability among veterans, relatively little is known about working-aged veterans' uptake of Department of Veterans Affairs (VA) Disability Compensation and Social Security Disability Insurance (DI). This study identifies levels of veteran participation in VA disability and/or DI benefit programs, examines transitions into and out of VA and DI programs among veterans, and estimates the size and composition of the veteran population receiving VA and/or DI benefits over time. Data from the 1992, 1993, 1996, 2001, 2004, and 2008 Survey of Income and Program Participation (SIPP) are used to describe VA and DI program participation among veterans under the age of 65. The majority of working-aged veterans do not receive VA or DI benefits and joint participation is low, but use of these programs has increased over time. A higher percentage of veterans receive VA compensation, which ranges from 4.9% in 1992 to 13.2% in 2008, than DI compensation, which ranges from 2.9% in 1992 to 6.7% in 2008. The rate of joint participation ranges from less than 1% in 1992 to 3.6% in 2008. Veterans experience few transitions between VA and DI programs during the 36-48 months they are observed. The number of veterans receiving benefits from VA and/or DI nearly doubled between 1992 and 2008. There have been substantial shifts in the composition of veterans using these programs, as cohorts who served prior to 1964 are replaced by those who served after 1964. The findings suggest potential gaps in veterans' access to disability programs that might be addressed through improved coordination of VA and DI benefits. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Continuation of Iranshahri Thoughts in Kalileh va Demne

    Directory of Open Access Journals (Sweden)

    Bijan Zahirinav

    2010-10-01

    Full Text Available In this essay, Iranshahri’s thoughts such as ideal king, divine charisma, togetherness of religion and kingdom, justice, truth etc in kalileh va Demneh are investigated. In Kalileh and Demneh, kingdom is a divine gift and the king is at the center of the state affairs. Therefore, affection and kindness must be imprinted on his forehead, otherwise he would be a devilish creature who disturbs governing orders of the universe. He must metaphysically be supported in the circus of governmental affairs, and this is possible only by divine charisma. Such a king must be decorated with justice ornament, so that every body does his best in his own special class and approaches the salvation of soul. The king must also be decorated with accomplishments such as battle assistance and with virtues such as religion assistance. He must strengthen the social connection by “truth”. Basically, without truth life has no harmony because falsehood diverts life form its regular direction. But finally, with the dominance of divine forces over devilish ones, utopia, which is a secure place for releasing from disorder and injustice is proven to be true. Therefore, we conclude that Kalileh and Demneh has a contribution to the continuation of Iranshahri’s thoughts and also to the historical and cultural continuation of Iran in transition to the Islamic period.

  12. The Global Value Chain

    DEFF Research Database (Denmark)

    Sørensen, Olav Jull

    The conference paper aims to develop the global value chain concept by including corporate internal value adding activities and competition to the basic framework in order to turn the global value chain into a strategic management tool......The conference paper aims to develop the global value chain concept by including corporate internal value adding activities and competition to the basic framework in order to turn the global value chain into a strategic management tool...

  13. Test-retest reliability of the VA National Center for Patient Safety culture questionnaire.

    Science.gov (United States)

    Shiner, Brian; Ronconi, Julia M; McKnight, Scott; Young-Xu, Yinong; Mills, Peter D; Watts, Bradley V

    2016-12-01

    Patient safety culture may have a significant influence on safety processes and outcomes. Therefore, it is important to have valid tools to measure patient safety culture in order to identify potential levers for cultural change that could improve patient safety. The 65-item Department of Veterans Affairs Patient Safety Culture Survey (VA PSCS) consists of 14 dimensions and is administered biannually to VA employees. Test-retest reliability of the VA PSCS has not been established. We conducted repeated administrations of the VA PSCS among 28 VA employees. We measured intraclass correlation coefficients for each item and dimension. Test-retest intraclass correlation coefficient values were 0.7 or greater for 13 out of 14 dimensions of the VA PSCS. Employees had difficulty reliably reporting how others feel about patient safety. In general, the VA PSCS survey showed adequate test-retest reliability. Items asking what others think or feel showed lower reliability. Further work is needed to better understand the relationship between safety culture, safety processes and safety outcomes. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  14. Probabilistic methods for verbal autopsy interpretation: InterVA robustness in relation to variations in a priori probabilities.

    Directory of Open Access Journals (Sweden)

    Edward Fottrell

    Full Text Available InterVA is a probabilistic method for interpreting verbal autopsy (VA data. It uses a priori approximations of probabilities relating to diseases and symptoms to calculate the probability of specific causes of death given reported symptoms recorded in a VA interview. The extent to which InterVA's ability to characterise a population's mortality composition might be sensitive to variations in these a priori probabilities was investigated.A priori InterVA probabilities were changed by 1, 2 or 3 steps on the logarithmic scale on which the original probabilities were based. These changes were made to a random selection of 25% and 50% of the original probabilities, giving six model variants. A random sample of 1,000 VAs from South Africa, were used as a basis for experimentation and were processed using the original InterVA model and 20 random instances of each of the six InterVA model variants. Rank order of cause of death and cause-specific mortality fractions (CSMFs from the original InterVA model and the mean, maximum and minimum results from the 20 randomly modified InterVA models for each of the six variants were compared.CSMFs were functionally similar between the original InterVA model and the models with modified a priori probabilities such that even the CSMFs based on the InterVA model with the greatest degree of variation in the a priori probabilities would not lead to substantially different public health conclusions. The rank order of causes were also similar between all versions of InterVA.InterVA is a robust model for interpreting VA data and even relatively large variations in a priori probabilities do not affect InterVA-derived results to a great degree. The original physician-derived a priori probabilities are likely to be sufficient for the global application of InterVA in settings without routine death certification.

  15. Variation in Utilization of Health Care Services for Rural VA Enrollees With Mental Health-Related Diagnoses.

    Science.gov (United States)

    Johnson, Christopher E; Bush, Ruth L; Harman, Jeffrey; Bolin, Jane; Evans Hudnall, Gina; Nguyen, Ann M

    2015-01-01

    Rural-dwelling Department of Veterans Affairs (VA) enrollees are at high risk for a wide variety of mental health-related disorders. The objective of this study is to examine the variation in the types of mental and nonmental health services received by rural VA enrollees who have a mental health-related diagnosis. The Andersen and Aday behavioral model of health services use and the Agency for Healthcare Research and Quality Medical Expenditure Panel Survey (MEPS) data were used to examine how VA enrollees with mental health-related diagnoses accessed places of care from 1999 to 2009. Population survey weights were applied to the MEPS data, and logit regression was conducted to model how predisposing, enabling, and need factors influence rural veteran health services use (measured by visits to different places of care). Analyses were performed on the subpopulations: rural VA, rural non-VA, urban VA, and urban non-VA enrollees. For all types of care, both rural and urban VA enrollees received care from inpatient, outpatient, office-based, and emergency room settings at higher odds than urban non-VA enrollees. Rural VA enrollees also received all types of care from inpatient, office-based, and emergency room settings at higher odds than urban VA enrollees. Rural VA enrollees had higher odds of a mental health visit of any kind compared to urban VA and non-VA enrollees. Based on these variations, the VA may want to develop strategies to increase screening efforts in inpatient settings and emergency rooms to further capture rural VA enrollees who have undiagnosed mental health conditions. © 2015 National Rural Health Association.

  16. Effects of inspired CO2, hyperventilation, and time on VA/Q inequality in the dog

    Science.gov (United States)

    Tsukimoto, K.; Arcos, J. P.; Schaffartzik, W.; Wagner, P. D.; West, J. B.

    1992-01-01

    In a recent study by Tsukimoto et al. (J. Appl. Physiol. 68: 2488-2493, 1990), CO2 inhalation appeared to reduce the size of the high ventilation-perfusion ratio (VA/Q) mode commonly observed in anesthetized mechanically air-ventilated dogs. In that study, large tidal volumes (VT) were used during CO2 inhalation to preserve normocapnia. To separate the influences of CO2 and high VT on the VA/Q distribution in the present study, we examined the effect of inspired CO2 on the high VA/Q mode using eight mechanically ventilated dogs (4 given CO2, 4 controls). The VA/Q distribution was measured first with normal VT and then with increased VT. In the CO2 group at high VT, data were collected before, during, and after CO2 inhalation. With normal VT, there was no difference in the size of the high VA/Q mode between groups [10.5 +/- 3.5% (SE) of ventilation in the CO2 group, 11.8 +/- 5.2% in the control group]. Unexpectedly, the size of the high VA/Q mode decreased similarly in both groups over time, independently of the inspired PCO2, at a rate similar to the fall in cardiac output over time. The reduction in the high VA/Q mode together with a simultaneous increase in alveolar dead space (estimated by the difference between inert gas dead space and Fowler dead space) suggests that poorly perfused high VA/Q areas became unperfused over time. A possible mechanism is that elevated alveolar pressure and decreased cardiac output eliminate blood flow from corner vessels in nondependent high VA/Q regions.

  17. Toxic effect of heavy metals on aquatic environment | Baby ...

    African Journals Online (AJOL)

    The indiscriminate discharge of industrial effluents, raw sewage wastes and other waste pollute most of the environments and affect survival and physiological activities of target organisms. Metals in particular have a tendency to accumulate and undergo food chain magnification. Heavy metals affect all groups of organisms ...

  18. Bioaccumulation of heavy metals by Dyera costulata cultivated in ...

    African Journals Online (AJOL)

    High concentrations of heavy metals are harmful to plants, animals and humans and their potential accumulation in human tissues and bio-magnification through the food chain cause serious health hazards. An experiment was conducted in the glasshouse to evaluate the potential of Dyera costulata as a bioaccumulator to ...

  19. Analysis of Some Heavy Metals in Grass ( Paspalum Orbiculare ...

    African Journals Online (AJOL)

    The increased deposition of trace metals from vehicle exhausts on plants has raised concerns about the risks of the quality of food consumed by humans since the heavy metals emitted through the exhaust by vehicles can enter food chain through deposition on grass grazed by animals. Grass (Paspalum Orbiculare) and ...

  20. Heavy metal contamination of mangrove sediments and the ...

    African Journals Online (AJOL)

    Mangrove wetlands are efficient in trapping pollutants that may have detrimental effects on mangrove dependent food chains. Mangrove ecosystems that are within ... Of the seven heavy metals (pb, zn, cu, co, ni, cr and v), only pb, zn and cu were found to be of anthropogenic origin. Overall, the mangroves and associated ...

  1. Heavy Flavour Production

    OpenAIRE

    Nason, P; Ridolfi, G.; Frixione, S.

    1995-01-01

    We review the status of heavy flavour production in QCD. Comparison of experimental and theoretical results for top and bottom production are given. Selected topics in charm production are also discussed.

  2. Atmospheric Heavy Metal Pollution

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 6; Issue 4. Atmospheric Heavy Metal Pollution - Development of Chronological Records and Geochemical Monitoring. Rohit Shrivastav. General Article Volume 6 Issue 4 April 2001 pp 62-68 ...

  3. Heavy Quarks: Summary Report

    CERN Document Server

    Baines, J.; Behnke, O.; Bracinik, J.; Cacciari, M.; Corradi, M.; Dainese, A.; Diglio, S.; Eskola, K.J.; Eynck, T.O.; Geiser, A.; Grindhammer, G.; Jung, H.; Kniehl, B.A.; Kolhinen, V.J.; Kretzer, S.; Kutak, K.; Laenen, Eric; Lagouri, Th.; Lipatov, A.V.; Maltoni, F.; Martin, A.D.; Meyer, A.; Morsch, A.; Motyka, L.; Peters, K.; Petrucci, F.; Piskounova, O.I.; Ranieri, R.; Ruiz, H.; Ryskin, M.G.; Schienbein, I.; Smith, J.; Smizanska, M.; Spiesberger, H.; Tonazzo, A.; Uwer, U.; Verducci, M.; Vogt, R.; Weiser, C.; Zotov, N.P.; Lagouri, Th.

    2006-01-01

    The present status of the heavy-quark production theory is critically reviewed in the first contribution. The second contribution summarises the present heavy flavour data from HERA and gives an outlook of what can be expected from HERA-II. The potential of the LHC experiments for charm and beauty physics is reviewed in the 3rd contribution. Then the relevance of saturation and small-x effects to heavy quark production at HERA and at the LHC are discussed. The non-perturbative aspects of heavy-quark fragmentation and their relevance to HERA and LHC are discussed in the next contribution. Finally, a comparison of different theoretical predictions for HERA and LHC based on different approaches is presented.

  4. Characteristics and VA Health Care Utilization of U.S. Veterans Who Completed Suicide in Oregon between 2000 and 2005

    Science.gov (United States)

    Basham, Chandra; Denneson, Lauren M.; Millet, Lisa; Shen, Xun; Duckart, Jonathan; Dobscha, Steven K.

    2011-01-01

    Oregon Violent Death Reporting System data were linked with Veterans Affairs (VA) administrative data to identify and describe veterans who completed suicide in Oregon from 2000 to 2005 (n = 968), and to describe their VA health care utilization in the year prior to death. Twenty-two percent had received health care in the VA system. Of these, 57%…

  5. Discrete kink dynamics in hydrogen-bonded chains: The two-component model

    DEFF Research Database (Denmark)

    Karpan, V.M.; Zolotaryuk, Yaroslav; Christiansen, Peter Leth

    2004-01-01

    -proton interaction in the hydrogen bond. (ii) a harmonic coupling between the protons in adjacent hydrogen bonds, and (iii) a harmonic coupling between the nearest-neighbor heavy ions (an isolated diatomic chain with the lowest acoustic band) or instead a harmonic on-site potential for the heavy ions (a diatomic...

  6. A role for myosin Va in cerebellar plasticity and motor learning: a possible mechanism underlying neurological disorder in myosin Va disease.

    Science.gov (United States)

    Miyata, Mariko; Kishimoto, Yasushi; Tanaka, Masahiko; Hashimoto, Kouichi; Hirashima, Naohide; Murata, Yoshiharu; Kano, Masanobu; Takagishi, Yoshiko

    2011-04-20

    Mutations of the myosin Va gene cause the neurological diseases Griscelli syndrome type 1 and Elejalde syndrome in humans and dilute phenotypes in rodents. To understand the pathophysiological mechanisms underlying the neurological disorders in myosin Va diseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mouse mutant. These mice manifest an ataxic gait and clonic seizures during postnatal development, but the neurological disorders are ameliorated in adulthood. We found that smooth endoplasmic reticulum (SER) rarely extended into the dendritic spines of Purkinje cells (PCs) of young d-n mice, and there were few, if any, IP(3) receptors. Moreover, long-term depression (LTD) at parallel fiber-PC synapses was abolished, consistent with our previous observations in juvenile lethal dilute mutants. Young d-n mice exhibited severe impairment of cerebellum-dependent motor learning. In contrast, adult d-n mice showed restoration of motor learning and LTD, and these neurological changes were associated with accumulation of SER and IP(3) receptors in some PC spines and the expression of myosin Va proteins in the PCs. RNA interference-mediated repression of myosin Va caused a reduction in the number of IP(3) receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER and IP(3) receptors in PC spines, LTD, and motor learning. Interestingly, d-n mice had defects of motor coordination from young to adult ages, suggesting that the role of myosin Va in PC spines is not sufficient for motor coordination.

  7. Gene duplication and conversion events shaped three homologous, differentially expressed myosin regulatory light chain (MLC2) genes.

    NARCIS (Netherlands)

    Gerrits, L.; Overheul, G.J.; Derks, R.C.; Wieringa, B.; Hendriks, W.J.A.J.; Wansink, D.G.

    2012-01-01

    Myosin II is a hexameric protein complex consisting of two myosin heavy chains, two myosin essential light chains and two myosin regulatory light chains. Multiple subunit isoforms exist, allowing great diversity in myosin II composition which likely impacts on its contractile properties. Little is

  8. Community resiliency through recovery resource supply chain planning.

    Science.gov (United States)

    Franklin, Charlotte; Todt, Kiersten

    2014-01-01

    Information in this paper is the result of recommendations and remedies developed at 'Local Supply Chain Capacity in a Crisis Summit Exercise' held in Arlington, VA on 30th-31st January,2013. At the event, which was funded through the Regional Catastrophic Preparedness Grant Program, national private sector and not-for-profit essential resource provider experts in sectors such as transportation, communication systems, energy/power, financial resources, medical supplies and other vital supplies, together with emergency managers, discussed best practices, major challenges and exchanged remedy recommendations.

  9. 75 FR 3970 - Fund Availability Under the VA Homeless Providers Grant and Per Diem Program

    Science.gov (United States)

    2010-01-25

    ... accordance with their ranked order until funding is expended (approximately 900 beds). Methodology: VA will... respective funding category based on score and any ranking criteria set forth in that funding category only...

  10. 75 FR 3968 - Fund Availability Under the VA Homeless Providers Grant and Per Diem Program

    Science.gov (United States)

    2010-01-25

    ... accordance with their ranked order until funding is expended (approximately $19 million). Methodology: VA... then be ranked within their respective funding category based on score and any ranking criteria set...

  11. EnviroAtlas -- Virginia Beach/Williamsburg, VA -- Meter-Scale Urban Land Cover (MULC)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Virginia Beach, VA EnviroAtlas Meter-scale Urban Land Cover (MULC) dataset comprises 3,724 km2 of southeast Virginia and includes Hampton, Newport News, Suffolk,...

  12. 75 FR 77664 - Vaughan Furniture Company, Galax, VA; Notice of Affirmative Determination Regarding Application...

    Science.gov (United States)

    2010-12-13

    ... Employment and Training Administration Vaughan Furniture Company, Galax, VA; Notice of Affirmative... apply for Trade Adjustment Assistance (TAA) applicable to workers and former workers of Vaughn Furniture... workers supply administrative and support services in support of furniture production at foreign...

  13. 75 FR 41577 - VBA/VHA Musculoskeletal Forum: Improving VA's Disability Evaluation Criteria

    Science.gov (United States)

    2010-07-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS VBA/VHA Musculoskeletal Forum: Improving VA's Disability Evaluation Criteria AGENCY: Department of... Veterans Benefits Administration (VBA)/Veterans Health Administration (VHA) Musculoskeletal Forum...

  14. 76 FR 10524 - Restricted Area, Potomac River, Marine Corps Base Quantico, Quantico, VA

    Science.gov (United States)

    2011-02-25

    ... Quantico, Quantico, VA AGENCY: United States Army Corps of Engineers, Department of Defense ACTION: Final... Base Quantico (MCB Quantico), located in Quantico, Virginia. DATES: Effective March 7, 2011. FOR...

  15. 78 FR 18425 - Proposed Information Collection VA Police Officer Pre-Employment Screening Checklist); Comment...

    Science.gov (United States)

    2013-03-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Proposed Information Collection VA Police Officer Pre-Employment Screening Checklist); Comment Request AGENCY: Office of Operations, Security, and Preparedness, Department of Veterans Affairs. ACTION...

  16. 78 FR 38452 - Agency Information Collection (VA Police Officer Pre-Employment Screening Checklist) Activities...

    Science.gov (United States)

    2013-06-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Agency Information Collection (VA Police Officer Pre-Employment Screening Checklist) Activities Under OMB Review AGENCY: Office of Policy, Planning and Preparedness, Department of Veterans Affairs...

  17. 77 FR 23204 - VA Acquisition Regulation: Electronic Submission of Payment Requests

    Science.gov (United States)

    2012-04-18

    ... Presentment and Payment System; (2) American National Standards Institute (ANSI) X12 electronic data... vendor payment process. The automated data validation, digital transmission, and expedited payment and... payments by including automated invoice data validation checks. VA's electronic invoicing system would...

  18. EnviroAtlas - Virginia Beach/Williamsburg, VA - BenMAP Results by Block Group

    Data.gov (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset demonstrates the effect of changes in pollution concentration on local populations in 1057 block groups in Virginia Beach/Williamsburg, VA....

  19. Federal Policy and the Rise in Disability Enrollment: Evidence for the VA's Disability Compensation Program

    OpenAIRE

    Mark Duggan; Robert Rosenheck; Perry Singleton

    2006-01-01

    The U.S. Department of Veterans' Affairs (VA) currently provides disability benefits to 2.72 million veterans of U.S. military service through the Disability Compensation (DC) program. Until recently, the medical eligibility criteria for this program were the same across service eras, with the key condition being that the disability was caused or aggravated by military service. But in July of 2001, the VA relaxed the eligibility criteria for Vietnam veterans by including diabetes in the list ...

  20. 46 CFR 7.55 - Cape Henry, VA to Cape Fear, NC.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Cape Henry, VA to Cape Fear, NC. 7.55 Section 7.55 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY PROCEDURES APPLICABLE TO THE PUBLIC BOUNDARY LINES Atlantic Coast § 7.55 Cape Henry, VA to Cape Fear, NC. (a) A line drawn from Rudee Inlet Jetty Light “2” to...

  1. Cell surface engineering of microorganisms towards adsorption of heavy metals.

    Science.gov (United States)

    Li, Peng-Song; Tao, Hu-Chun

    2015-06-01

    Heavy metal contamination has become a worldwide environmental concern due to its toxicity, non-degradability and food-chain bioaccumulation. Conventional physical and chemical treatment methods for heavy metal removal have disadvantages such as cost-intensiveness, incomplete removal, secondary pollution and the lack of metal specificity. Microbial biomass-based biosorption is one of the approaches gaining increasing attention because it is effective, cheap, and environmental friendly and can work well at low concentrations. To enhance the adsorption properties of microbial cells to heavy metal ions, the cell surface display of various metal-binding proteins/peptides have been performed using a cell surface engineering approach. The surface engineering of Gram-negative bacteria, Gram-positive bacteria and yeast towards the adsorption of heavy metals are reviewed in this article. The problems and future perspectives of this technology are discussed.

  2. Supply Chain Management og Supply Chain costing

    DEFF Research Database (Denmark)

    Nielsen, Steen; Mortensen, Ole

    2002-01-01

    Formålet med denne artikel er at belyse de muligheder som ligger i at integrere virksomhedens økonomiske styring med begrebet Supply Chain Management (SCM). Dette søges belyst ved først at beskrive den teoretiske ramme, hvori SCM indgår. Herefter analyseres begrebet Supply Chain Costing (SCC) som...... Århus. Et resultat er, at via begrebet Supply Chain Costing skabes der mulighed for at måle logistikkædens aktiviteter i kr./øre. Anvendelsen af denne information har også strategisk betydning for at kunne vælge kunde og leverandør. Ved hjælp af integrationen skabes der også helt nye mulighed...

  3. Editorial: Supply Chain Management

    Directory of Open Access Journals (Sweden)

    Dimitrios Aidonis

    2017-05-01

    Full Text Available This special issue has followed up the 3rd Olympus International Conference on Supply Chains held on Athens Metropolitan Expo, November 7 & 8 2015, Greece. The Conference was organized by the Department of Logistics Technological Educational Institute of Central Macedonia, in collaboration with the: a Laboratory of Quantitative Analysis, Logistics and Supply Chain Management of the Department of Mechanical Engineering, Aristotle University of Thessaloniki (AUTH, b Greek Association of Supply Chain Management (EEL of Northern Greece and the c Supply Chain & Logistics Journal. During the 2-Days Conference more than 60 research papers were presented covering the following thematic areas: (i Transportation, (ii Best Practices in Logistics, (iii Information and Communication Technologies in Supply Chain Management, (iv Food Logistics, (v New Trends in Business Logistics, and (vi Green Supply Chain Management. Three keynote invited speakers addressed interesting issues for the Operational Research, the Opportunities and Prospects of Greek Ports chaired Round Tables with other Greek and Foreign Scientists and Specialists.

  4. Understanding the Chain Fountain

    CERN Document Server

    Biggins, John Simeon

    2013-01-01

    If a chain is initially at rest in a beaker at a height h1 above the ground, and the end of the chain is pulled over the rim of the beaker and down towards the ground and then released, the chain will spontaneously "flow" out of the beaker under gravity. Furthermore, if h1 is sufficient, the beads do not simply drag over the edge of the beaker but form a fountain reaching a height h2 above it. We show that the formation of a fountain requires that the beads come into motion not only by being pulled upwards by the part of the chain immediately above the pile, but also by being pushed upwards by an anomalous reaction force from the pile of stationary chain. We propose possible origins for this force, argue that its magnitude will be proportional to the square of the chain velocity, and predict and verify experimentally that h2 is proportional to h1.

  5. The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN).

    Science.gov (United States)

    Srodon, Monica; Stoler, Mark H; Baber, Gwen B; Kurman, Robert J

    2006-12-01

    It has been proposed that low-grade vulvar and vaginal lesions (VIN 1 and VaIN 1) are flat condylomas and should be designated as such. Moreover, their relationship to high-grade lesions (VIN 3 and VaIN 3) is unclear. Accordingly, this study was undertaken to address these issues by comparing the distribution of human papillomavirus (HPV) types in vulvar and vaginal intraepithelial lesions. We identified 33 cases of VIN 1, 34 cases of VIN 3, 17 cases of VaIN 1, and 16 cases of VaIN 3. In addition, 36 cases of low-grade squamous intraepithelial lesion (LSIL) in the cervix and 116 cases of cervical high-grade squamous intraepithelial lesion were used for comparison. Polymerase chain reaction analysis was performed using both the Roche PGMY and DDL SPF 10 systems. In cases where HPV was detected, the majority of low-grade and high-grade lesions contained a single HPV type. However, a minority of cases were found to have multiple HPV types. Of the VIN 1 cases, a low-risk virus was seen in 22 (67%), with HPV 6 or 11 accounting for 14 (42%). A high-risk virus was detected in 14 (42%) of cases of which 2 (6%) contained HPV 16. Of the VIN 3 cases, all had high-risk HPV of which 31 (91%) were found to have HPV 16. Of the VaIN 1 cases, 6 (35%) were found to have low-risk HPV types. HPV 6 or 11 were not found in these cases. High-risk virus was seen in 13 (76%) VaIN 1 cases, with 1 (6%) containing HPV 16. HPV was detected in 15 of 16 (94%) VaIN 3 lesions, all of which had high-risk types. HPV 16 was found in 8 (50%). In contrast, 2 (6%) of cervical LSIL had low-risk HPV (HPV 6 and 11), whereas 34 (94%) of LSIL cases had high-risk HPVs. Of the cervical high-grade squamous intraepithelial lesion cases, 100% had high-risk HPVs of which 87 (75%) were found to have HPV 16. The findings demonstrate that a significant number of low-grade vulvar and vaginal lesions contain high-risk HPV types, supporting their designation as low-grade intraepithelial lesions rather than flat

  6. Partnership to improve quality care for veterans: the VA Nursing Academy.

    Science.gov (United States)

    Harper, Doreen C; Selleck, Cynthia S; Eagerton, Gregory; Froelich, Kimberly

    2015-01-01

    More than 22 million living veterans reside in the United States. In fact, understanding military culture and the experiences of these veterans is important to their ongoing health care and the unique challenges faced by many. The Veterans Affairs (VA) Nursing Academy began in 2007 to fund pilot partnerships between schools of nursing and local VA health care facilities to better serve our veteran population. Fifteen academic/service partnerships were selected for funding between 2007 and 2009 with the goals of expanding faculty and professional development, increasing nursing student enrollment, providing opportunities for educational and practice innovations, and increasing the recruitment and retention of VA nurses. This article details critical components of the partnership developed between the Birmingham VA Medical Center and the University of Alabama at Birmingham School of Nursing, a VA Nursing Academy partnership funded in the 2009 cohort. Site-specific goals of the partnership are described along with a discussion of the framework used to develop the Birmingham VA Nursing Academy, which includes relationship building, engagement, governance, evaluation of outcomes, and sustainability. The logic model developed for the partnership is included, and the interim outputs and outcomes of this practice-academic partnership are detailed, a number of which can be replicated by VAs and schools of nursing across the country. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. PERHITUNGAN VaR PORTOFOLIO SAHAM MENGGUNAKAN DATA HISTORIS DAN DATA SIMULASI MONTE CARLO

    Directory of Open Access Journals (Sweden)

    WAYAN ARTHINI

    2012-09-01

    Full Text Available Value at Risk (VaR is the maximum potential loss on a portfolio based on the probability at a certain time.  In this research, portfolio VaR values calculated from historical data and Monte Carlo simulation data. Historical data is processed so as to obtain stock returns, variance, correlation coefficient, and variance-covariance matrix, then the method of Markowitz sought proportion of each stock fund, and portfolio risk and return portfolio. The data was then simulated by Monte Carlo simulation, Exact Monte Carlo Simulation and Expected Monte Carlo Simulation. Exact Monte Carlo simulation have same returns and standard deviation  with historical data, while the Expected Monte Carlo Simulation satistic calculation similar to historical data. The results of this research is the portfolio VaR  with time horizon T=1, T=10, T=22 and the confidence level of 95 %, values obtained VaR between historical data and Monte Carlo simulation data with the method exact and expected. Value of VaR from both Monte Carlo simulation is greater than VaR historical data.

  8. Semi-nonparametric VaR forecasts for hedge funds during the recent crisis

    Science.gov (United States)

    Del Brio, Esther B.; Mora-Valencia, Andrés; Perote, Javier

    2014-05-01

    The need to provide accurate value-at-risk (VaR) forecasting measures has triggered an important literature in econophysics. Although these accurate VaR models and methodologies are particularly demanded for hedge fund managers, there exist few articles specifically devoted to implement new techniques in hedge fund returns VaR forecasting. This article advances in these issues by comparing the performance of risk measures based on parametric distributions (the normal, Student’s t and skewed-t), semi-nonparametric (SNP) methodologies based on Gram-Charlier (GC) series and the extreme value theory (EVT) approach. Our results show that normal-, Student’s t- and Skewed t- based methodologies fail to forecast hedge fund VaR, whilst SNP and EVT approaches accurately success on it. We extend these results to the multivariate framework by providing an explicit formula for the GC copula and its density that encompasses the Gaussian copula and accounts for non-linear dependences. We show that the VaR obtained by the meta GC accurately captures portfolio risk and outperforms regulatory VaR estimates obtained through the meta Gaussian and Student’s t distributions.

  9. Teacher factors contributing to dosage of the KiVa anti-bullying program.

    Science.gov (United States)

    Swift, Lauren E; Hubbard, Julie A; Bookhout, Megan K; Grassetti, Stevie N; Smith, Marissa A; Morrow, Michael T

    2017-12-01

    The KiVa Anti-Bullying Program (KiVa) seeks to meet the growing need for anti-bullying programming through a school-based, teacher-led intervention for elementary school children. The goals of this study were to examine how intervention dosage impacts outcomes of KiVa and how teacher factors influence dosage. Participants included 74 teachers and 1409 4th- and 5th-grade students in nine elementary schools. Teachers and students completed data collection at the beginning and end of the school year, including measures of bullying and victimization, correlates of victimization (depression, anxiety, peer rejection, withdrawal, and school avoidance), intervention cognitions/emotions (anti-bullying attitudes, and empathy toward victims), bystander behaviors, and teacher factors thought to relate to dosage (self-efficacy for teaching, professional burnout, perceived principal support, expected effectiveness of KiVa, perceived feasibility of KiVa). The dosage of KiVa delivered to classrooms was measured throughout the school year. Results highlight dosage as an important predictor of change in bullying, victimization, correlates of victimization, bystander behavior, and intervention cognitions/emotions. Of the teacher factors, professional burnout uniquely predicted intervention dosage. A comprehensive structural equation model linking professional burnout to dosage and then to child-level outcomes demonstrated good fit. Implications for intervention design and implementation are discussed. Copyright © 2017 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  10. VaRank: a simple and powerful tool for ranking genetic variants

    Directory of Open Access Journals (Sweden)

    Véronique Geoffroy

    2015-03-01

    Full Text Available Background. Most genetic disorders are caused by single nucleotide variations (SNVs or small insertion/deletions (indels. High throughput sequencing has broadened the catalogue of human variation, including common polymorphisms, rare variations or disease causing mutations. However, identifying one variation among hundreds or thousands of others is still a complex task for biologists, geneticists and clinicians.Results. We have developed VaRank, a command-line tool for the ranking of genetic variants detected by high-throughput sequencing. VaRank scores and prioritizes variants annotated either by Alamut Batch or SnpEff. A barcode allows users to quickly view the presence/absence of variants (with homozygote/heterozygote status in analyzed samples. VaRank supports the commonly used VCF input format for variants analysis thus allowing it to be easily integrated into NGS bioinformatics analysis pipelines. VaRank has been successfully applied to disease-gene identification as well as to molecular diagnostics setup for several hundred patients.Conclusions. VaRank is implemented in Tcl/Tk, a scripting language which is platform-independent but has been tested only on Unix environment. The source code is available under the GNU GPL, and together with sample data and detailed documentation can be downloaded from http://www.lbgi.fr/VaRank/.

  11. Supply chain components

    Directory of Open Access Journals (Sweden)

    Vieraşu, T.

    2011-01-01

    Full Text Available In this article I will go through three main logistics components, which are represented by: transportation, inventory and facilities, and the three secondary logistical components: information, production location, price and how they determine performance of any supply chain. I will discuss then how these components are used in the design, planning and operation of a supply chain. I will also talk about some obstacles a supply chain manager may encounter.

  12. Heavy-Load Lifting

    DEFF Research Database (Denmark)

    Bloomquist, Kira; Oturai, Peter; Steele, Megan L

    2017-01-01

    PURPOSE: Despite a paucity of evidence, prevention guidelines typically advise avoidance of heavy lifting in an effort to protect against breast cancer-related lymphedema. This study compared acute responses in arm swelling and related symptoms after low- and heavy-load resistance exercise among...... women at risk of lymphedema while receiving adjuvant taxane-based chemotherapy. METHODS: This is a randomized, cross-over equivalence trial. Women receiving adjuvant taxane-based chemotherapy for breast cancer who had undergone axillary lymph node dissection (n=21) participated in low- (60-65% 1...... repetition maximum (RM), two sets of 15-20 repetitions) and heavy-load (85-90% 1RM, three sets of 5-8 repetition) upper-extremity resistance exercise separated by a one-week wash-out period. Swelling was determined by bioimpedance spectroscopy and dual energy x-ray absorptiometry, with breast cancer...

  13. Very heavy dark Skyrmions

    Science.gov (United States)

    Dick, Rainer

    2017-12-01

    A dark sector with a solitonic component provides a means to circumvent the problem of generically low annihilation cross sections of very heavy dark matter particles. At the same time, enhanced annihilation cross sections are necessary for indirect detection of very heavy dark matter components beyond 100 TeV. Non-thermally produced dark matter in this mass range could therefore contribute to the cosmic γ -ray and neutrino flux above 100 TeV, and massive Skyrmions provide an interesting framework for the discussion of these scenarios. Therefore a Higgs portal and a neutrino portal for very heavy Skyrmion dark matter are discussed. The Higgs portal model demonstrates a dark mediator bottleneck, where limitations on particle annihilation cross sections will prevent a signal from the potentially large soliton annihilation cross sections. This problem can be avoided in models where the dark mediator decays. This is illustrated by the neutrino portal for Skyrmion dark matter.

  14. Heavy exotic molecules

    Science.gov (United States)

    Liu, Yizhuang; Zahed, Ismail

    We briefly review the formation of pion-mediated heavy-light exotic molecules with both charm and bottom, under the general structures of chiral and heavy quark symmetries. The charm isosinglet exotic molecules with JPC = 1++ binds, which we identify as the reported neutral X(3872). The bottom isotriplet exotic with JPC = 1+1 binds, and is identified as a mixed state of the reported charged exotics Zb+(10610) and Zb-(10650). The bound bottom isosinglet molecule with JPC = 1++ is a possible neutral Xb(10532) to be observed.

  15. Pollution status of Pakistan: a retrospective review on heavy metal contamination of water, soil, and vegetables.

    Science.gov (United States)

    Waseem, Amir; Arshad, Jahanzaib; Iqbal, Farhat; Sajjad, Ashif; Mehmood, Zahid; Murtaza, Ghulam

    2014-01-01

    Trace heavy metals, such as arsenic, cadmium, lead, chromium, nickel, and mercury, are important environmental pollutants, particularly in areas with high anthropogenic pressure. In addition to these metals, copper, manganese, iron, and zinc are also important trace micronutrients. The presence of trace heavy metals in the atmosphere, soil, and water can cause serious problems to all organisms, and the ubiquitous bioavailability of these heavy metal can result in bioaccumulation in the food chain which especially can be highly dangerous to human health. This study reviews the heavy metal contamination in several areas of Pakistan over the past few years, particularly to assess the heavy metal contamination in water (ground water, surface water, and waste water), soil, sediments, particulate matter, and vegetables. The listed contaminations affect the drinking water quality, ecological environment, and food chain. Moreover, the toxicity induced by contaminated water, soil, and vegetables poses serious threat to human health.

  16. Pollution Status of Pakistan: A Retrospective Review on Heavy Metal Contamination of Water, Soil, and Vegetables

    Directory of Open Access Journals (Sweden)

    Amir Waseem

    2014-01-01

    Full Text Available Trace heavy metals, such as arsenic, cadmium, lead, chromium, nickel, and mercury, are important environmental pollutants, particularly in areas with high anthropogenic pressure. In addition to these metals, copper, manganese, iron, and zinc are also important trace micronutrients. The presence of trace heavy metals in the atmosphere, soil, and water can cause serious problems to all organisms, and the ubiquitous bioavailability of these heavy metal can result in bioaccumulation in the food chain which especially can be highly dangerous to human health. This study reviews the heavy metal contamination in several areas of Pakistan over the past few years, particularly to assess the heavy metal contamination in water (ground water, surface water, and waste water, soil, sediments, particulate matter, and vegetables. The listed contaminations affect the drinking water quality, ecological environment, and food chain. Moreover, the toxicity induced by contaminated water, soil, and vegetables poses serious threat to human health.

  17. Failures of chain systems

    CSIR Research Space (South Africa)

    James, A

    1997-03-01

    Full Text Available Chains are used for various purposes in a wide range of industries. This paper describes three case studies where a failure analysis was carried out on chains used in markedly different applications namely: a furnace health, a drilling rig for rock...

  18. Value Chain Engineering

    DEFF Research Database (Denmark)

    Wæhrens, Brian Vejrum; Slepniov, Dmitrij

    2015-01-01

    This workbook is recommended for the attention of students of and managers in Danish small and medium sized enterprises (SMEs). Danish SMEs are currently facing a number of key challenges related to their position in global value chains. This book provides an insight into value chain management...

  19. Shared Value Chain Design

    DEFF Research Database (Denmark)

    Bals, Lydia; Tate, Wendy L.

    In Sustainable Supply Chain Management (SSCM) research still the classic economic perspective is the dominating perspective, although the triple bottom line (including economic, social and ecological) is well accepted. The theoretical foundation for the paper is Stakeholder Theory. Case studies...... in local communities, fundamentally changing supply chains....

  20. Supply Chain Management

    DEFF Research Database (Denmark)

    Wieland, Andreas; Handfield, Robert B.

    Supply chain management has made great strides in becoming a discipline with a standalone body of theories. As part of this evolution, researchers have sought to embed and integrate observed supply chain management phenomena into theoretical statements. In our review, we explore where we have been...

  1. REVERSE SUPPLY CHAIN

    Directory of Open Access Journals (Sweden)

    Tomasz DOMAGAŁA

    2013-10-01

    Full Text Available The paper focuses on the presentation of the reverse supply chain, of which the role in the modern business grows along with the increasing number of environmental regulations and possibilities of reducing an operating cost. The paper also describes main problems in developing the profitable chain and possibilities to take an action in order to overcome them.

  2. Electroencephalogram (EEG spectral features discriminate between Alzheimer’s (AD and Vascular dementia (VaD

    Directory of Open Access Journals (Sweden)

    Emanuel eNeto

    2015-02-01

    Full Text Available Alzheimer’s disease (AD and vascular dementia (VaD present with similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms differ. To determine whether clinical electroencephalography (EEG can provide information relevant to discriminate between these diagnoses, we used quantitative EEG analysis to compare the spectra between non-medicated patients with AD (n=77 and VaD (n=77 and healthy elderly normal controls (NC (n=77. We use curve-fitting with a combination of a power loss and Gaussian function to model the averaged resting-state spectra of each EEG channel extracting six parameters. We assessed the performance of our model and tested the extracted parameters for group differentiation. We performed regression analysis in a MANCOVA with group, age, gender, and number of epochs as predictors and further explored the topographical group differences with pair-wise contrasts. Significant topographical differences between the groups were found in several of the extracted features. Both AD and VaD groups showed increased delta power when compared to NC, whereas the AD patients showed a decrease in alpha power for occipital and temporal regions when compared with NC. The VaD patients had higher alpha power than NC and AD. The AD and VaD groups showed slowing of the alpha rhythm. Variability of the alpha frequency was wider for both AD and VaD groups. There was a general decrease in beta power for both AD and VaD. The proposed model is a useful to parameterize spectra which allowed extracting relevant clinical EEG key features that move towards simple and interpretable diagnostic criteria.

  3. Bioaccumulation of Heavy Metals

    African Journals Online (AJOL)

    komla

    acute toxicity and sublethal chronic action the devastating effects that the accumulation - ... surrounding waters. The results showed a programmes of heavy metals in aquatic strong and positive correlation (r = 0.97) ecosystems. between amounts of metals in the aquatic ...... Chemical composition of agricultural waste.

  4. Heavy liquid bubble chamber

    CERN Multimedia

    CERN PhotoLab

    1965-01-01

    The CERN Heavy liquid bubble chamber being installed in the north experimental hall at the PS. On the left, the 1180 litre body; in the centre the magnet, which can produce a field of 26 800 gauss; on the right the expansion mechanism.

  5. Understanding the supply chain

    Directory of Open Access Journals (Sweden)

    Aćimović Slobodan

    2006-01-01

    Full Text Available Supply chain management represents new business philosophy and includes strategically positioned and much wider scope of activity in comparison with its "older brother" - management of logistics. Philosophy of the concept of supply chain is directed to more coordination of key business functions of every link in distribution chain in the process of organization of the flow of both goods and information, while logistic managing instruments are focused on internal optimum of flows of goods and information within one company. Applying the concept of integrated supply chain among several companies makes the importance of operative logistics activity even greater on the level of one company, thus advancing processes of optimum and coordination within and between different companies and confirms the importance of logistics performances for the company’s profitability. Besides the fact that the borders between companies are being deleted, this concept of supply chain in one distribution channel influences increasing of importance of functional, i.e. traditional business managing approaches but instead it points out the importance of process managing approaches. Although the author is aware that "there is nothing harder, more dangerous and with uncertain success, but to find a way for introducing some novelties (Machiavelli, it would be even his additional stimulation for trying to bring closer the concept and goals of supply chain implementation that are identified in key, relevant, modern, theoretical and consulting approaches in order to achieve better understanding of the subject and faster implementation of the concept of supply chain management by domestic companies.

  6. In aftermath of financial investigation Phoenix VA employee demoted after her testimony

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2013-03-01

    Full Text Available No abstract available. Article truncated after 150 words. A previous Southwest Journal of Pulmonary and Critical Care Journal editorial commented on fiscal mismanagement at the Department of Veterans Affairs (VA Medical Center in Phoenix (1. Now Paula Pedene, the former Phoenix VA public affairs officer, claims she was demoted for testimony she gave to the VA Inspector General’s Office (OIG regarding that investigation (2. In 2011, the OIG investigated the Phoenix VA for excess spending on private care of patients (3. The report blamed systemic failures for controls so weak that $56 million in medical fees were paid during 2010 without adequate review. The report particularly focused on one clinician assigned by the Chief of Staff to review hundreds of requests per week and the intensive care unit physicians for transferring patients to chronic ventilator units (1,3. After the investigation, the director and one of the associate directors left the VA and the chief of staff was promoted …

  7. Isolation and characterization of specific bacteriophage Va1 to Vibrio alginolyticus

    Directory of Open Access Journals (Sweden)

    Carla Fernández Espinel

    2017-04-01

    Full Text Available Vibrio alginolyticus is associated with diseases in aquaculture. The misuse of antibiotics has led to the search for alternatives in the treatment of bacterial diseases, among them the application of bacteriophages that infect and destroy bacteria selectively. In this way, a highly lytic V. alginolyticus bacteriophage, termed Va1, was isolated, with the aim to evaluate its physical chemical parameters. For this purpose, different temperature, pH, chloroform exposure and host range conditions were evaluated. The temperature stability of phage Va1 showed higher titers at 20 and 30 °C decreasing from 40 °C. With respect to pH, the highest titers for the bacteriophage were between 5 and 8, and chloroform exposure reduced viability of the Va1 phage by 25%. The one-step curve determined that the latency period and the burst size were 20 minutes and 192 PFU / infective center respectively. Under the transmission electron microscope, the Va1 phage showed an icosahedral head and a non-contractile tail, belonging to the Podoviridae family. In conclusion, Va1 phage presents potential characteristics for use in phage therapy.

  8. Value at risk (VaR in uncertainty: Analysis with parametric method and black & scholes simulations

    Directory of Open Access Journals (Sweden)

    Humberto Banda Ortiz

    2014-07-01

    Full Text Available VaR is the most accepted risk measure worldwide and the leading reference in any risk management assessment. However, its methodology has important limitations which makes it unreliable in contexts of crisis or high uncertainty. For this reason, the aim of this work is to test the VaR accuracy when is employed in contexts of volatility, for which we compare the VaR outcomes in scenarios of both stability and uncertainty, using the parametric method and a historical simulation based on data generated with the Black & Scholes model. VaR main objective is the prediction of the highest expected loss for any given portfolio, but even when it is considered a useful tool for risk management under conditions of markets stability, we found that it is substantially inaccurate in contexts of crisis or high uncertainty. In addition, we found that the Black & Scholes simulations lead to underestimate the expected losses, in comparison with the parametric method and we also found that those disparities increase substantially in times of crisis. In the first section of this work we present a brief context of risk management in finance. In section II we present the existent literature relative to the VaR concept, its methods and applications. In section III we describe the methodology and assumptions used in this work. Section IV is dedicated to expose the findings. And finally, in Section V we present our conclusions.

  9. Project Decision Chain

    DEFF Research Database (Denmark)

    Rolstadås, Asbjørn; Pinto, Jeffrey K.; Falster, Peter

    2015-01-01

    To add value to project performance and help obtain project success, a new framework for decision making in projects is defined. It introduces the project decision chain inspired by the supply chain thinking in the manufacturing sector and uses three types of decisions: authorization, selection......, and plan decision. A primitive decision element is defined where all the three decision types can be accommodated. Each task in the primitive element can in itself contain subtasks that in turn will comprise new primitive elements. The primitive elements are nested together in a project decision chain....

  10. Global Value Chain Configuration

    DEFF Research Database (Denmark)

    Hernandez, Virginia; Pedersen, Torben

    2017-01-01

    This paper reviews the literature on global value chain configuration, providing an overview of this topic. Specifically, we review the literature focusing on the concept of the global value chain and its activities, the decisions involved in its configuration, such as location, the governance...... modes chosen and the different ways of coordinating them. We also examine the outcomes of a global value chain configuration in terms of performance and upgrading. Our aim is to review the state of the art of these issues, identify research gaps and suggest new lines for future research that would...

  11. Plastic value chains

    DEFF Research Database (Denmark)

    Baxter, John; Wahlstrom, Margareta; Zu Castell-Rüdenhausen, Malin

    2014-01-01

    Optimizing plastic value chains is regarded as an important measure in order to increase recycling of plastics in an efficient way. This can also lead to improved awareness of the hazardous substances contained in plastic waste, and how to avoid that these substances are recycled. As an example......, plastics from WEEE is chosen as a Nordic case study. The project aims to propose a number of improvements for this value chain together with representatives from Nordic stakeholders. Based on the experiences made, a guide for other plastic value chains shall be developed....

  12. VA health service utilization for homeless and low-income Veterans: a spotlight on the VA Supportive Housing (VASH) program in greater Los Angeles.

    Science.gov (United States)

    Gabrielian, Sonya; Yuan, Anita H; Andersen, Ronald M; Rubenstein, Lisa V; Gelberg, Lillian

    2014-05-01

    The US Department of Housing and Urban Development (HUD)-VA Supportive Housing (VASH) program-the VA's Housing First effort-is central to efforts to end Veteran homelessness. Yet, little is known about health care utilization patterns associated with achieving HUD-VASH housing. We compare health service utilization at the VA Greater Los Angeles among: (1) formerly homeless Veterans housed through HUD-VASH (HUD-VASH Veterans); (2) currently homeless Veterans; (3) housed, low-income Veterans not in HUD-VASH; and (4) housed, not low-income Veterans. We performed a secondary database analysis of Veterans (n=62,459) who received VA Greater Los Angeles care between October 1, 2010 and September 30, 2011. We described medical/surgical and mental health utilization [inpatient, outpatient, and emergency department (ED)]. We controlled for demographics, need, and primary care use in regression analyses of utilization data by housing and income status. HUD-VASH Veterans had more inpatient, outpatient, and ED use than currently homeless Veterans. Adjusting for demographics and need, HUD-VASH Veterans and the low-income housed Veterans had similar likelihoods of medical/surgical inpatient and outpatient utilization, compared with the housed, not low-income group. Adjusting first for demographics and need (model 1), then also for primary care use (model 2), HUD-VASH Veterans had the greatest decrease in incident rates of specialty medical/surgical, mental health, and ED care from models 1 to 2, becoming similar to the currently homeless, compared with the housed, not low-income group. Our findings suggest that currently homeless Veterans underuse health care relative to housed Veterans. HUD-VASH may address this disparity by providing housing and linkages to primary care.

  13. Military and Veteran Support: DOD and VA Programs That Address the Effects of Combat and Transition to Civilian Life

    Science.gov (United States)

    2014-11-01

    transfer their benefits to dependents. VA – Veterans Benefit Administration ( VBA ) Spinal Cord Injury and Disorders Centers Disability; Physical...who are temporarily residing in a home owned by a family member to help adapt the home to meet his or her special needs. VA - VBA Yellow Ribbon...member and Veteran X X Allowance for Aid and Attendance for Housebound Veterans VA/ VBA Veteran X X X Appendix III

  14. Moldova - Value Chain Training

    Data.gov (United States)

    Millennium Challenge Corporation — The evaluation of the GHS value chain training subactivity wwas designed to measure the extent, if any, to which the training activities improved the productivity...

  15. Editorial: Supply Chain Management

    Directory of Open Access Journals (Sweden)

    Aidonis, D.

    2012-01-01

    Full Text Available This special issue has followed up the 2nd Olympus International Conference on Supply Chains held on October 5-6, 2012, in Katerini, Greece. The Conference was organized by the Department of Logistics of Alexander Technological Educational Institution (ATEI of Thessaloniki, in collaboration with the Laboratory of Quantitative Analysis, Logistics and Supply Chain Management of the Department of Mechanical Engineering, Aristotle University of Thessaloniki (AUTH. During the 2-Days Conference more than 50 research papers were presented covering the following thematic areas: (i Business Logistics, (ii Transportation, Telematics and Distribution Networks, (iii Green Logistics, (iv Information and Communication Technologies in Supply Chain Management, and (v Services and Quality. Three keynote invited speakers addressed interesting issues for the Humanitarian Logistics, Green Supply Chains of the Agrifood Sector and the Opportunities and Prospects of Greek Ports chaired Round Tables with other Greek and Foreign Scientists and Specialists.

  16. Characterizing Oregon's supply chains.

    Science.gov (United States)

    2013-03-01

    In many regions throughout the world, freight models are used to aid infrastructure investment and : policy decisions. Since freight is such an integral part of efficient supply chains, more realistic : transportation models can be of greater assista...

  17. The VA and VCD spectra of various isotopomers of L-alanine in aqueous solution

    DEFF Research Database (Denmark)

    Abdali, Salim; Jalkanen, Karl J.; Bohr, Henrik

    2002-01-01

    Density functional theory (DFT) at the Becke 3LYP level has been used to calculate the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of various deuterated species Of L-alanine. The effect of replacing the methine hydrogen, CH1, the methyl group, CH3, and both...... changes in the VA and VCD spectra are used as a check of the Becke 3LYP hybrid model to successfully reproduce these fine features in the VA and VCD intensities. Furthermore, several aspects of the isotopomers and the isotope effects on vibrational spectra are discussed in the light of the approximation......, i.e., validity of Born-Oppenheimer approximation. (C) 2002 Elsevier Science B.V. All rights reserved....

  18. VA Disability Compensation and Money Spent on Substance Use Among Homeless Veterans: A Controversial Association.

    Science.gov (United States)

    Tsai, Jack; Rosenheck, Robert A

    2015-06-01

    There has long been concern that public support payments are used to support addictive behaviors. This study examined the amount of money homeless veterans spend on alcohol and drugs and the association between public support income, including VA disability compensation, and expenditures on alcohol and drugs. Data were from 1,160 veterans from 19 sites on entry into the Housing and Urban Development-Veterans Affairs Supportive Housing program. Descriptive statistics and nonparametric analyses were conducted. About 33% of veterans reported spending money on alcohol and 22% reported spending money on drugs in the past month. No significant association was found between public support income, VA disability compensation, and money spent on alcohol and drugs. A substantial proportion of homeless veterans spend some income on alcohol and drugs, but disability income, including VA compensation, does not seem to be related to substance use or money spent on addictive substances.

  19. Calculating operational value-at-risk (OpVaR in a retail bank

    Directory of Open Access Journals (Sweden)

    Ja'nel Esterhuysen

    2012-05-01

    Full Text Available The management of operational value-at-risk (OpVaR in financial institutions is presented by means of a novel, robust calculation technique and the influence of this value on the capital held by a bank for operational risk. A clear distinction between economic and regulatory capital is made, as well as the way OpVaR models may be used to calculate both types of capital. Under the Advanced Measurement Approach (AMA, banks may employ OpVaR models to calculate regulatory capital; this article therefore illustrates the differences in regulatory capital when using the AMA and the Standardised Approach (SA, by means of an example. Economic capital is found to converge with regulatory capital using the AMA, but not if the SA is used.

  20. LIFE JOURNEY: MEDICAL AND SCIENTIFIC WORK OF PROFESSOR V.A. SOKOLOV

    Directory of Open Access Journals (Sweden)

    P. A. Ivanov

    2017-01-01

    Full Text Available The article is dedicated to doctor of medicine, professor V.A. Sokolov. In 2017 he celebrates his eightieth birthday. Professor V.A. .Sokolov is one of the founders of polytrauma treatment in USSR and Russia. For a long time he had been heading polytrauma department at the N.V. Sklifosovsky Research Institute for Emergency Medicine. Due to his work, algorithms of life sustaining and recovery of serious patients were developed. Professor V.A. Sokolov is the author of 6 monographies and about 300 periodical papers. Besides, he is the holder of 32 patents. Some of his inventions were popularized and manufactured. He had been leading active scientific work, which resulted in 6 doctoral dissertations and 15 candidate theses. The staff of N.V. Sklifosovsky Research Institute for Emergency Medicine congratulates on the anniversary.