TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice.

PubMed

Pihlgren, Maria; Silva, Alberto B; Madani, Rime; Giriens, Valérie; Waeckerle-Men, Ying; Fettelschoss, Antonia; Hickman, David T; López-Deber, María Pilar; Ndao, Dorin Mlaki; Vukicevic, Marija; Buccarello, Anna Lucia; Gafner, Valérie; Chuard, Nathalie; Reis, Pedro; Piorkowska, Kasia; Pfeifer, Andrea; Kündig, Thomas M; Muhs, Andreas; Johansen, Pål

2013-01-03

Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.

Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching

PubMed Central

Horns, Felix; Vollmers, Christopher; Croote, Derek; Mackey, Sally F; Swan, Gary E; Dekker, Cornelia L; Davis, Mark M; Quake, Stephen R

2016-01-01

Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every class are created and delineates a two-tiered hierarchy of class switch pathways. Using somatic hypermutations as a molecular clock, we discovered that closely related B cells often switch to the same class, but lose coherence as somatic mutations accumulate. Such correlations between closely related cells exist when purified B cells class switch in vitro, suggesting that class switch recombination is directed toward specific isotypes by a cell-autonomous imprinted state. DOI: http://dx.doi.org/10.7554/eLife.16578.001 PMID:27481325

Immunoglobulin class switch recombination is impaired in Atm-deficient mice.

PubMed

Lumsden, Joanne M; McCarty, Thomas; Petiniot, Lisa K; Shen, Rhuna; Barlow, Carrolee; Wynn, Thomas A; Morse, Herbert C; Gearhart, Patricia J; Wynshaw-Boris, Anthony; Max, Edward E; Hodes, Richard J

2004-11-01

Immunoglobulin class switch recombination (Ig CSR) involves DNA double strand breaks (DSBs) at recombining switch regions and repair of these breaks by nonhomologous end-joining. Because the protein kinase ataxia telengiectasia (AT) mutated (ATM) plays a critical role in DSB repair and AT patients show abnormalities of Ig isotype expression, we assessed the role of ATM in CSR by examining ATM-deficient mice. In response to T cell-dependent antigen (Ag), Atm-/- mice secreted substantially less Ag-specific IgA, IgG1, IgG2b, and IgG3, and less total IgE than Atm+/+ controls. To determine whether Atm-/- B cells have an intrinsic defect in their ability to undergo CSR, we analyzed in vitro responses of purified B cells. Atm-/- cells secreted substantially less IgA, IgG1, IgG2a, IgG3, and IgE than wild-type (WT) controls in response to stimulation with lipopolysaccharide, CD40 ligand, or anti-IgD plus appropriate cytokines. Molecular analysis of in vitro responses indicated that WT and Atm-/- B cells produced equivalent amounts of germline IgG1 and IgE transcripts, whereas Atm-/- B cells produced markedly reduced productive IgG1 and IgE transcripts. The reduction in isotype switching by Atm-/- B cells occurs at the level of genomic DNA recombination as measured by digestion-circularization PCR. Analysis of sequences at CSR sites indicated that there is greater microhomology at the mu-gamma1 switch junctions in ATM B cells than in wild-type B cells, suggesting that ATM function affects the need or preference for sequence homology in the CSR process. These findings suggest a role of ATM in DNA DSB recognition and/or repair during CSR.

Newly Identified TLR9 Stimulant, M6-395 Is a Potent Polyclonal Activator for Murine B Cells.

PubMed

Park, Mi-Hee; Jung, Yu-Jin; Kim, Pyeung-Hyeun

2012-02-01

Toll-like receptors (TLRs) have been extensively studied in recent years. However, functions of these molecules in murine B cell biology are largely unknown. A TLR4 stimulant, LPS is well known as a powerful polyclonal activator for murine B cells. In this study, we explored the effect of a murine TLR9 stimulant, M6-395 (a synthetic CpG ODNs) on B cell proliferation and Ig production. First, M6-395 was much more potent than LPS in augmenting B cell proliferation. As for Ig expression, M6-395 facilitated the expression of both TGF-β1-induced germ line transcript α (GLTα) and IL-4-induced GLTγ1 as levels as those by LPS and Pam3CSK4 (TLR1/2 agonist) : a certain Ig GLT expression is regarded as an indicative of the corresponding isotype switching recombination. However, IgA and IgG1 secretion patterns were quite different--these Ig isotype secretions by M6-395 were much less than those by LPS and Pam3CSK4. Moreover, the increase of IgA and IgG1 production by LPS and Pam3CSK4 was virtually abrogated by M6-395. The same was true for the secretion of IgG3. We found that this unexpected phenomena provoked by M6-395 is attributed, at least in part, to its excessive mitogenic nature. Taken together, these results suggest that M6-395 can act as a murine polyclonal activator but its strong mitogenic activity is unfavorable to Ig isotype switching.

Glycosylation of IgG B cell receptor (IgG BCR) in multiple myeloma: relationship between sialylation and the signal activity of IgG BCR.

PubMed

Ilić, Vesna; Milosević-Jovcić, Nadezda; Petrović, Sonja; Marković, Dragana; Stefanović, Gordana; Ristić, Tatjana

2008-05-01

Little is known about the glycosylation of the isotype switched B cell receptor (BCR) in multiple myeloma, and the way it might affect receptor function. In this work IgG BCRs isolated from the individual lysates of peripheral blood lymphocytes (PBL) of 32 patients with IgG multiple myeloma and healthy controls were investigated for the expression of sialic acid (SA), galactose (Gal) and N-acetylglucosamine (GlcNAc), the sugars known to specify the glycoforms of human serum IgG. The degree of glycosylation and signaling status of all 32 isolated myeloma IgG BCRs were correlated and compared with the glycosylation of the IgG paraproteins isolated from sera of the same patients. It was shown that BCR IgG in myeloma is more heavily sialylated when compared with normal controls, that the increased sialylation of IgG BCR is associated with higher levels of tyrosine phosphorylation (signaling activity) of the IgG BCR supramolecular complex and that BCR IgG and serum IgG paraprotein from the same patient differed in all cases in the levels of terminal sugar expression. The results suggest that the development of the malignant clone in MM from post-switch B cells expressing IgG BCR at their surfaces to plasma cells secreting IgG paraprotein may be followed by permanent glycosylation changes in the IgG molecules.

Synthesis and Immunological Properties of N-Modified GM3 Antigens as Therapeutic Cancer Vaccines

PubMed Central

Pan, Yanbin; Chefalo, Peter; Nagy, Nancy; Harding, Clifford; Guo, Zhongwu

2011-01-01

The problem of immunotolerance to GM3, an important tumor-associated trisaccharide antigen, seriously hinders its usage in cancer vaccine development. To solve this problem, the keyhole limpet hemocyanin (KLH) conjugates of a series of GM3 derivatives were synthesized and screened as therapeutic cancer vaccines. First, the β-linked anomeric azides of differently N-acylated GM3 analogs were prepared by a highly convergent procedure. Next, a pentenoyl group was linked to the reducing end of the carbohydrate antigens following selective reduction of the azido group. The linker was thereafter ozonolyzed to give an aldehyde functionality permitting the conjugation of the antigens to KLH via reductive amination. Finally, the immunological properties of the resultant glycoconjugates were studied in C57BL/6 mice by assessing the titers of specific antibodies induced by the GM3 analogs. While KLH-GM3 elicited low levels of immune response, the KLH conjugates of N-propionyl, N-butanoyl, N-iso-butanoyl and N-phenylacetyl GM3’s induced robust immune reactions with antibodies of multiple isotypes, indicating significantly improved and T-cell dependent immune responses that lead to isotype switching, affinity maturation and the induction of immunological ‘memory’. It was suggested that GM3PhAc-KLH is a promising vaccine candidate for glycoengineered immunotherapy of cancer with GM3 as the primary target. PMID:15689172

TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling

PubMed Central

Jin, Jin; Xiao, Yichuan; Chang, Jae-Hoon; Yu, Jiayi; Hu, Hongbo; Starr, Robyn; Brittain, George C.; Chang, Mikyoung; Cheng, Xuhong; Sun, Shao-Cong

2012-01-01

Immunoglobulin (Ig) class switching is crucial for generating antibody diversity in humoral immunity and, if deregulated, also has severe pathological consequences. How the magnitude of Ig isotype switching is controlled is still poorly understood. Here we identify TANK-binding kinase 1 (TBK1) as a pivotal negative regulator of IgA class switching. B cell-specific TBK1 ablation in mice resulted in uncontrolled production of IgA and development of nephropathy-like disease symptoms. TBK1 negatively regulated IgA class switching by attenuating noncanonical NF-κB signaling, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase. These findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and highlight a unique mechanism that controls IgA production. PMID:23023393

Improving the solubility of anti-LINGO-1 monoclonal antibody Li33 by isotype switching and targeted mutagenesis

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

Pepinsky, R. Blake; Silvian, Laura; Berkowitz, Steven A.

2010-11-15

Monoclonal antibodies (Mabs) are a favorite drug platform of the biopharmaceutical industry. Currently, over 20 Mabs have been approved and several hundred others are in clinical trials. The anti-LINGO-1 Mab Li33 was selected from a large panel of antibodies by Fab phage display technology based on its extraordinary biological activity in promoting oligodendrocyte differentiation and myelination in vitro and in animal models of remyelination. However, the Li33 Fab had poor solubility when converted into a full antibody in an immunoglobulin G1 framework. A detailed analysis of the biochemical and structural features of the antibody revealed several possible reasons for itsmore » propensity to aggregate. Here, we successfully applied three molecular approaches (isotype switching, targeted mutagenesis of complementarity determining region residues, and glycosylation site insertion mutagenesis) to address the solubility problem. Through these efforts we were able to improve the solubility of the Li33 Mab from 0.3 mg/mL to >50 mg/mL and reduce aggregation to an acceptable level. These strategies can be readily applied to other proteins with solubility issues.« less

Roles of Alum and Monophosphoryl Lipid A Adjuvants in Overcoming CD4+ T Cell Deficiency to Induce Isotype-Switched IgG Antibody Responses and Protection by T-Dependent Influenza Vaccine

PubMed Central

Ko, Eun-Ju; Lee, Young-Tae; Kim, Ki-Hye; Lee, Youri; Jung, Yu-Jin; Kim, Min-Chul; Lee, Yu-Na; Kang, Taeuk; Kang, Sang-Moo

2016-01-01

Vaccine adjuvant effects in CD4 deficient condition largely remain unknown. We investigated the roles of combined monophosphoryl lipid A (MPL) and Alum adjuvant (MPL+Alum) in inducing immunity after immunization of CD4-knockout (CD4KO) and wild-type (WT) mice with T-dependent influenza vaccine. MPL+Alum adjuvant mediated IgG isotype-switched antibodies, IgG secreting cell responses, and protection in CD4KO mice, which were comparable to those in WT mice. In contrast, Alum adjuvant effects were dependent on CD4+ T cells. MPL+Alum adjuvant was effective in recruiting monocytes and neutrophils as well as in protecting macrophages from alum-mediated cell loss at the injection site in CD4KO mice. MPL+Alum appeared to attenuate MPL-induced inflammatory responses in WT mice, likely improving the safety. Additional studies in CD4-depleted WT mice and MHCII KO mice suggest that MHCII positive antigen presenting cells contribute to providing alternative B cell help in CD4 deficient condition in the context of MPL+Alum adjuvanted vaccination. PMID:27881702

Newly Identified TLR9 Stimulant, M6-395 Is a Potent Polyclonal Activator for Murine B Cells

PubMed Central

Park, Mi-Hee; Jung, Yu-Jin

2012-01-01

Background Toll-like receptors (TLRs) have been extensively studied in recent years. However, functions of these molecules in murine B cell biology are largely unknown. A TLR4 stimulant, LPS is well known as a powerful polyclonal activator for murine B cells. Methods In this study, we explored the effect of a murine TLR9 stimulant, M6-395 (a synthetic CpG ODNs) on B cell proliferation and Ig production. Results First, M6-395 was much more potent than LPS in augmenting B cell proliferation. As for Ig expression, M6-395 facilitated the expression of both TGF-β1-induced germ line transcript α (GLTα) and IL-4-induced GLTγ1 as levels as those by LPS and Pam3CSK4 (TLR1/2 agonist) : a certain Ig GLT expression is regarded as an indicative of the corresponding isotype switching recombination. However, IgA and IgG1 secretion patterns were quite different--these Ig isotype secretions by M6-395 were much less than those by LPS and Pam3CSK4. Moreover, the increase of IgA and IgG1 production by LPS and Pam3CSK4 was virtually abrogated by M6-395. The same was true for the secretion of IgG3. We found that this unexpected phenomena provoked by M6-395 is attributed, at least in part, to its excessive mitogenic nature. Conclusion Taken together, these results suggest that M6-395 can act as a murine polyclonal activator but its strong mitogenic activity is unfavorable to Ig isotype switching. PMID:22536167

CD73 expression identifies a subset of IgM+ antigen-experienced cells with memory attributes that is T cell and CD40 signalling dependent.

PubMed

D'Souza, Lucas; Gupta, Sneh Lata; Bal, Vineeta; Rath, Satyajit; George, Anna

2017-12-01

B-cell memory was long characterized as isotype-switched, somatically mutated and germinal centre (GC)-derived. However, it is now clear that the memory pool is a complex mixture that includes unswitched and unmutated cells. Further, expression of CD73, CD80 and CD273 has allowed the categorization of B-cell memory into multiple subsets, with combinatorial expression of the markers increasing with GC progression, isotype-switching and acquisition of somatic mutations. We have extended these findings to determine whether these markers can be used to identify IgM memory phenotypically as arising from T-dependent versus T-independent responses. We report that CD73 expression identifies a subset of antigen-experienced IgM + cells that share attributes of functional B-cell memory. This subset is reduced in the spleens of T-cell-deficient and CD40-deficient mice and in mixed marrow chimeras made with mutant and wild-type marrow, the proportion of CD73 + IgM memory is restored in the T-cell-deficient donor compartment but not in the CD40-deficient donor compartment, indicating that CD40 ligation is involved in its generation. We also report that CD40 signalling supports optimal expression of CD73 on splenic T cells and age-associated B cells (ABCs), but not on other immune cells such as neutrophils, marginal zone B cells, peritoneal cavity B-1 B cells and regulatory T and B cells. Our data indicate that in addition to promoting GC-associated memory generation during B-cell differentiation, CD40-signalling can influence the composition of the unswitched memory B-cell pool. They also raise the possibility that a fraction of ABCs may represent T-cell-dependent IgM memory. © 2017 John Wiley & Sons Ltd.

An Unmutated IgM Response to the Vi Polysaccharide of Salmonella Typhi Contributes to Protective Immunity in a Murine Model of Typhoid.

PubMed

Pandya, Kalgi D; Palomo-Caturla, Isabel; Walker, Justin A; K Sandilya, Vijay; Zhong, Zhijiu; Alugupalli, Kishore R

2018-06-15

T cell-dependent B cell responses typically develop in germinal centers. Abs generated during such responses are isotype switched and have a high affinity to the Ag because of somatic hypermutation of Ab genes. B cell responses to purified polysaccharides are T cell independent and do not result in the formation of bona fide germinal centers, and the dominant Ab isotype produced during such responses is IgM with very few or no somatic mutations. Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and Ig isotype switching in humans and mice. To test the extent to which unmutated polysaccharide-specific IgM confers protective immunity, we immunized wildtype and AID -/- mice with either heat-killed Salmonella enterica serovar Typhi ( S. Typhi) or purified Vi polysaccharide (ViPS). We found that wildtype and AID -/- mice immunized with heat-killed S. Typhi generated similar anti-ViPS IgM responses. As expected, wildtype, but not AID -/- mice generated ViPS-specific IgG. However, the differences in the Ab-dependent killing of S. Typhi mediated by the classical pathway of complement activation were not statistically significant. In ViPS-immunized wildtype and AID -/- mice, the ViPS-specific IgM levels and S. Typhi bactericidal Ab titers at 7 but not at 28 d postimmunization were also comparable. To test the protective immunity conferred by these immunizations, mice were challenged with a chimeric S. Typhimurium strain expressing ViPS. Compared with their naive counterparts, immunized wildtype and AID -/- mice exhibited significantly reduced bacterial burden regardless of the route of infection. These data indicate that an unmutated IgM response to ViPS contributes to protective immunity to S. Typhi. Copyright © 2018 by The American Association of Immunologists, Inc.

Immunoglobulin class-switch recombination deficiencies.

PubMed

Durandy, Anne; Kracker, Sven

2012-07-30

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

Immunoglobulin class-switch recombination deficiencies

PubMed Central

2012-01-01

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches. PMID:22894609

B cell Toll-like receptors and immunoglobulin class-switch DNA recombination

PubMed Central

Pone, Egest J.; Xu, Zhenming; White, Clayton A.; Zan, Hong; Casali, Paolo

2014-01-01

Toll-like receptors (TLRs) are a family of conserved pattern recognition receptors (PRRs). Engagement of TLRs in B cells by microbe-associated molecular patterns (MAMPs) induces T-independent (TI) antibody responses and plays an important role in the early stages of T-dependent (TD) antibody responses before specific T cell help becomes available, in part by facilitating B cell entry into the germinal center reaction. The role of B cell TLRs in the antibody response is magnified by the synergy of B cell receptor (BCR) crosslinking and TLR engagement in promoting B cell proliferation and efficiently inducing immunoglobulin (Ig) class switch DNA recombination (CSR), which crucially diversifies the antibody biological effector functions. Dual engagement of TLRs and BCR can be mediated by complex MAMPs such as lipopolysaccharides (LPS), which engages TLR4 through its lipid A moiety and crosslinks the BCR through its polysaccharidic moiety (O-antigen). Dual BCR/TLR engagement induces CSR to all Ig isotypes, as directed by different cytokines, while engagement of any TLR alone induces only marginal CSR. Integration of BCR and TLR signaling results in activation of the canonical and non-canonical NF-κB pathways, induction of activation-induced cytidine deaminase (AID) and germline transcription of switch (S) regions in the IgH locus. The last two are essential events for CSR to unfold. A critical role of dual BCR/TLR engagement in induction of CSR and generation of neutralizing antibodies is emphasized by the emergence of TLR ligands as integral components of vaccines that greatly boost humoral immunity in a B cell-intrinsic fashion. Further, dual BCR/TLR engagement by complex self-antigens will result in dysregulation of AID expression and CSR in autoreactive B cells, leading to generation of isotype-switched pathogenic autoantibodies. Finally, an important aspect of dual BCR/TLR engagement is the boosting of specific antibody response to tumor antigens, as suggested by high titers of anti-tumor antibodies in response to tumor vaccines that contain TLR agonists. PMID:22652800

DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner.

PubMed

Wiedemann, Eva-Maria; Peycheva, Mihaela; Pavri, Rushad

2016-12-13

Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR. Assembly of CSR-associated origins is facilitated by R loops and promotes the physical proximity (synapsis) of recombining switch regions, which is reduced by R loop inhibition or Mcm complex depletion. Thus, R loops contribute to replication origin specification that promotes DSB resolution in CSR. This suggests a mechanism for the dependence of CSR on S phase and cell division. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

PubMed

Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar; Westerberg, Katharine G; Mach, Linh; Hensley-McBain, Tiffany; Sutherland, Laura; Mildenberg, Benjamin; Morton, Georgeanna; Yates, Nicole L; Mize, Gregory J; Pollara, Justin; Hladik, Florian; Ochsenbauer, Christina; Denny, Thomas N; Warrier, Ranjit; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Nitayapan, Sorachai; Kaewkungwal, Jaranit; Ferrari, Guido; Shaw, George M; Xia, Shi-Mao; Liao, Hua-Xin; Montefiori, David C; Tomaras, Georgia D; Haynes, Barton F; McElrath, Juliana M

2016-12-01

HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1 JR-CSF and HIV-1 Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Collaboration between tumor-specific CD4+ T cells and B cells in anti-cancer immunity.

PubMed

Guy, Thomas V; Terry, Alexandra M; Bolton, Holly A; Hancock, David G; Zhu, Erhua; Brink, Robert; McGuire, Helen M; Shklovskaya, Elena; Fazekas de St. Groth, Barbara

2016-05-24

The role of B cells and antibodies in anti-tumor immunity is controversial, with both positive and negative effects reported in animal models and clinical studies. We developed a murine B16.F10 melanoma model to study the effects of collaboration between tumor-specific CD4+ T cells and B cells on tumor control. By incorporating T cell receptor transgenic T cells and B cell receptor isotype switching B cells, we were able to track the responses of tumor-reactive T and B cells and the development of anti-tumor antibodies in vivo. In the presence of tumor-specific B cells, the number of tumor-reactive CD4+ T cells was reduced in lymphoid tissues and the tumor itself, and this correlated with poor tumor control. B cells had little effect on the Th1 bias of the CD4+ T cell response, and the number of induced FoxP3+ regulatory cells (iTregs) generated from within the original naive CD4+ T cell inoculum was unrelated to the degree of B cell expansion. In response to CD4+ T cell help, B cells produced a range of isotype-switched anti-tumor antibodies, principally IgG1, IgG2a/c and IgG2b. In the absence of CD4+ T cells, B cells responded to agonistic anti-CD40 administration by switching to production of IgG2a/c and, to a lesser extent, IgG1, IgG3, IgA and IgE, which reduced the number of lung metastases after i.v. tumor inoculation but had no effect on the growth of subcutaneous tumors.

Distinct functional roles of β-tubulin isotypes in microtubule arrays of Tetrahymena thermophila, a model single-celled organism.

PubMed

Pucciarelli, Sandra; Ballarini, Patrizia; Sparvoli, Daniela; Barchetta, Sabrina; Yu, Ting; Detrich, H William; Miceli, Cristina

2012-01-01

The multi-tubulin hypothesis proposes that each tubulin isotype performs a unique role, or subset of roles, in the universe of microtubule function(s). To test this hypothesis, we are investigating the functions of the recently discovered, noncanonical β-like tubulins (BLTs) of the ciliate, Tetrahymena thermophila. Tetrahymena forms 17 distinct microtubular structures whose assembly had been thought to be based on single α- and β-isotypes. However, completion of the macronuclear genome sequence of Tetrahymena demonstrated that this ciliate possessed a β-tubulin multigene family: two synonymous genes (BTU1 and BTU2) encode the canonical β-tubulin, BTU2, and six genes (BLT1-6) yield five divergent β-tubulin isotypes. In this report, we examine the structural features and functions of two of the BLTs (BLT1 and BLT4) and compare them to those of BTU2. With respect to BTU2, BLT1 and BLT4 had multiple sequence substitutions in their GTP-binding sites, in their interaction surfaces, and in their microtubule-targeting motifs, which together suggest that they have specialized functions. To assess the roles of these tubulins in vivo, we transformed Tetrahymena with expression vectors that direct the synthesis of GFP-tagged versions of the isotypes. We show that GFP-BLT1 and GFP-BLT4 were not detectable in somatic cilia and basal bodies, whereas GFP-BTU2 strongly labeled these structures. During cell division, GFP-BLT1 and GFP-BLT4, but not GFP-BTU2, were incorporated into the microtubule arrays of the macronucleus and into the mitotic apparatus of the micronucleus. GFP-BLT1 also participated in formation of the microtubules of the meiotic apparatus of the micronucleus during conjugation. Partitioning of the isotypes between nuclear and ciliary microtubules was confirmed biochemically. We conclude that Tetrahymena uses a family of distinct β-tubulin isotypes to construct subsets of functionally different microtubules, a result that provides strong support for the multi-tubulin hypothesis.

The constant region affects antigen binding of antibodies to DNA by altering secondary structure.

PubMed

Xia, Yumin; Janda, Alena; Eryilmaz, Ertan; Casadevall, Arturo; Putterman, Chaim

2013-11-01

We previously demonstrated an important role of the constant region in the pathogenicity of anti-DNA antibodies. To determine the mechanisms by which the constant region affects autoantibody binding, a panel of isotype-switch variants (IgG1, IgG2a, IgG2b) was generated from the murine PL9-11 IgG3 autoantibody. The affinity of the PL9-11 antibody panel for histone was measured by surface plasmon resonance (SPR). Tryptophan fluorescence was used to determine wavelength shifts of the antibody panel upon binding to DNA and histone. Finally, circular dichroism spectroscopy was used to measure changes in secondary structure. SPR analysis revealed significant differences in histone binding affinity between members of the PL9-11 panel. The wavelength shifts of tryptophan fluorescence emission were found to be dependent on the antibody isotype, while circular dichroism analysis determined that changes in antibody secondary structure content differed between isotypes upon antigen binding. Thus, the antigen binding affinity is dependent on the particular constant region expressed. Moreover, the effects of antibody binding to antigen were also constant region dependent. Alteration of secondary structures influenced by constant regions may explain differences in fine specificity of anti-DNA antibodies between antibodies with similar variable regions, as well as cross-reactivity of anti-DNA antibodies with non-DNA antigens. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Immunoglobulins of Cold-Blooded Vertebrates

PubMed Central

Pettinello, Rita; Dooley, Helen

2014-01-01

Although lymphocyte-like cells secreting somatically-recombining receptors have been identified in the jawless fishes (hagfish and lamprey), the cartilaginous fishes (sharks, skates, rays and chimaera) are the most phylogenetically distant group relative to mammals in which bona fide immunoglobulins (Igs) have been found. Studies of the antibodies and humoral immune responses of cartilaginous fishes and other cold-blooded vertebrates (bony fishes, amphibians and reptiles) are not only revealing information about the emergence and roles of the different Ig heavy and light chain isotypes, but also the evolution of specialised adaptive features such as isotype switching, somatic hypermutation and affinity maturation. It is becoming increasingly apparent that while the adaptive immune response in these vertebrate lineages arose a long time ago, it is most definitely not primitive and has evolved to become complex and sophisticated. This review will summarise what is currently known about the immunoglobulins of cold-blooded vertebrates and highlight the differences, and commonalities, between these and more “conventional” mammalian species. PMID:25427250

Peyer’s patches: Organizing B cell responses at the intestinal frontier

PubMed Central

Reboldi, Andrea; Cyster, Jason G

2015-01-01

Summary Secondary lymphoid tissues share the important function of bringing together antigens and rare antigen-specific lymphocytes to foster induction of adaptive immune responses. Peyer’s patches (PPs) are unique compared to other secondary lymphoid tissues in their continual exposure to an enormous diversity of microbiome- and food-derived antigens and in the types of pathogens they encounter. Antigens are delivered to PPs by specialized microfold (M) epithelial cells and they may be captured and presented by resident dendritic cells (DCs). In accord with their state of chronic microbial antigen exposure, PPs exhibit continual germinal center (GC) activity. These GCs contribute to the generation of B cells and plasma cells producing somatically mutated gut antigen-specific IgA antibodies, but have also been suggested to support antigen-nonspecific diversification of the B cell repertoire. Here we review current understanding of how PPs foster B cell encounters with antigen, how they favor isotype switching to the secretory IgA isotype, and how their GC responses may uniquely contribute to mucosal immunity. PMID:27088918

Regulation of Immunoglobulin Class-Switch Recombination: Choreography of Noncoding Transcription, Targeted DNA Deamination, and Long-Range DNA Repair

PubMed Central

Matthews, Allysia J.; Zheng, Simin; DiMenna, Lauren J.; Chaudhuri, Jayanta

2014-01-01

Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., Cγ, Cε, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming. PMID:24507154

The AID enzyme induces class switch recombination in fibroblasts.

PubMed

Okazaki, Il-mi; Kinoshita, Kazuo; Muramatsu, Masamichi; Yoshikawa, Kiyotsugu; Honjo, Tasuku

2002-03-21

The switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA is mediated by class switch recombination (CSR). CSR changes the immunoglobulin heavy chain constant region (CH) gene from Cmu to one of the other CH genes. Somatic hypermutation introduces massive numbers of point mutations in the immunoglobulin variable (V) region gene, giving rise to immunoglobulin with higher affinity. Activation-induced cytidine deaminase (AID), a putative RNA-editing cytidine deaminase, is expressed strictly in activated B cells and is indispensable in both CSR and somatic hypermutation. But the exact function of AID is unknown. Here we show that ectopic expression of AID induces CSR in an artificial switch construct in fibroblasts at a level comparable to that in stimulated B cells. Sequences around recombination junctions in the artificial substrate have features similar to endogenous CSR junctions. Furthermore, AID-induced CSR in fibroblasts is dependent on transcription of the target S region, as shown in endogenous CSR in B cells. The results show that AID is the only B-cell-specific factor required for initiation of the CSR reaction in the activated locus.

Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching.

PubMed

Guttormsen, Hilde-Kari; Paoletti, Lawrence C; Mansfield, Keith G; Jachymek, Wojcieck; Jennings, Harold J; Kasper, Dennis L

2008-04-15

Many pathogens are sheltered from host immunity by surface polysaccharides that would be ideal as vaccines except that they are too similar to host antigens to be immunogenic. The production of functional IgG is a desirable response to vaccines; because IgG is the only isotype that crosses the placenta, it is of particular importance in maternal vaccines against neonatal disease due to group B Streptococcus (GBS). Clinical studies found a substantially lower proportion of IgG-relative to IgM-among antibodies elicited by conjugates prepared with purified GBS type V capsular polysaccharide (CPS) than among those evoked by CPSs of other GBS serotypes. The epitope specificity of IgG elicited in humans by a conjugate prepared with type V CPS is for chemically desialylated type V CPS (dV CPS). We studied desialylation as a mechanism for enhancing the ability of type V CPS to induce IgM-to-IgG switching. Desialylation did not affect the structural conformation of type V CPS. Rhesus macaques, whose isotype responses to GBS conjugates match those of humans, produced functionally active IgG in response to a dV CPS-tetanus toxoid conjugate (dV-TT), and 98% of neonatal mice born to dams vaccinated with dV-TT survived lethal challenge with viable GBS. Targeted chemical engineering of a carbohydrate to create a molecule less like host self may be a rational approach for improving other glycoconjugates.

YY1 Controls Immunoglobulin Class Switch Recombination and Nuclear Activation-Induced Deaminase Levels

PubMed Central

Zaprazna, Kristina

2012-01-01

Activation-induced deaminase (AID) is an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), processes that ensure antibody maturation and expression of different immunoglobulin isotypes. AID function is tightly regulated by tissue- and stage-specific expression, nuclear localization, and protein stability. Transcription factor YY1 is crucial for early B cell development, but its function at late B cell stages is unknown. Here, we show that YY1 conditional knockout in activated splenic B cells interferes with CSR. Knockout of YY1 did not affect B cell proliferation, transcription of the AID and IgM genes, or levels of various switch region germ line transcripts. However, we show that YY1 physically interacts with AID and controls the accumulation of nuclear AID, at least in part, by increasing nuclear AID stability. We show for the first time that YY1 plays a novel role in CSR and controls nuclear AID protein levels. PMID:22290437

Distinct Functional Roles of β-Tubulin Isotypes in Microtubule Arrays of Tetrahymena thermophila, a Model Single-Celled Organism

PubMed Central

Pucciarelli, Sandra; Ballarini, Patrizia; Sparvoli, Daniela; Barchetta, Sabrina; Yu, Ting; Detrich, H. William; Miceli, Cristina

2012-01-01

Background The multi-tubulin hypothesis proposes that each tubulin isotype performs a unique role, or subset of roles, in the universe of microtubule function(s). To test this hypothesis, we are investigating the functions of the recently discovered, noncanonical β-like tubulins (BLTs) of the ciliate, Tetrahymena thermophila. Tetrahymena forms 17 distinct microtubular structures whose assembly had been thought to be based on single α- and β-isotypes. However, completion of the macronuclear genome sequence of Tetrahymena demonstrated that this ciliate possessed a β-tubulin multigene family: two synonymous genes (BTU1 and BTU2) encode the canonical β-tubulin, BTU2, and six genes (BLT1-6) yield five divergent β-tubulin isotypes. In this report, we examine the structural features and functions of two of the BLTs (BLT1 and BLT4) and compare them to those of BTU2. Methodology/Principal Findings With respect to BTU2, BLT1 and BLT4 had multiple sequence substitutions in their GTP-binding sites, in their interaction surfaces, and in their microtubule-targeting motifs, which together suggest that they have specialized functions. To assess the roles of these tubulins in vivo, we transformed Tetrahymena with expression vectors that direct the synthesis of GFP-tagged versions of the isotypes. We show that GFP-BLT1 and GFP-BLT4 were not detectable in somatic cilia and basal bodies, whereas GFP-BTU2 strongly labeled these structures. During cell division, GFP-BLT1 and GFP-BLT4, but not GFP-BTU2, were incorporated into the microtubule arrays of the macronucleus and into the mitotic apparatus of the micronucleus. GFP-BLT1 also participated in formation of the microtubules of the meiotic apparatus of the micronucleus during conjugation. Partitioning of the isotypes between nuclear and ciliary microtubules was confirmed biochemically. Conclusion/Significance We conclude that Tetrahymena uses a family of distinct β-tubulin isotypes to construct subsets of functionally different microtubules, a result that provides strong support for the multi-tubulin hypothesis. PMID:22745812

A simple and sensitive method for determining plasma cell isotype and monoclonality in bone marrow using flowcytometry.

PubMed

van Zaanen, H C; Vet, R J; de Jong, C M; von dem Borne, A E; van Oers, M H

1995-09-01

In this paper we describe a new, rapid and sensitive method to determine plasma cell isotype and clonality in bone marrow using flowcytometry. With the use of a new fixation and permeabilization reagent (Permeafix), which preserves cell structure and morphology, and a monoclonal antibody (Mab) specific for plasma cells (B-B4), it has become possible to specifically select plasma cells and to determine the cytoplasmatic immunoglobulins by flowcytometry. Thirty successive bone marrow aspirates from multiple myeloma patients and patients with MGUS were studied as well as 10 bone marrow samples from patients with reactive plasmacytosis. Each sample was analysed both by immunofluorescence on cytospin smears and FACS analysis. There were no discrepancies between plasma cell isotype as determined by FACS and cytospin. Moreover, FACS analysis was shown to allow detection of very low numbers of plasma cells and to determine whether these plasma cells are mono- or polyclonal. Possible applications are discussed.

Effect of CpG dinucleotides within IgH switch region repeats on immunoglobulin class switch recombination.

PubMed

Zhang, Zheng Z; Hsieh, Chih-Lin; Okitsu, Cindy Yen; Han, Li; Yu, Kefei; Lieber, Michael R

2015-08-01

Immunoglobulin (Ig) heavy chains undergo class switch recombination (CSR) to change the heavy chain isotype from IgM to IgG, A or E. The switch regions are several kilobases long, repetitive, and G-rich on the nontemplate strand. They are also relatively depleted of CpG (also called CG) sites for unknown reasons. Here we use synthetic switch regions at the IgH switch alpha (Sα) locus to test the effect of CpG sites and to try to understand why the IgH switch sequences evolved to be relatively depleted of CpG. We find that even just two CpG sites within an 80 bp synthetic switch repeat iterated 15 times (total switch region length of 1200 bp containing 30 CpG sites) are sufficient to dramatically reduce both Ig CSR and transcription through the switch region from the upstream Iα sterile transcript promoter, which is the promoter that directs transcripts through the Sα region. De novo DNA methylation occurs at the four CpG sites in and around the Iα promoter when each 80 bp Iα switch repeat contains the two CpG sites. Thus, a relatively low density of CpG sites within the switch repeats can induce upstream CpG methylation at the IgH alpha locus, and cause a substantial decrease in transcription from the sterile transcript promoter. This effect is likely the reason that switch regions evolved to contain very few CpG sites. We discuss these findings as they relate to DNA methylation and to Ig CSR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of “Humanized” Multiple Sclerosis-like Disease*

PubMed Central

Kaushansky, Nathali; Eisenstein, Miriam; Boura-Halfon, Sigalit; Hansen, Bjarke Endel; Nielsen, Claus Henrik; Milo, Ron; Zeilig, Gabriel; Lassmann, Hans; Altmann, Daniel M.; Ben-Nun, Avraham

2015-01-01

Gene-wide association and candidate gene studies indicate that the greatest effect on multiple sclerosis (MS) risk is driven by the HLA-DRB1*15:01 allele within the HLA-DR15 haplotype (HLA-DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01). Nevertheless, linkage disequilibrium makes it difficult to define, without functional studies, whether the functionally relevant effect derives from DRB1*15:01 only, from its neighboring DQA1*01:02-DQB1*06:02 or DRB5*01:01 genes of HLA-DR15 haplotype, or from their combinations or epistatic interactions. Here, we analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new “humanized” model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11 (hOSP), one of the bona fide potential primary target antigens in MS. We show that the hOSP-associated MS-like disease is dominated by the DRB1*15:01 allele not only as the DRA1*01:01;DRB1*15:01 isotypic heterodimer but also, unexpectedly, as a functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. The contribution of HLA-DQA1/DRB1 mixed isotype heterodimer to OSP pathogenesis was revealed in (DRB1*1501xDQB1*0602)F1 double-Tg mice immunized with hOSP(142–161) peptide, where the encephalitogenic potential of prevalent DRB1*1501/hOSP(142–161)-reactive Th1/Th17 cells is hindered due to a single amino acid difference in the OSP(142–161) region between humans and mice; this impedes binding of DRB1*1501 to the mouse OSP(142–161) epitope in the mouse CNS while exposing functional binding of mouse OSP(142–161) to DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. This study, which shows for the first time a functional HLA-DQA1/DRB1 mixed isotype heterodimer and its potential association with disease susceptibility, provides a rationale for a potential effect on MS risk from DQA1*01:02 through functional DQA1*01:02;DRB1*15:01 antigen presentation. Furthermore, it highlights a potential contribution to MS risk also from interisotypic combination between products of neighboring HLA-DR15 haplotype alleles, in this case the DQA1/DRB1 combination. PMID:25911099

Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and sCD23.

PubMed

Jeannin, P; Delneste, Y; Lecoanet-Henchoz, S; Gretener, D; Bonnefoy, J Y

1998-02-15

Interleukin-7 (IL-7) is a B-cell growth factor produced by both bone marrow stroma cells and follicular dendritic cells (FDCs) located in primary lymphoid follicles and germinal centers. In this study, we have evaluated the role of IL-7 on human Ig class switching. IL-7 was added to peripheral blood mononuclear cells (PBMCs) or tonsillar B cells in the absence or presence of IL-4 and/or anti-CD40 monoclonal antibody (MoAb). Alone, IL-7 did not affect Ig production by PBMCs or by anti-CD40 MoAb-stimulated B cells. Rather, IL-7 potentiated IL-4-induced IgE and IgG4 production by PBMCs. In parallel, IgG3 production was also enhanced but to a lesser extent, whereas the production of the other isotypes was unaltered. The activity of IL-2, IL-9, or IL-15, which share usage of the common gamma chain for signaling, was also assessed. IL-9, like IL-7, potentiated mainly IgE and IgG4 production by IL-4-stimulated PBMCs. IL-15, in contrast, was ineffective, whereas IL-2 enhanced the production of all isotypes. More precisely, IL-7 potentiation of IgE and IgG4 production required the presence of T cells and was accompanied by an increase of the expression of two soluble molecules favoring preferentially IgE and IgG4 synthesis: CD23 (sCD23) and IL-9. Moreover, neutralizing anti-CD23 and anti-IL-9 antibodies partly inhibited the increase of IgE synthesis induced by IL-7. Thus, IL-7 produced locally in the germinal centers by FDCs may interact with T cells and potentiate human IgE and IgG4 switching by favoring IL-9 and sCD23 production.

IL-27 induces the production of IgG1 by human B cells.

PubMed

Boumendjel, Amel; Tawk, Lina; Malefijt, René de Waal; Boulay, Vera; Yssel, Hans; Pène, Jérôme

2006-12-01

It has been reported that IL-27 specifically induces the production of IgG2a by mouse B cells and inhibits IL-4-induced IgG1 synthesis. Here, we show that human naïve cord blood expresses a functional IL-27 receptor, consisting of the TCCR and gp130 subunits, although at lower levels as compared to naïve and memory splenic B cells. IL-27 does not induce proliferative responses and does not increase IgG1 production by CD19(+)CD27(+) memory B cells. However, it induces a low, but significant production of IgG1 by naïve CD19(+)CD27(-)IgD(+)IgG(-) spleen and cord blood B cells, activated via CD40, whereas it has no effect on the production of the other IgG subclasses. In addition, IL-27 induces the differentiation of a population of B cells that express high levels of CD38, in association with a down-regulation of surface IgD expression, and that are surface IgG(+/int), CD20(low), CD27(high), indicating that IL-27 promotes isotype switching and plasma cell differentiation of naive B cells. However, as compared to the effects of IL-21 and IL-10, both switch factors for human IgG1 and IgG3, those of IL-27 are modest and regulate exclusively the production of IgG1. Finally, although IL-27 has no effect on IL-4 and anti-CD40-induced Cepsilon germline promoter activity, it up-regulates IL-4-induced IgE production by naive B cells. These results point to a partial redundancy of switch factors regulating the production of IgG1 in humans, and furthermore indicate the existence of a common regulation of the human IgG1and murine IgG2a isotypes by IL-27.

Biased Immunoglobulin Light Chain Gene Usage in the Shark.

PubMed

Iacoangeli, Anna; Lui, Anita; Naik, Ushma; Ohta, Yuko; Flajnik, Martin; Hsu, Ellen

2015-10-15

This study of a large family of κ L chain clusters in nurse shark completes the characterization of its classical Ig gene content (two H chain isotypes, μ and ω, and four L chain isotypes, κ, λ, σ, and σ-2). The shark κ clusters are minigenes consisting of a simple VL-JL-CL array, where V to J recombination occurs over an ~500-bp interval, and functional clusters are widely separated by at least 100 kb. Six out of ~39 κ clusters are prerearranged in the germline (germline joined). Unlike the complex gene organization and multistep assembly process of Ig in mammals, each shark Ig rearrangement, somatic or in the germline, appears to be an independent event localized to the minigene. This study examined the expression of functional, nonproductive, and sterile transcripts of the κ clusters compared with the other three L chain isotypes. κ cluster usage was investigated in young sharks, and a skewed pattern of split gene expression was observed, one similar in functional and nonproductive rearrangements. These results show that the individual activation of the spatially distant κ clusters is nonrandom. Although both split and germline-joined κ genes are expressed, the latter are prominent in young animals and wane with age. We speculate that, in the shark, the differential activation of the multiple isotypes can be advantageously used in receptor editing. Copyright © 2015 by The American Association of Immunologists, Inc.

Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha

EPA Science Inventory

Peroxisome proliferators, including perfluorooctanoic acid (PFOA), are environmentally widespread and persistent and multiple toxicities have been reported in experimental animals and humans. These compounds trigger biological activity via activation of the alpha isotype of pero...

T cell-dependent antibody production by Ly-1 B cells.

PubMed

Taki, S; Schmitt, M; Tarlinton, D; Förster, I; Rajewsky, K

1992-05-04

Through the use of a SCID transfer system, we have demonstrated that under certain conditions, the production of Ig by Ly-1 B cells can be modulated by T cells. This modulation can take the form of enhanced isotype production or isotype-switch induction and to some extent appears to be dependent on the activation state of the T cells. Furthermore we have shown that Ly-1 B cells can mount an idiotypically restricted T cell-dependent immune response to the antigen PC-KLH. This result suggests that the previous failure to observe T cell-dependent responses by Ly-1 B cells has been due to these B cells being "blind" to the antigens used and is not due to some inherent property of these B cells. When one considers the previous reports of the substantial contribution of Ly-1 B cells to the natural serum immunoglobulin levels and the ability of T cells to affect Ig production by Ly-1 B cells documented in this report, it is clear that the interaction of T cells with the Ly-1 B-cell population is important in determining the "natural" serum Ig repertoire of the mouse.

Foot-and-Mouth Disease Virus Can Induce a Specific and Rapid CD4+ T-Cell-Independent Neutralizing and Isotype Class-Switched Antibody Response in Naïve Cattle▿ †

PubMed Central

Juleff, Nicholas; Windsor, Miriam; Lefevre, Eric A.; Gubbins, Simon; Hamblin, Pip; Reid, Elizabeth; McLaughlin, Kerry; Beverley, Peter C. L.; Morrison, Ivan W.; Charleston, Bryan

2009-01-01

The role of T-lymphocyte subsets in recovery from foot-and-mouth disease virus (FMDV) infection in calves was investigated by administering subset-specific monoclonal antibodies. The depletion of circulating CD4+ or WC1+ γδ T cells was achieved for a period extending from before challenge to after resolution of viremia and peak clinical signs, whereas CD8+ cell depletion was only partial. The depletion of CD4+ cells was also confirmed by analysis of lymph node biopsy specimens 5 days postchallenge. Depletion with anti-WC1 and anti-CD8 antibodies had no effect on the kinetics of infection, clinical signs, and immune responses following FMDV infection. Three of the four CD4+ T-cell-depleted calves failed to generate an antibody response to the nonstructural polyprotein 3ABC but generated a neutralizing antibody response similar to that in the controls, including rapid isotype switching to immunoglobulin G antibody. We conclude that antibody responses to sites on the surface of the virus capsid are T cell independent, whereas those directed against the nonstructural proteins are T cell dependent. CD4 depletion was found to substantially inhibit antibody responses to the G-H peptide loop VP1135-156 on the viral capsid, indicating that responses to this particular site, which has a more mobile structure than other neutralizing sites on the virus capsid, are T cell dependent. The depletion of CD4+ T cells had no adverse effect on the magnitude or duration of clinical signs or clearance of virus from the circulation. Overall, we conclude that CD4+ T-cell-independent antibody responses play a major role in the resolution of foot-and-mouth disease in cattle. PMID:19176618

The use of isotypic control antibodies in the analysis of CD3+ and CD3+, CD4+ lymphocyte subsets by flow cytometry. Are they really necessary?

PubMed

Sreenan, J J; Tbakhi, A; Edinger, M G; Tubbs, R R

1997-02-01

Isotypic control reagents are defined as irrelevant antibodies of the same immunoglobulin class as the relevant reagent antibody in a flow cytometry panel. The use of the isotypic control antibody has been advocated as a necessary quality control measure in analysis of flow cytometry. The purpose of this study was to determine the necessity of an isotypic control antibody in the analysis of CD3+ and CD3+, CD4+ lymphocyte subsets. We performed a prospective study of 46 consecutive patient samples received for lymphocyte subset analysis to determine the need for the isotypic control. For each sample, a sham buffer (autocontrol) and isotypic control reagent were stained for three-color immunofluorescence, processed, and identically analyzed with Attractors software. The Attractors software allowed independent, multiparametric, simultaneous gating; was able to identically and reproducibly process each list mode file; and yielded population data in spreadsheet form. Statistical analysis (Fisher's z test) revealed no difference between the CD3+ autocontrol and CD3+ isotypic control (correlation = 1, P < .0001) or between the CD3+, CD4+ autocontrol and the CD3+, CD4+ isotypic control (correlation = 1, P < .0001). The elimination of the isotypic control reagent resulted in a total cost savings of $3.36 per test. Additionally, the subtraction of isotypic background can artifactually depress population enumeration. The use of an isotypic control antibody is not necessary to analyze flow cytometric data that result in discrete cell populations, such as CD3+ and CD3+, CD4+ lymphocyte subsets. The elimination of this unnecessary quality control measure results in substantial cost savings.

Serum Levels of Two Immunological Markers, the Soluble Low Affinity Receptor for IGE (SFCERII, SCD23) and their Correlation with Age, Gender and the Onset of Childhood Atopy

DTIC Science & Technology

1993-01-01

immunoglobulin receptor because it is the only known Fc Receptor which does not belong to the same gene I 0 superfamily as its ligand. (9, 14, 46). This FC...type) animal lectins. (2, 3, 4, 6, 8, 9, 13, 14, 20, 46). This homology domain spanning from cysteine 163 through cysteine 282, contAins four highly...substantial amount of CD23a and CD23b. (12) The expression of CD23 is lost after immunoglobulin isotype switching and during the differentiation of B cells into

Exploring the Origin of Differential Binding Affinities of Human Tubulin Isotypes αβII, αβIII and αβIV for DAMA-Colchicine Using Homology Modelling, Molecular Docking and Molecular Dynamics Simulations

PubMed Central

Panda, Dulal; Kunwar, Ambarish

2016-01-01

Tubulin isotypes are found to play an important role in regulating microtubule dynamics. The isotype composition is also thought to contribute in the development of drug resistance as tubulin isotypes show differential binding affinities for various anti-cancer agents. Tubulin isotypes αβII, αβIII and αβIV show differential binding affinity for colchicine. However, the origin of differential binding affinity is not well understood at the molecular level. Here, we investigate the origin of differential binding affinity of a colchicine analogue N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) for human αβII, αβIII and αβIV isotypes, employing sequence analysis, homology modeling, molecular docking, molecular dynamics simulation and MM-GBSA binding free energy calculations. The sequence analysis study shows that the residue compositions are different in the colchicine binding pocket of αβII and αβIII, whereas no such difference is present in αβIV tubulin isotypes. Further, the molecular docking and molecular dynamics simulations results show that residue differences present at the colchicine binding pocket weaken the bonding interactions and the correct binding of DAMA-colchicine at the interface of αβII and αβIII tubulin isotypes. Post molecular dynamics simulation analysis suggests that these residue variations affect the structure and dynamics of αβII and αβIII tubulin isotypes, which in turn affect the binding of DAMA-colchicine. Further, the binding free-energy calculation shows that αβIV tubulin isotype has the highest binding free-energy and αβIII has the lowest binding free-energy for DAMA-colchicine. The order of binding free-energy for DAMA-colchicine is αβIV ≃ αβII >> αβIII. Thus, our computational approaches provide an insight into the effect of residue variations on differential binding of αβII, αβIII and αβIV tubulin isotypes with DAMA-colchicine and may help to design new analogues with higher binding affinities for tubulin isotypes. PMID:27227832

Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells.

PubMed

Pène, Jérôme; Gauchat, Jean-François; Lécart, Sandrine; Drouet, Elodie; Guglielmi, Paul; Boulay, Vera; Delwail, Adriana; Foster, Don; Lecron, Jean-Claude; Yssel, Hans

2004-05-01

IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40. In this study, we show that rIL-21 strongly induces the production of all IgG isotypes by purified CD19(+) human spleen or peripheral blood B cells stimulated with anti-CD40 mAb. Moreover, it was found to specifically induce the production of IgG(1) and IgG(3) by CD40-activated CD19(+)CD27(-) naive human B cells. Although stimulation of CD19(+) B cells via CD40 alone induced gamma 1 and gamma 3 germline transcripts, as well as the expression of activation-induced cytidine deaminase, only stimulation with both anti-CD40 mAb and rIL-21 resulted in the production of S gamma/S mu switch circular DNA. These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG(1) and IgG(3).

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

USGS Publications Warehouse

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.

[Demonstration of immunoglobulin isotypes in the vitreous body as a contribution to the etiology of recurrent equine uveitis].

PubMed

Wagner, B; Brandt, K; Sheoran, A; Holmes, M A; Deegen, E; Leibold, W

1997-11-01

The functional properties of different immunoglobulin isotypes in equine recurrent uveitis (ERU) has not been investigated yet. Here, we describe the quantitative determination of total immunoglobulin levels and isotype differentiation in the vitreous of four horses with ERU as compared to that of seven healthy horses. In contrast to almost equal amounts of total immunoglobulin in the vitreous of both groups, remarkable differences were found: All four of the horses with ERU had significantly higher IgA contents in their vitreous as compared to the control group. However, the other isotypes monitored (IgM, IgGa, IgGb, IgGc and IgG(T)) indicated no differences between both groups. Comparing the individual ratios of immunoglobulin isotypes in the vitreous and the autologous serum of two horses with ERU and two control animals provided informative results: IgM was only detected in serum but not at all in vitreous of all horses investigated. All four IgG isotypes monitored in the diseased animals as well as these IgG isotypes and the IgA in healthy animals were present in the same ratios in serum and in vitreous of the individual horses. In general, the content of such isotypes in the vitreous was about 1000 fold lower then the respective isotypes in the autologous serum. These results are compatible with a transfer of the IgG and IgA isotypes from the serum into the vitreous in healthy individuals. All four horses with ERU, however, had a selectively increased relative IgA content in the vitreous as compared to their serum. This argues for a preferential local IgA production within the framework of a local immunological reaction to antigens located within the eyes of horses with ERU.

Pathfinding in a large vertebrate axon tract: isotypic interactions guide retinotectal axons at multiple choice points

PubMed Central

Pittman, Andrew J.; Law, Mei-Yee; Chien, Chi-Bin

2008-01-01

Summary Navigating axons respond to environmental guidance signals, but can also follow axons that have gone before—pioneer axons. Pioneers have been studied extensively in simple systems, but the role of axon-axon interactions remains largely unexplored in large vertebrate axon tracts, where cohorts of identical axons could potentially use isotypic interactions to guide each other through multiple choice points. Furthermore, the relative importance of axon-axon interactions compared to axon-autonomous receptor function has not been assessed. Here we test the role of axon-axon interactions in retinotectal development, by devising a technique to selectively remove or replace early-born retinal ganglion cells (RGCs). We find that early RGCs are both necessary and sufficient for later axons to exit the eye. Furthermore, introducing misrouted axons by transplantation reveals that guidance from eye to tectum relies heavily on interactions between axons, including both pioneer-follower and community effects. We conclude that axon-axon interactions and ligand-receptor signaling have coequal roles, cooperating to ensure the fidelity of axon guidance in developing vertebrate tracts. PMID:18653554

Cutting Edge: Active TGF-β1 Released from GARP/TGF-β1 Complexes on the Surface of Stimulated Human B Lymphocytes Increases Class-Switch Recombination and Production of IgA.

PubMed

Dedobbeleer, Olivier; Stockis, Julie; van der Woning, Bas; Coulie, Pierre G; Lucas, Sophie

2017-07-15

Production of active TGF-β is regulated at a posttranslational level and implies release of the mature cytokine dimer from the inactive, latent TGF-β precursor. There are several cell-type specific mechanisms of TGF-β activation. We identified a new mechanism operating on the surface of human regulatory T cells and involving membrane protein GARP, which binds latent TGF-β1. The paracrine activity of regulatory T cell-derived TGF-β1 contributes to immunosuppression and can be inhibited with anti-GARP Abs. Whether other immune cell types use surface GARP to activate latent TGF-β1 was not known. We show in this study that stimulated, human B lymphocytes produce active TGF-β1 from surface GARP/latent TGF-β1 complexes with isotype switching to IgA production. Copyright © 2017 by The American Association of Immunologists, Inc.

Dynamics of the Murine Humoral Immune Response to Neisseria meningitidis Group B Capsular Polysaccharide

PubMed Central

Colino, Jesús; Outschoorn, Ingrid

1998-01-01

Immunization with Neisseria meningitidis group B capsular polysaccharide (CpsB) elicited responses in adult mice that showed the typical dynamic characteristics of the response to a thymus-independent antigen, in contrast to the thymus-dependent behavior of antibody responses to CpsC. The former had a short latent period and showed a rapid increase in serum antibodies that peaked at day 5, and immunoglobulin M (IgM) was the major isotype even though IgG (mainly IgG2a and IgG2b) was also detectable. This response was of short duration, and the specific antibodies were rapidly cleared from the circulation. The secondary responses were similar in magnitude, kinetics, IgM predominance, and IgG distribution. Nevertheless, a threefold IgG increase, a correlation between IgM and IgG levels, and dose-dependent secondary responses were observed. Hyperimmunization considerably reinforced these responses: 10-fold for IgM and 300-fold for IgG. This favored isotype switch was accompanied by a progressive change in the subclass distribution to IgG3 (62%) and IgG1 (28%), along with the possible generation of B-cell memory. The results indicate that CpsB is being strictly thymus independent and suggest that unresponsiveness to purified CpsB is due to tolerance. PMID:9453603

Dynamics of the murine humoral immune response to Neisseria meningitis group B capsular polysaccharide.

PubMed

Colino, J; Outschoorn, I

1998-02-01

Immunization with Neisseria meningitidis group B capsular polysaccharide (CpsB) elicited responses in adult mice that showed the typical dynamic characteristics of the response to a thymus-independent antigen, in contrast to the thymus-dependent behavior of antibody responses to CpsC. The former had a short latent period and showed a rapid increase in serum antibodies that peaked at day 5, and immunoglobulin M (IgM) was the major isotype even though IgG (mainly IgG2a and IgG2b) was also detectable. This response was of short duration, and the specific antibodies were rapidly cleared from the circulation. The secondary responses were similar in magnitude, kinetics, IgM predominance, and IgG distribution. Nevertheless, a threefold IgG increase, a correlation between IgM and IgG levels, and dose-dependent secondary responses were observed. Hyperimmunization considerably reinforced these responses: 10-fold for IgM and 300-fold for IgG. This favored isotype switch was accompanied by a progressive change in the subclass distribution to IgG3 (62%) and IgG1 (28%), along with the possible generation of B-cell memory. The results indicate that CpsB is being strictly thymus independent and suggest that unresponsiveness to purified CpsB is due to tolerance.

CCCTC-Binding Factor Locks Premature IgH Germline Transcription and Restrains Class Switch Recombination

PubMed Central

Marina-Zárate, Ester; Pérez-García, Arantxa; Ramiro, Almudena R.

2017-01-01

In response to antigenic stimulation B cells undergo class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) to replace the primary IgM/IgD isotypes by IgG, IgE, or IgA. CSR is initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues at the switch (S) regions of IgH. B cell stimulation promotes germline transcription (GLT) of specific S regions, a necessary event prior to CSR because it facilitates AID access to S regions. Here, we show that CCCTC-binding factor (CTCF)-deficient mice are severely impaired in the generation of germinal center B cells and plasma cells after immunization in vivo, most likely due to impaired cell survival. Importantly, we find that CTCF-deficient B cells have an increased rate of CSR under various stimulation conditions in vitro. This effect is not secondary to altered cell proliferation or AID expression in CTCF-deficient cells. Instead, we find that CTCF-deficient B cells harbor an increased mutation frequency at switch regions, probably reflecting an increased accessibility of AID to IgH in the absence of CTCF. Moreover, CTCF deficiency triggers premature GLT of S regions in naïve B cells. Our results indicate that CTCF restricts CSR by enforcing GLT silencing and limiting AID access to IgH. PMID:28928744

Genetic parameters for natural antibody isotype titers in milk of Dutch Holstein-Friesians.

PubMed

Wijga, S; Bovenhuis, H; Bastiaansen, J W M; van Arendonk, J A M; Ploegaert, T C W; Tijhaar, E; van der Poel, J J

2013-08-01

The objective of the present study was to estimate genetic parameters for natural antibody isotypes immunoglobulin (Ig) A, IgG1 and IgM titers binding the bacterial antigens lipopolysaccharide, peptidoglycan and the model antigen keyhole limpet hemocyanin in Dutch Holstein-Friesian cows (n = 1695). Further, this study included total natural antibody titers binding the antigens mentioned above, making no isotype distinction, as well as total natural antibody titers and natural antibody isotypes IgA, IgG1 and IgM binding lipoteichoic acid. The study showed that natural antibody isotype titers are heritable, ranging from 0.06 to 0.55, and that these heritabilities were generally higher than heritabilities for total natural antibody titers. Genetic correlations, the combinations of total natural antibody titers and natural antibody isotype titers, were nearly all positive and ranged from -0.23 to 0.99. Strong genetic correlations were found between IgA and IgM. Genetic correlations were substantially weaker when they involved an IgG1 titer, indicating that IgA and IgM have a common genetic basis, but that the genetic basis for IgG1 differs from that for IgA or IgM. Results from this study indicate that natural antibody isotype titers show the potential for effective genetic selection. Further, natural antibody isotypes may provide a better characterization of different elements of the immune response or immune competence. As such, natural antibody isotypes may enable more effective decisions when breeding programs start to include innate immune parameters. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis.

PubMed

De Winter, Liesbeth M; Geusens, Piet; Lenaerts, Jan; Vanhoof, Johan; Stinissen, Piet; Somers, Veerle

2016-06-07

Recently, autoantibodies against novel UH-RA peptides (UH-RA.1 and UH-RA.21) were identified as candidate biomarkers for patients with rheumatoid arthritis (RA) who are seronegative for the current diagnostic markers rheumatoid factor and anticitrullinated protein antibodies. Previously, screening for anti-UH-RA autoantibodies was based on measuring the immunoglobulin (Ig) G response. We aimed to investigate whether measurement of other isotypes could improve the performance of diagnostic testing. In addition, assigning the isotype profile might provide valuable information on effector functions of the antibodies. The isotype profile of antibodies against UH-RA.1 and UH-RA.21 was studied. The IgG, IgM, and IgA classes, together with the 4 different IgG subclasses, were determined in 285 patients with RA, 88 rheumatic control subjects, and 90 healthy control subjects. Anti-UH-RA.1 antibodies were primarily of the IgM isotype and twice as prevalent as IgG (IgG3-dominated) and IgA. RA sensitivity when testing for anti-UH-RA.1 IgM was shown to be higher than when testing for the IgG isotype: 18 % versus 9 % sensitivity when RA specificity was set to 90 %. Within antibodies against UH-RA.21, IgG and IgA were more common than IgM. Different anti-UH-RA.21 IgG subclasses were found, with the highest prevalence found for IgG2. Combined testing for IgG and IgA slightly increased RA sensitivity of UH-RA.21-specific antibody testing to 27 % compared with solely testing for IgG (23 %). Notably, a higher number of anti-UH-RA.21 antibody isotypes was related to increased levels of erythrocyte sedimentation rate. Finally, for both antibody responses, the full antibody isotype use was demonstrated in early and seronegative disease. The isotype distribution of anti-UH-RA.1 and anti-UH-RA.21 antibodies was successfully outlined, and, for antibodies against UH-RA.1, we found that isotype-specific testing might have implications for diagnostic testing. The exact mechanisms by which the different antibody isotypes act still have to be unraveled.

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

PubMed Central

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

2015-01-01

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

PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cell-intrinsic mechanism

PubMed Central

McKay, Jerome T.; Egan, Ryan P.; Yammani, Rama D.; Chen, Lieping; Shin, Tahiro; Yagita, Hideo; Haas, Karen M.

2015-01-01

Despite the emergence of the PD-1:PD-1 ligand (PD-L) regulatory axis as a promising target for treating multiple human diseases, remarkably little is known about how this pathway regulates responses to extracellular bacterial infections. We found that PD-1−/− mice, as well as wild type mice treated with a PD-1 blocking antibody, exhibited significantly increased survival against lethal Streptococcus pneumoniae infection following either priming with low-dose pneumococcal respiratory infection or S. pneumoniae-capsular polysaccharide immunization. Enhanced survival in mice with disrupted PD-1:PD-L interactions was explained by significantly increased proliferation, isotype switching, and IgG production by pneumococcal capsule-specific B cells. Both PD-1 ligands, B7-H1 and B7-DC, contributed to PD-1-mediated suppression of protective capsule-specific IgG. Importantly, PD-1 was induced on capsule-specific B cells and suppressed IgG production and protection against pneumococcal infection in a B cell-intrinsic manner. These results provide the first demonstration of a physiologic role for B cell-intrinsic PD-1 expression in vivo. In summary, our study reveals that B cell-expressed PD-1 plays a central role in regulating protection against S. pneumoniae, and thereby represents a promising target for bolstering immunity to encapsulated bacteria. PMID:25624454

Assembly Properties of Divergent Tubulin Isotypes and Altered Tubulin Polypeptides in Vivo

NASA Astrophysics Data System (ADS)

Gu, Wei

1990-01-01

Mbeta1 is one of the closely related (though distinct) gene products termed isotypes encoded by the mouse beta-tubulin multigene family. These isotypes typically share 95%-98% homology at the amino acid level. However, Mbeta 1 is unusual in its relatively high degree of divergence compared to other beta-tubulin isotypes; furthermore, its tissue-restricted pattern of expression (Mbeta1 is only expressed in hematopoietic tissue) led to speculation that this isotype might be specialized for assembly into unique microtubule structures (such as the marginal band in some erythropoietic cell types). To test if this isotype is capable of coassembly into microtubules in cell types other than those in which it is normally expressed, a method was developed for the generation of an anti-Mbeta1 specific antibody. The Mbeta1 tubulin isotype was introduced into tissue culture cells by transfection and its expression and assembly properties were studied in both transiently transfected cells and stable cell lines using the anti -Mbeta1 specific antibody. The successful expression and coassembly of a 'foreign' tubulin isotype into microtubules in tissue culture cells and the generation of an antibody that can specifically recognize this isotype provided an approach to study the properties of altered beta-tubulin polypeptides in vivo. beta-tubulin synthesis in eukaryotic cells is autoregulated by a posttranscriptional mechanism in which the first four amino acids are responsible for determining the stability of beta -tubulin mRNA. To test if the beta -tubulin amino-terminal regulatory domain also contributes to the capacity of the tubulin monomer to polymerize into microtubules, altered sequences encoding Mbeta 1 but containing deletions encompassing amino acids 2-5 were expressed in HeLa cells. Stable cell lines expressing the altered Mbeta1 isotype were also generated. The assembly properties and stability of these altered Mbeta1 tubulin polypeptides were tested using the anti-Mbeta1 specific antibody. The data suggest that the first four amino acids of beta-tubulin play a regulatory rather than a structural role.

Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock

PubMed Central

1994-01-01

Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine g1 antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-alpha monoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric g1 and g2a anti- murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p < or = 0.004), and prolonged survival to 45 h (p < or = 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p < or = 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the g1 isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p < or = 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine g1) being more efficacious than active isotypes (human g1 and murine g2a). PMID:8113678

Inactivated infectious bronchitis virus vaccine encapsulated in chitosan nanoparticles induces mucosal immune responses and effective protection against challenge.

PubMed

Lopes, Priscila Diniz; Okino, Cintia Hiromi; Fernando, Filipe Santos; Pavani, Caren; Casagrande, Viviane Mariguela; Lopez, Renata F V; Montassier, Maria de Fátima Silva; Montassier, Helio José

2018-05-03

Avian infectious bronchitis virus (IBV) is one of the most important viral diseases of poultry. The mucosa of upper respiratory tract, specially the trachea, is the primary replication site for this virus. However, conventional inactivate IBV vaccines usually elicit reduced mucosal immune responses and local protection. Thus, an inactivated IBV vaccine containing BR-I genotype strain encapsulated in chitosan nanoparticles (IBV-CS) was produced by ionic gelation method to be administered by oculo-nasal route to chickens. IBV-CS vaccine administered alone resulted in markedly mucosal immune responses, characterized by high levels of anti-IBV IgA isotype antibodies and IFNγ gene expression at 1dpi. The association of live attenuated Massachusetts IBV and IBV-CS vaccine also induced strong mucosal immune responses, though a switch from IgA isotype to IgG was observed, and IFNγ gene expression peak was late (at 5 dpi). Efficacy of IBV-CS was evaluated by tracheal ciliostasis analysis, histopathology examination, and viral load determination in the trachea and kidney. The results indicated that IBV-CS vaccine administered alone or associated with a live attenuated heterologous vaccine induced both humoral and cell-mediated immune responses at the primary site of viral replication, and provided an effective protection against IBV infection at local (trachea) and systemic (kidney) sites. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Assessment of Heavy/ Light Chain Pairs of Immunoglobulin (Hevylite assay) -  Benefit for Stratification of Multiple Myeloma?].

PubMed

Ščudla, V; Lochaman, P; Pika, T; Zapletalová, J; Minařík, J; Bačovský, J

2015-01-01

The aim of the study was the comparison of two novel stratification models in multiple myeloma (MM), ie. according to Avet- Loiseau (A L) and according to Ludwig (L), based on the HLC r index (ratio of serum levels of involved- HLC/ uninvolved HLC, ie. HLC κ/ HLC  λ assessed using ie. nephelometric/turbidimetric technique using specific polyclonal antibodies on a Binding Site SPA(PLUS)) technique) and β(2) microglobulin (β(2) M) with selected prognostic factors (PF) of MM and staging systems according to Durie- Salmon (D S) and International Staging System (ISS). In a cohort of 132 patients (94 with IgG and 38 with IgA type of MM) at the time of dia-gnosis, we assessed HLC r, select-ed PF and D S, ISS, A L and L stratification systems. Unlike in IgA isotype, in IgG isotype we found a significant relationship of HLC r to stratification according to D S and ISS with the difference between A and B substages according to D S (p = 0.049) and between ISS stages 1 vs. 3 (p = 0.001). In the IgG group, there was highly significant relationship of the depth of Hb and albumin decrease and β(2) M increase to the results of stratification according to ISS, A L and L model (p < 0.0001), increase of LDH in the ISS system and A L, and creatinine according to ISS and L but not the relationship of the stages according to any of the stratification systems to the values of FLC r (ratio of serum free light chains κ/ λ of immunoglobulin), thrombocytes and Ca. In the IgA type, there was a significant relationship of the depth of the decrease of Hb, thrombocytes, albumin and increase of β(2) M to the results of stratification according to ISS, A L and L and increase of creatinine in the case of ISS, but not of the values of FLC r, Ca and LDH in the case of any of the stratification systems. The degree of correlation of selected PF, especially of Hb, albumin and β(2) M, event. of thrombocytes, LDH and creatinine to the stages according to ISS and to stage 1-3 according to A L and L model was in IgG vs IgA isotype significantly different (p < 0.0001- 0.030). Staging system according to ISS had proportional distribution of stages 1- 3, whereas in the A L model prevailed in IgA and IgG isotype risk category 2, ie. intermediate-risk (47.3 and 44.7%) and in the L model prevailed risk category 3, ie. high-risk (41.5 and 52.6%) with low count of category 1, ie. low- risk category (23.4 and 10.5%). McNemar- Bowker test of symmetry showed in both types of MM the highest concordance between the stratification according to D S and L in category 3, ie. high-risk (31.9 vs. 28.9%) with overall accord only in 53.2 and 42.1% and with significant shift in the case of IgG isotype only (p = 0.036). In IgG and IgA isotype there was an overall concordance in the distribution of categories 1- 3 according to ISS vs. A L (62.4 and 63.2%) but with significant shift of the stratification (p = 0.002 and 0.028). In the case of IgG and IgA isotype there was a close relationship between the models A L and L (64.5 and 81.6%) with significant stratification shift (p < 0.0001 and 0.030). The new stratification models for MM according to A L and L are easily practically applicable, with close relationship to principal PF but they need separate assessment of IgG and IgA isotypes of MM. The choice of optimal model for routine practice needs a validation study aimed at progression free survival and overall survival.

Immunologic memory response induced by a meningococcal serogroup C conjugate vaccine using the P64k recombinant protein as carrier.

PubMed

Guirola, María; Urquiza, Dioslaida; Alvarez, Anabel; Cannan-Haden, Leonardo; Caballero, Evelin; Guillén, Gerardo

2006-03-01

In this study, we used an adoptive lymphocyte transfer experiment to evaluate the ability of the P64k recombinant protein to recruit T-helper activity and induce immunologic memory response to the polysaccharide moiety in a meningococcal serogroup C conjugate vaccine. Adoptive transfer of splenocytes from mice immunized with the glycoconjugate conferred antipolysaccharide immunologic memory to naive recipient mice. The observed anamnestic immune response was characterized by more rapid kinetics, isotype switching from IgM to IgG and higher antipolysaccharide antibody titers compared with those reached in groups transferred with splenocytes from plain polysaccharide or phosphate-immunized mice. The memory response generated was also long lasting. Sera from mice transferred with cells from conjugate-immunized mice were the only protective in the infant rat passive protection assay, and also showed higher bactericidal titers. We demonstrated that priming the mice immune system with the glycoconjugate using the P64k protein as carrier induced a memory response to the polysaccharide, promoting a switch of the T-cell-independent response to a T-cell dependent one.

High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway.

PubMed

Hara, Yasushi; Tashiro, Yasuyuki; Murakami, Akikazu; Nishimura, Miyuki; Shimizu, Takeyuki; Kubo, Masato; Burrows, Peter D; Azuma, Takachika

2015-12-01

During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM(+) memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4-hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM(+) as well as IgG(+) memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1(+)/IgM(+) GC B cells remained unchanged. Together these findings suggest that IgM(+) B cells undergo SHM in the GC to generate high affinity IgM(+) memory cells and that this process continues even after CSR is accomplished. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evidence for Ig Light Chain Isotype Exclusion in Shark B Lymphocytes Suggests Ordered Mechanisms.

PubMed

Iacoangeli, Anna; Lui, Anita; Haines, Ashley; Ohta, Yuko; Flajnik, Martin; Hsu, Ellen

2017-09-01

Unlike most vertebrates, the shark IgL gene organization precludes secondary rearrangements that delete self-reactive VJ rearranged genes. Nurse sharks express four L chain isotypes, κ, λ, σ, and σ-2, encoded by 35 functional minigenes or clusters. The sequence of gene activation/expression and receptor editing of these isotypes have not been studied. We therefore investigated the extent of isotypic exclusion in separated B cell subpopulations. Surface Ig (sIg)κ-expressing cells, isolated with mAb LK14 that recognizes Cκ, carry predominantly nonproductive rearrangements of other L chain isotypes. Conversely, after depletion with LK14, sIgM + cells contained largely nonproductive κ and enrichment for in-frame VJ of the others. Because some isotypic inclusion was observed at the mRNA level, expression in the BCR was examined. Functional λ mRNA was obtained, as expected, from the LK14-depleted population, but was also in sIgκ + splenocytes. Whereas λ somatic mutants from the depleted sample displayed evidence of positive selection, the λ genes in sIgκ + cells accumulated bystander mutations indicating a failure to express their products at the cell surface in association with the BCR H chain. In conclusion, a shark B cell expresses one L chain isotype at the surface and other isotypes as nonproductive VJ, sterile transcripts, or in-frame VJ whose products may not associate with the H chain. Based on the mRNA content found in the B cell subpopulations, an order of L chain gene activation is suggested as: σ-2 followed by κ, then σ and λ. Copyright © 2017 by The American Association of Immunologists, Inc.

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

PubMed Central

Papista, Christina; Berthelot, Laureline; Monteiro, Renato C

2011-01-01

Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy. PMID:21278767

Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox

PubMed Central

Ota, Tatsuya; Rast, Jonathan P.; Litman, Gary W.; Amemiya, Chris T.

2003-01-01

The lineage leading to lungfishes is one of the few major jawed vertebrate groups in which Ig heavy chain isotype structure has not been investigated at the genetic level. In this study, we have characterized three different Ig heavy chain isotypes of the African lungfish, Protopterus aethiopicus, including an IgM-type heavy chain and short and long forms of non-IgM heavy chains. Northern blot analysis as well as patterns of VH utilization suggest that the IgM and non-IgM isotypes are likely encoded in separate loci. The two non-IgM isotypes identified in Protopterus share structural features with the short and long forms of IgX/W/NARC (referred to hereafter as IgW), which were previously considered to be restricted to the cartilaginous fish. It seems that the IgW isotype has a far broader phylogenetic distribution than considered originally and raises questions with regard to the origin and evolutionary divergence of IgM and IgW. Moreover, its absence in other gnathostome lineages implies paradoxically that the IgW-type genes were lost from teleost and tetrapod lineages. PMID:12606718

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

PubMed

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

2015-04-01

Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

IgX antibodies in the urodele amphibian Ambystoma mexicanum.

PubMed

Schaerlinger, Bérénice; Frippiat, Jean-Pol

2008-01-01

Until recently, it was believed that urodele amphibians are able to synthesize only two immunoglobulin isotypes, IgM and IgY. We reinvestigated this issue in the Iberian ribbed newt Pleurodeles waltl and reported recently that this urodele expresses at least three isotypes: IgM, IgP and IgY. In this study, we demonstrate that another urodele, Ambystoma mexicanum, has also a third isotype whose amino acid sequence presents the highest homology with the amino acid sequence of Xenopus IgX. This isotype has typical Ig H-chain characteristics, could form multimers and is mainly expressed in mucosal tissues thereby indicating that it is likely the physiological counterpart of Xenopus IgX and mammalian IgA. Interestingly, no IgP could be found in A. mexicanum, in contrast to P. waltl, in which IgX was not found in previous investigations. These data indicate, for the first time, that different families of urodeles can express different immunoglobulin isotypes.

Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation

PubMed Central

Chen, Shuowen; Khan, Muhammad J.; Loor, Juan J.

2013-01-01

Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID:23737762

Sperm, nuclear, phospholipid, and red blood cell antibodies and isotype RF in infertile couples and patients with autoimmune rheumatic diseases.

PubMed

Fichorova, R; Nakov, L; Baleva, M; Nikolov, K; Gegova, I

1996-12-01

To determine if measuring of nonorgan-specific autoantibodies is useful for better understanding and management of unexplained infertility. Sera were obtained from 70 infertile couples, 57 rheumatic patients, and 76 fertile donors. Sperm antibodies (SA) were detected by the tests of Kibrick and Friberg, anti-histones, anti-cardiolipin antibodies, and RF isotypes by ELISA, antinuclear antibodies by indirect immunofluorescence, and anti-red blood cell antibodies by Capture-R. Multiple autoimmune reactivity (both partners positive and/or more than one type of autoantibody involved), higher than naturally occurring in fertile individuals, was found in 55% of the idiopathically infertile couples. IgA-RF was the dominant autoimmune marker. SA revealed similar rates in patients with rheumatic diseases and in infertiles with or without other autoantibodies. Although no single autoimmunity marker could predict occurrence of SA, the coincidence of enhanced polyclonal autoimmunity in both partners of infertile couples might potentiate their negative effect on reproduction.

Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis.

PubMed

Cabrera-Villalba, Sonia; Gomara, María José; Cañete, Juan D; Ramírez, Julio; Salvador, Georgina; Ruiz-Esquide, Virginia; Hernández, Maria Victoria; Inciarte-Mundo, José; Haro, Isabel; Sanmartí, Raimon

2017-06-15

To analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA). ACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA. CCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized ≥2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients. The ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.

Study of optoelectronic switch for satellite-switched time-division multiple access

NASA Technical Reports Server (NTRS)

Su, Shing-Fong; Jou, Liz; Lenart, Joe

1987-01-01

The use of optoelectronic switching for satellite switched time division multiple access will improve the isolation and reduce the crosstalk of an IF switch matrix. The results are presented of a study on optoelectronic switching. Tasks include literature search, system requirements study, candidate switching architecture analysis, and switch model optimization. The results show that the power divided and crossbar switching architectures are good candidates for an IF switch matrix.

Alterations of rings B and C of colchicine are cumulative in overall binding to tubulin but modify each kinetic step.

PubMed

Dumortier, C; Gorbunoff, M J; Andreu, J M; Engelborghs, Y

1996-12-10

The role of the elimination of ring B and/or the modification of ring C of colchicine in tubulin binding kinetics and thermodynamics has been characterized, using four different molecules. These ligands are colchicine (COL); 2-methoxy-5-(2',3',4'-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-on e (MTC), in which the central ring B has been reduced to one bond; allocolchicine (ALLO), in which ring C has been replaced by a six-membered ring; and 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB), where the same two modifications are made simultaneously. This paper describes the kinetics of association of ALLO with tubulin. The binding is accompanied by a fluorescence increase with slow biphasic kinetics, indicating binding to fast and slow tubulin isotypes. Binding to each of these isotypes occurs in two steps: a fast initial binding followed by a slower isomerization step. The K1 and k2 values for ALLO at 25 degrees C are 14,000 +/- 2,000 and 25,000 +/- 6,000 M-1 (fast and slow isotypes) and 0.055 +/- 0.003 s-1 and 0.013 +/- 0.001 s-1 (fast and slow isotype), respectively. For ALLO the reaction standard enthalpy change of the initial binding is 68 +/- 5 kJ.mol-1 (fast isotype) and 45 +/- 33 kJ.mol-1 (slow isotype) and the activation energy for the second forward step is 58 +/- 14 kJ.mol-1 (fast isotype) and 81 +/- 17 kJ.mol-1 (slow isotype). Displacement kinetics of bound ALLO by podophyllotoxin was monoexponential. The activation energy for the isomerization in the off direction is 107 +/- 7 kJ.mol-1. Comparison of the thermodynamic parameters for all four compounds shows that the modifications of both rings are cumulative with respect to overall binding. For the intermediate state there is a mutual influence of both modifications, suggesting an alteration of the reaction pathway.

CSReport: A New Computational Tool Designed for Automatic Analysis of Class Switch Recombination Junctions Sequenced by High-Throughput Sequencing.

PubMed

Boyer, François; Boutouil, Hend; Dalloul, Iman; Dalloul, Zeinab; Cook-Moreau, Jeanne; Aldigier, Jean-Claude; Carrion, Claire; Herve, Bastien; Scaon, Erwan; Cogné, Michel; Péron, Sophie

2017-05-15

B cells ensure humoral immune responses due to the production of Ag-specific memory B cells and Ab-secreting plasma cells. In secondary lymphoid organs, Ag-driven B cell activation induces terminal maturation and Ig isotype class switch (class switch recombination [CSR]). CSR creates a virtually unique IgH locus in every B cell clone by intrachromosomal recombination between two switch (S) regions upstream of each C region gene. Amount and structural features of CSR junctions reveal valuable information about the CSR mechanism, and analysis of CSR junctions is useful in basic and clinical research studies of B cell functions. To provide an automated tool able to analyze large data sets of CSR junction sequences produced by high-throughput sequencing (HTS), we designed CSReport, a software program dedicated to support analysis of CSR recombination junctions sequenced with a HTS-based protocol (Ion Torrent technology). CSReport was assessed using simulated data sets of CSR junctions and then used for analysis of Sμ-Sα and Sμ-Sγ1 junctions from CH12F3 cells and primary murine B cells, respectively. CSReport identifies junction segment breakpoints on reference sequences and junction structure (blunt-ended junctions or junctions with insertions or microhomology). Besides the ability to analyze unprecedentedly large libraries of junction sequences, CSReport will provide a unified framework for CSR junction studies. Our results show that CSReport is an accurate tool for analysis of sequences from our HTS-based protocol for CSR junctions, thereby facilitating and accelerating their study. Copyright © 2017 by The American Association of Immunologists, Inc.

IGG Subclass and Isotype Specific Immunoglobulin Responses to Lassa Fever and Venezuelan Equine Encephalomyelitis: Natural Infection and Immunization

DTIC Science & Technology

1991-12-30

AD-A246 912 AD ARMY PROJECT ORDER 88PP8804 TITLE: IGG SUBCLASS AND ISOTYPE SPECIFIC IMMUNOGLOBULIN RESPONSES TO LASSA FEVER AND VENEZUELAN EQUINE ...and Isotype Specific Immunoglobulin responses Army Project Order to Lassa Fever and Venezuelan Equine Encephalitis: 88PP8804 Natual...unlimited 13. ABSTRACT (Maximum 200 words) Venezuelan Equine Encephalitis (VEE) specific inimunoglobulin responses to the two vaccines, TC-83 (A live

Molecular insight of isotypes specific β-tubulin interaction of tubulin heterodimer with noscapinoids

NASA Astrophysics Data System (ADS)

Santoshi, Seneha; Naik, Pradeep K.

2014-07-01

Noscapine and its derivatives bind stoichiometrically to tubulin, alter its dynamic instability and thus effectively inhibit the cellular proliferation of a wide variety of cancer cells including many drug-resistant variants. The tubulin molecule is composed of α- and β-tubulin, which exist as various isotypes whose distribution and drug-binding properties are significantly different. Although the noscapinoids bind to a site overlapping with colchicine, their interaction is more biased towards β-tubulin. In fact, their precise interaction and binding affinity with specific isotypes of β-tubulin in the αβ-heterodimer has never been addressed. In this study, the binding affinity of a panel of noscapinoids with each type of tubulin was investigated computationally. We found that the binding score of a specific noscapinoid with each type of tubulin isotype is different. Specifically, amino-noscapine has the highest binding score of -6.4, -7.2, -7.4 and -7.3 kcal/mol with αβI, αβII, αβIII and αβIV isotypes, respectively. Similarly 10 showed higher binding affinity of -6.8 kcal/mol with αβV, whereas 8 had the highest binding affinity of -7.2, -7.1 and -7.2 kcal/mol, respectively with αβVI, αβVII and αβVIII isotypes. More importantly, both amino-noscapine and its clinical derivative, bromo-noscapine have the highest binding affinity of -46.2 and -38.1 kcal/mol against αβIII (overexpression of αβIII has been associated with resistance to a wide range of chemotherapeutic drugs for several human malignancies) as measured using MM-PBSA. Knowledge of the isotype specificity of the noscapinoids may allow for development of novel therapeutic agents based on this class of drugs.

Significance of anti-phospholipid antibodies in patients with lupus nephritis.

PubMed

Frampton, G; Hicks, J; Cameron, J S

1991-06-01

Anti-phospholipid antibodies (APA) as markers or mediators of thrombosis in lupus could be of pathogenetic significance in nephritis, since glomerular capillary thrombi are an indicator of subsequent renal dysfunction. Isotype specific APA antibodies were measured, using cardiolipin as the antigen, in 76 patients with lupus nephritis. Twenty-nine percent of the patients had elevated IgG APA. Overall, 43% of patients showed raised levels of at least one isotype. In general, APA had specificity for anionic phospholipids. In vitro lupus anticoagulant activity was associated with all three isotypes of APA, but only the IgM isotype correlated with the biological false positive test for syphilis. APA were not associated with thromboses or neurological involvement, and only the IgA isotype correlated with thrombocytopenia. We confirmed an association between the presence of intraglomerular thrombi and serum IgG APA. However, we found no association between APA and renal histological pattern, or long-term renal function. Our data, therefore, do not support a major pathogenetic role for APA in the nephritis of lupus in treated patients.

Idiotypic properties of the murine anti-arsonate antibody response: B- and T-cell influences.

PubMed

Conger, J D; Lewis, G K; Goodman, J W

1985-10-01

In a previous report characterizing the arsonate (ABA)-specific plaque-forming cell (PFC) responses of A/J mice induced by ABA-KLH, two interesting characteristics of the idiotypic (Id) profile were noted: (1) an apparent Id selectivity in the isotype switch since the earliest appearing IgG PFC in the primary response were significantly more "cross-reactive Id" (CRI)-dominant than the IgM PFC population, and, (2) a temporal waning of CRI dominance with time among IgG PFC, from 75-100% CRI+ PFC to about 25-45% CRI+ PFC in secondary responses. Experiments were performed to determine whether these effects are largely attributable to T or to B cells. Mice were immunized with a T-independent (TI) form of ABA (ABA-Brucella abortus) and apparent Id selectivity was observed; the earliest IgG PFC averaged 75% CRI+ while IgM PFC were only 39% CRI+. Due to the TI nature of the Ag, this provides suggestive, but not conclusive, evidence that the Id asymmetry in the isotype switch may be attributable to the direct interaction of Ag with B cells. Other studies addressed the temporal shift in CRI dominance. First, it was found that preexposure of mice to either KLH or to ABA (on an irrelevant carrier) resulted in diminished CRI dominance in subsequent "primary" responses to ABA-KLH. Secondly, adoptive transfer experiments with B and T cells from virgin mice (Bv, Tv) or ABA-KLH-primed mice (Bp, Tp) showed that recipients of Bv + Tp or Bp + Tv generated anti-ABA PFC responses with intermediate CRI levels. The Tv cells had some preferential tendency to activate CRI+ clones in the Bp population. The results demonstrate that CRI levels are jointly determined by the immune status of both B and T cells. A simple model is offered which accounts for early Id dominance and its gradual decline and has as its central postulate the assumption that CRI+ B cells in the virgin ABA-specific repertoire have an affinity advantage over CRI- clones.

CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease.

PubMed

Valentine, Kristen M; Davini, Dan; Lawrence, Travis J; Mullins, Genevieve N; Manansala, Miguel; Al-Kuhlani, Mufadhal; Pinney, James M; Davis, Jason K; Beaudin, Anna E; Sindi, Suzanne S; Gravano, David M; Hoyer, Katrina K

2018-05-09

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2-deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2-deficient mice. CD8 T cells express the B cell follicle-localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality. Copyright © 2018 by The American Association of Immunologists, Inc.

Cloning and structural analysis of two highly divergent IgA isotypes, IgA1 and IgA2 from the duck billed platypus, Ornithorhynchus anatinus.

PubMed

Vernersson, M; Belov, K; Aveskogh, M; Hellman, L

2010-01-01

To trace the emergence of modern IgA isotypes during vertebrate evolution we have studied the immunoglobulin repertoire of a model monotreme, the platypus. Two highly divergent IgA-like isotypes (IgA1 and IgA2) were identified and their primary structures were determined from full-length cDNAs. A comparative analysis of the amino acid sequences for IgA from various animal species showed that the two platypus IgA isotypes form a branch clearly separated from their eutherian (placental) counterparts. However, they still conform to the general structure of eutherian IgA, with a hinge region and three constant domains. This indicates that the deletion of the second domain and the formation of a hinge region in IgA did occur very early during mammalian evolution, more than 166 million years ago. The two IgA isotypes in platypus differ in primary structure and appear to have arisen from a very early gene duplication, possibly preceding the metatherian eutherian split. Interestingly, one of these isotypes, IgA1, appears to be expressed in only the platypus, but is present in the echidna based on Southern blot analysis. The platypus may require a more effective mucosal immunity, with two highly divergent IgA forms, than the terrestrial echidna, due to its lifestyle, where it is exposed to pathogens both on land and in the water. Copyright 2010 Elsevier Ltd. All rights reserved.

Large-scale isotype-specific quantification of Serum amyloid A 1/2 by multiple reaction monitoring in crude sera.

PubMed

Sung, Hye-Jin; Jeon, Seon-Ae; Ahn, Jung-Mo; Seul, Kyung-Jo; Kim, Jin Young; Lee, Ju Yeon; Yoo, Jong Shin; Lee, Soo-Youn; Kim, Hojoong; Cho, Je-Yoel

2012-04-03

Quantification is an essential step in biomarker development. Multiple reaction monitoring (MRM) is a new modified mass spectrometry-based quantification technology that does not require antibody development. Serum amyloid A (SAA) is a positive acute-phase protein identified as a lung cancer biomarker in our previous study. Acute SAA exists in two isoforms with highly similar (92%) amino acid sequences. Until now, studies of SAA have been unable to distinguish between SAA1 and SAA2. To overcome the unavailability of a SAA2-specific antibody, we developed MRM methodology for the verification of SAA1 and SAA2 in clinical crude serum samples from 99 healthy controls and 100 lung adenocarcinoma patients. Differential measurement of SAA1 and SAA2 was made possible for the first time with the developed isotype-specific MRM method. Most healthy control samples had small or no MS/MS peaks of the targeted peptides otherwise, higher peak areas with 10- to 34-fold increase over controls were detected in lung cancer samples. In addition, our SAA1 MRM data demonstrated good agreement with the SAA1 enzyme-linked immunosorbent assay (ELISA) data. Finally, successful quantification of SAA2 in crude serum by MRM, for the first time, shows that SAA2 can be a good biomarker for the detection of lung cancers. Copyright © 2012 Elsevier B.V. All rights reserved.

Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation

PubMed Central

Fan, Liping; Fu, Danhui; Zhang, Jinping; Wang, Qingqing; Ye, Yamei; Xie, Qianling

2017-01-01

The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and β2-microglobulin (β2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts < 100 × 109/L, Scr level ≥ 177 μmol/L, serum β2-MG ≥ 5.5 μmol/L, serum calcium (Ca) ≥ 2.75 mmol/L, and thalidomide use were associated with both OS and PFS in MM patients. Age ≥ 60 was associated with OS and Ig isotype was associated with PFS in MM patients. Moreover, blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival. PMID:28567420

IL-21: an executor of B cell fate.

PubMed

Konforte, Danijela; Simard, Nathalie; Paige, Christopher J

2009-02-15

IL-21 is a type I cytokine that shares the common receptor gamma-chain with IL-2, IL-4, IL-7, IL-9, and IL-15. B cells are one of the lymphoid cell types whose development and function are regulated by IL-21. Depending on the interplay with costimulatory signals and on the developmental stage of a B cell, IL-21 can induce proliferation, differentiation into Ig-producing plasma cells, or apoptosis in both mice and humans. Alone and in combination with Th cell-derived cytokines IL-21 can regulate class switch recombination to IgG, IgA, or IgE isotypes, indicating its important role in shaping the effector function of B cells. This review highlights the role of IL-21 in B cell development, function, and disease and provides some perspectives on the future studies in this area.

Induction of IgA B cell differentiation of bone marrow-derived B cells by Peyer's patch autoreactive helper T cells.

PubMed

Kihira, T; Kawanishi, H

1995-08-01

The objective of this study was to demonstrate in vitro that bone marrow-derived pro/pre-B cells bearing mu mRNA can switch their Ig heavy-chain isotype to that of alpha mRNA-expressing B cells after contact with Peyer's patches-derived activated autoreactive CD4+ T cells. Bone marrow-derived pro/pre-B cells and activated autoreactive Peyer's patch, mesenteric lymph node, or spleen CD4+ T cells were co-cultured in the presence of recombinant (r) IL-2, rIL-7, and Con A for 3 days. The mixed cultured cells were isolated for preparation of total RNA. Dot/slot hybridization, using murine C mu (pu3741) and C alpha (P alpha J558) Ig heavy-chain cDNA probes, detected C mu and C alpha Ig heavy-chain mRNA transcripts. The magnitude of each mRNA expression was measured demsitometrically. In addition, the secreted class-specific Ig contents from the co-cultured supernatants were measured. The results indicate that activated autoreactive Peyer's patch and mesenteric lymph node CD4+ T cells provide a specific Ig heavy-chain switch from mu to alpha (Peyer's patch CD4+ T cells > mesenteric lymph node CD4+ T cells) in bone marrow-derived pro/pre-B cells and also assist to develop IgA-secreting plasma cells. The alpha heavy-chain switch and IgA production do not occur in the presence of activated autoreactive spleen CD4+ T cells. These results support the view that autoreactive gut Peyer's patch CD4+ T cells, at least, regulate IgA B cell heavy-chain switching and terminal differentiation during gut mucosal B cell development.

Multi-line triggering and interdigitated electrode structure for photoconductive semiconductor switches

DOEpatents

Mar, Alan [Albuquerque, NM; Zutavern, Fred J [Albuquerque, NM; Loubriel, Guillermo [Albuquerque, NM

2007-02-06

An improved photoconductive semiconductor switch comprises multiple-line optical triggering of multiple, high-current parallel filaments between the switch electrodes. The switch can also have a multi-gap, interdigitated electrode for the generation of additional parallel filaments. Multi-line triggering can increase the switch lifetime at high currents by increasing the number of current filaments and reducing the current density at the contact electrodes in a controlled manner. Furthermore, the improved switch can mitigate the degradation of switching conditions with increased number of firings of the switch.

Multiple switching modes and multiple level states in memristive devices

NASA Astrophysics Data System (ADS)

Miao, Feng; Yang, J. Joshua; Borghetti, Julien; Strachan, John Paul; Zhang, M.-X.; Goldfarb, Ilan; Medeiros-Ribeiro, Gilberto; Williams, R. Stanley

2011-03-01

As one of the most promising technologies for next generation non-volatile memory, metal oxide based memristive devices have demonstrated great advantages on scalability, operating speed and power consumption. Here we report the observation of multiple switching modes and multiple level states in different memristive systems. The multiple switching modes can be obtained by limiting the current during electroforming, and related transport behaviors, including ionic and electronic motions, are characterized. Such observation can be rationalized by a model of two effective switching layers adjacent to the bottom and top electrodes. Multiple level states, corresponding to different composition of the conducting channel, will also be discussed in the context of multiple-level storage for high density, non-volatile memory applications.

Design and synthesis of multifunctional gold nanoparticles bearing tumor-associated glycopeptide antigens as potential cancer vaccines.

PubMed

Brinãs, Raymond P; Sundgren, Andreas; Sahoo, Padmini; Morey, Susan; Rittenhouse-Olson, Kate; Wilding, Greg E; Deng, Wei; Barchi, Joseph J

2012-08-15

The development of vaccines against specific types of cancers will offer new modalities for therapeutic intervention. Here, we describe the synthesis of a novel vaccine construction prepared from spherical gold nanoparticles of 3-5 nm core diameters. The particles were coated with both the tumor-associated glycopeptides antigens containing the cell-surface mucin MUC4 with Thomsen Friedenreich (TF) antigen attached at different sites and a 28-residue peptide from the complement derived protein C3d to act as a B-cell activating "molecular adjuvant". The synthesis entailed solid-phase glycopeptide synthesis, design of appropriate linkers, and attachment chemistry of the various molecules to the particles. Attachment to the gold surface was mediated by a novel thiol-containing 33 atom linker which was further modified to be included as a third "spacer" component in the synthesis of several three-component vaccine platforms. Groups of mice were vaccinated either with one of the nanoplatform constructs or with control particles without antigen coating. Evaluation of sera from the immunized animals in enzyme immunoassays (EIA) against each glycopeptide antigen showed a small but statistically significant immune response with production of both IgM and IgG isotypes. Vaccines with one carbohydrate antigen (B, C, and E) gave more robust responses than the one with two contiguous disaccharides (D), and vaccine E with a TF antigen attached to threonine at the 10th position of the peptide was selected for IgG over IgM suggesting isotype switching. The data suggested that this platform may be a viable delivery system for tumor-associated glycopeptide antigens.

Interactions of β tubulin isotypes with glutathione in differentiated neuroblastoma cells subject to oxidative stress.

PubMed

Guo, Jiayan; Kim, Hong Seok; Asmis, Reto; Ludueña, Richard F

2018-04-16

Microtubules are a major component of the neuronal cytoskeleton. Tubulin, the subunit protein of microtubules, is an α/β heterodimer. Both α and β exist as families of isotypes, whose members are encoded by different genes and have different amino acid sequences. The βII and βIII isotypes are very prominent in the nervous system. Our previous work has suggested that βII may play a role in neuronal differentiation, but the role of βIII in neurons is not well understood. In the work reported here, we examined the roles of the different β-tubulin isotypes in response to glutamate/glycine treatment, and found that both βII and βIII bind to glutathione in the presence of ROS, especially βIII. In contrast, βI did not bind to glutathione. Our results suggest that βII and βIII, but especially βIII, may play an important role in the response of neuronal cells to stress. In view of the high levels of βII and βIII expressed in the nervous system it is conceivable that these tubulin isotypes may use their sulfhydryl groups to scavenge ROS and protect neuronal cells against oxidative stress. © 2018 Wiley Periodicals, Inc.

The influence of H-2 genetic factors on the development of benign monoclonal gammopathy in ageing H-2 congenic C57BL and BALB mice.

PubMed Central

van den Akker, T W; Tio-Gillen, A P; Benner, R; Zurcher, C; Radl, J

1987-01-01

The role of H-2 genetic factors in the development of benign monoclonal gammopathy (BMG) was investigated in six H-2 congenic C57BL and BALB strains (C57BL/10.ScSn and BALB.B: H-2b; B10.D2 and BALB/c: H-2d; B10.BR and BALB.K: H-2k) during ageing. The frequencies of homogeneous immunoglobulins (H-Ig), both single and multiple, in the three C57BL strains were higher than those in the corresponding three BALB strains. No relationship was found with a particular H-2 haplotype. The most frequent H-Ig isotype within the C57BL strains was IgG2a, within BALB.B and BALB.K mice IgG3 and in BALB/c mice IgG1. Categorization of the monoclonal gammopathies (MG) on the basis of their origin showed a single transient monoclonal B-cell proliferation in 2-5% and 3-9% of the C57BL and BALB mice positive for H-Ig, respectively. Multiple myeloma or B-cell lymphoma were found to be responsible for about 1% of the paraproteinaemias in all strains. Persistent, non-progressive MG, most likely BMG, was detected in 70-81% and 39-46% of the C57BL and BALB mice positive for H-Ig, respectively. The remaining 14-24% and 50-58% of the, respectively, C57BL and BALB mice positive for H-Ig could not be evaluated in time. The H-2 haplotypes under investigation were not associated with the onset, occurrence, multiplicity, persistence or isotype of the MG developing in these H-2 congenic C57BL and BALB strains during ageing. PMID:3443448

Antibody repertoire development in camelids.

PubMed

De Genst, Erwin; Saerens, Dirk; Muyldermans, Serge; Conrath, Katja

2006-01-01

The humoral immune response of the Camelidae is unique as these animals are the only known mammals that seem to possess functional homodimeric heavy-chain antibodies besides the classical heteromeric antibodies composed of heavy (H) and light (L) chains. By definition, the heavy-chain antibodies lack the L-chain, and it was noticed that their H-chain is devoid of the typical first constant domain (CH1) and contains a dedicated variable domain, referred to as VHH. The VHH exon is assembled from separate V-D-J gene segments. The recombined VHH region is subjected to somatic hypermutations; however, the timing and actual mechanism of the class switch from mu to the dedicated gamma-isotype remains elusive. Interestingly, antigen-specific VHHs are easily retrieved after panning of a phage-displayed rearranged V-gene pool cloned from an immunised camelid. These single-domain antigen binding entities possess a number of biophysical properties that offer particular advantages in various medical and biotechnological applications.

Effect of whole-body irradiation of mice on the number of background plaque-forming cells

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

Anderson, R.E.; Lefkovits, I.; Soeederberg, A.

1983-08-01

Mice were exposed in whole-body fashion to several doses of radiation and killed at various times thereafter for a determination of the number of background plaque-forming cells (PFCs) as assayed on either sheep erythrocytes or bromelain-treated autologous mouse erythrocytes. Increased numbers of both types of PFC were found in the irradiated groups. These increases were dependent on radiation dose and time after exposure. They did not appear to be caused by a disruption of normal lymphocyte traffic or a switch in immunoglobulin isotype. An increased number of PFCs on bromelain-treated mouse RBCs but not on sheep RBCs were found inmore » irradiated congenitally athymic nude mice. On the basis of this and related observations, background PFCs on bromelain-treated mouse RBCs and on sheep RBCs appear to fall under different forms of homeostatic control.« less

Immunoglobulins G, M, and A against Sporothrix schenckii Exoantigens in Patients with Sporotrichosis before and during Treatment with Itraconazole▿

PubMed Central

Almeida-Paes, Rodrigo; Pimenta, Monique Amorim; Monteiro, Paulo Cezar F.; Nosanchuk, Joshua D.; Zancopé-Oliveira, Rosely Maria

2007-01-01

Sporotrichosis is an important subcutaneous mycosis, with an increasing worldwide incidence. However, few data are available regarding the immunological aspects of Sporothrix schenckii infection, particularly the humoral responses to the fungus. In this study we measured immunoglobulin G (IgG), IgM, and IgA in sera from 41 patients with sporotrichosis before antifungal treatment and from another 35 patients with sporotrichosis during itraconazole treatment by using a recently described S. schenckii exoantigen enzyme-linked immunosorbent assay (ELISA). More than 95% of patients had detectable IgA antibodies, and more than 85% had IgM and IgG antibodies before treatment. The number of patients with IgG antibodies increased to 91% during treatment. Conversely, significantly fewer samples from treated patients were positive for IgM (71%) and IgA (89%). Overall, 78% of patients had detectable levels of all isotypes tested at diagnosis, and this percentage dropped to 62.9% in patients receiving itraconazole. Testing of all three isotypes improved the sensitivity; at least two isotypes were detected in 93% of patients before and 89% after treatment. The reactivity of 94 sera from patients with other diseases and healthy individuals was also tested. Cross-reactivity occurred in 33% of the heterologous sera. Most of them were positive only in one isotype, 8.5% were positive for at least two isotypes, and only one serum (1.1%) was positive for the three isotypes. Antibodies produced during S. schenckii infection are diverse, and we demonstrate that an exoantigen ELISA for the detection of combinations of IgA, IgG, and IgM antibodies is a highly sensitive and specific diagnostic assay for sporotrichosis. PMID:17634504

Poly(ADP-ribose) polymerase-1 (Parp-1)-deficient mice demonstrate abnormal antibody responses

PubMed Central

Ambrose, Helen E; Willimott, Shaun; Beswick, Richard W; Dantzer, Françoise; de Murcia, Josiane Ménissier; Yelamos, José; Wagner, Simon D

2009-01-01

Poly(ADP-ribosylation) of acceptor proteins is an epigenetic modification involved in DNA strand break repair, recombination and transcription. Here we provide evidence for the involvement of poly(ADP-ribose) polymerase-1 (Parp-1) in antibody responses. Parp-1−/− mice had increased numbers of T cells and normal numbers of total B cells. Marginal zone B cells were mildly reduced in number, and numbers of follicular B cells were preserved. There were abnormal levels of basal immunoglobulins, with reduced levels of immunoglobulin G2a (IgG2a) and increased levels of IgA and IgG2b. Analysis of specific antibody responses showed that T cell-independent responses were normal but T cell-dependent responses were markedly reduced. Germinal centres were normal in size and number. In vitro purified B cells from Parp-1−/− mice proliferated normally and showed normal IgM secretion, decreased switching to IgG2a but increased IgA secretion. Collectively our results demonstrate that Parp-1 has essential roles in normal T cell-dependent antibody responses and the regulation of isotype expression. We speculate that Parp-1 forms a component of the protein complex involved in resolving the DNA double-strand breaks that occur during class switch recombination. PMID:18778284

Characterization of the immunoglobulin repertoire of the spiny dogfish (Squalus acanthias).

PubMed

Smith, Lauren E; Crouch, Kathryn; Cao, Wei; Müller, Mischa R; Wu, Leeying; Steven, John; Lee, Michael; Liang, Musen; Flajnik, Martin F; Shih, Heather H; Barelle, Caroline J; Paulsen, Janet; Gill, Davinder S; Dooley, Helen

2012-04-01

The cartilaginous fish (chimeras, sharks, skates and rays) are the oldest group relative to mammals in which an adaptive immune system founded upon immunoglobulins has been found. In this manuscript we characterize the immunoglobulins of the spiny dogfish (Squalus acanthias) at both the molecular and expressed protein levels. Despite the presence of hundreds of IgM clusters in this species the serum levels of this isotype are comparatively low. However, analysis of cDNA sequences and serum protein suggests microheterogeneity in the IgM heavy chains and supports the proposal that different clusters are preferentially used in the two forms (monomer or pentamer) of this isotype. We also found that the IgNAR isotype in this species exists in a previously unknown multimeric format in serum. Finally, we identified a new form of the IgW isotype (the shark IgD orthologue), in which the leader is spliced directly to the first constant domain, resulting in a molecule lacking an antigen-binding domain. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ornithorhynchus anatinus (platypus) links the evolution of immunoglobulin genes in eutherian mammals and nonmammalian tetrapods.

PubMed

Zhao, Yaofeng; Cui, Huiting; Whittington, Camilla M; Wei, Zhiguo; Zhang, Xiaofeng; Zhang, Ziding; Yu, Li; Ren, Liming; Hu, Xiaoxiang; Zhang, Yaping; Hellman, Lars; Belov, Katherine; Li, Ning; Hammarström, Lennart

2009-09-01

The evolutionary origins of mammalian immunoglobulin H chain isotypes (IgM, IgD, IgG, IgE, and IgA) are still incompletely understood as these isotypes differ considerably in structure and number from their counterparts in nonmammalian tetrapods. We report in this study that the platypus (Ornithorhynchus anatinus) Ig H chain constant region gene locus contains eight Ig encoding genes, which are arranged in an mu-delta-omicron-gamma2-gamma1-alpha1-epsilon-alpha2 order, spanning a total of approximately 200 kb DNA, encoding six distinct isotypes. The omicron (omicron for Ornithorhynchus) gene encodes a novel Ig H chain isotype that consists of four constant region domains and a hinge, and is structurally different from any of the five known mammalian Ig classes. This gene is phylogenetically related to upsilon (epsilon) and gamma, and thus appears to be a structural intermediate between these two genes. The platypus delta gene encodes ten heavy chain constant region domains, lacks a hinge region and is similar to IgD in amphibians and fish, but strikingly different from that in eutherian mammals. The platypus Ig H chain isotype repertoire thus shows a unique combination of genes that share similarity both to those of nonmammalian tetrapods and eutherian animals and demonstrates how phylogenetically informative species can be used to reconstruct the evolutionary history of functionally important genes.

An absorptive single-pole four-throw switch using multiple-contact MEMS switches and its application to a monolithic millimeter-wave beam-forming network

NASA Astrophysics Data System (ADS)

Lee, Sanghyo; Kim, Jong-Man; Kim, Yong-Kweon; Kwon, Youngwoo

2009-01-01

In this paper, a new absorptive single-pole four-throw (SP4T) switch based on multiple-contact switching is proposed and integrated with a Butler matrix to demonstrate a monolithic beam-forming network at millimeter waves (mm waves). In order to simplify the switching driving circuit and reduce the number of unit switches in an absorptive SP4T switch, the individual switches were replaced with long-span multiple-contact switches using stress-free single-crystalline-silicon MEMS technology. This approach improves the mechanical stability as well as the manufacturing yield, thereby allowing successful integration into a monolithic beam former. The fabricated absorptive SP4T MEMS switch shows insertion loss less than 1.3 dB, return losses better than 11 dB at 30 GHz and wideband isolation performance higher than 39 dB from 20 to 40 GHz. The absorptive SP4T MEMS switch is integrated with a 4 × 4 Butler matrix on a single chip to implement a monolithic beam-forming network, directing beam into four distinct angles. Array factors from the measured data show that the proposed absorptive SPnT MEMS switch can be effectively used for high-performance mm-wave beam-switching systems. This work corresponds to the first demonstration of a monolithic beam-forming network using switched beams.

Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease.

PubMed

Nagata, Keiko; Kumata, Keisuke; Nakayama, Yuji; Satoh, Yukio; Sugihara, Hirotsugu; Hara, Sayuri; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Hayashi, Kazuhiko

2017-04-01

Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.

Molecular cloning of IGλ rearrangements using long-distance inverse PCR (LDI-PCR).

PubMed

Shimanuki, Masaya; Sonoki, Takashi; Hosoi, Hiroki; Watanuki, Jyuri; Murata, Shogo; Kawakami, Keiki; Matsuoka, Hiroshi; Hanaoka, Nobuyoshi; Nakakuma, Hideki

2013-01-01

Malignant cells of mature B-cell origin show tumor-specific clonal immunoglobulin gene (IG) rearrangements, including V(D)J recombinations, nucleotide mutations, or translocations. Rapid molecular cloning of the breakpoint sequence by long-distance inverse PCR (LDI-PCR) has so far been applied to rearrangements targeted to IGH joining, IGH switch, and IGκ regions. We tended to apply LDI-PCR method for cloning of IGλ rearrangements. To identify which IGλ isotype segment was rearranged, we performed Southern blot analysis using isotype-specific probes. We set inverse primers on the telomeric side of each joining region and amplified rearranged bands detected by Southern blot analysis as corresponding PCR products. All germline IGλ segments were successfully amplified as expected PCR products. We determined breakpoint sequences of five chromosome translocations involving IGλ locus: three novel t(8;22)(q24;q11), one known t(3;22)(q27;q11), and one partially known t(11;22)(q13;q11). Two of the three t(8;22)(q24;q11) were involved in Jλ with a recombination signal sequence and one of three in the first exon of IGLL5, which lies upstream of Jλ1. Three 8q24 breakpoints were widespread at 132, 260 and 366 kb downstream of MYC locus. The t(3;22)(q27;q11) showed a juxtaposition of Jλ2 and the first intron of BCL6, as previously reported. In t(11;22)(q13;q11), 3'UTR of cyclin D1 fused to the constant region of λ7 with nucleotide mutations. We also amplified four Vλ/Jλ recombination sequences. Our method is a useful tool for molecular analysis of genetic events in IGλ. © 2012 John Wiley & Sons A/S.

Antibody Response Specific to the Capsular Polysaccharide Is Impaired in Streptococcus suis Serotype 2-Infected Animals

PubMed Central

Calzas, Cynthia; Lemire, Paul; Auray, Gael; Gerdts, Volker; Gottschalk, Marcelo

2014-01-01

Streptococcus suis serotype 2 is an extracellular encapsulated bacterium that causes severe septicemia and meningitis in swine and humans. Albeit crucial in the fight against encapsulated bacteria, the nature of the capsular polysaccharide (CPS)-specific antibody (Ab) response during S. suis type 2 infection is unknown. We compared for the first time the features of CPS-specific versus protein-specific Ab responses during experimental infections with live virulent S. suis type 2 in mice. The primary protein-specific Ab response was dominated by both type 1 and 2 IgG subclasses, whereas IgM titers were more modest. The secondary protein-specific Ab response showed all of the features of a memory response with faster kinetics and boosted the titers of all Ig isotypes. In contrast, the primary CPS-specific Ab response was either inexistent or had titers only slightly higher than those in noninfected animals and was essentially composed of IgM. A poor CPS-specific memory response was observed, with only a moderate boost in IgM titers and no IgG. Both protein- and CPS-specific Ab responses were Toll-like receptor 2 independent. By using S. suis type 2 strains of European or North American origin, the poor CPS-specific Ab response was demonstrated to be independent of the genotypic/phenotypic diversity of the strain within serotype 2. Finally, the CPS-specific Ab response was also impaired and lacked isotype switching in S. suis-infected pigs, the natural host of the bacterium. The better resistance of preinfected animals to reinfection with the same strain of S. suis type 2 might thus more likely be related to the development of a protein rather than CPS Ab response. PMID:25385801

Epstein–Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease

PubMed Central

Kumata, Keisuke; Nakayama, Yuji; Satoh, Yukio; Sugihara, Hirotsugu; Hara, Sayuri; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Hayashi, Kazuhiko

2017-01-01

Abstract Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein–Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases. PMID:28333576

B cell immunopoiesis: visualizing the impact of CD40 engagement on the course of T cell-independent immune responses in an Ig transgenic system.

PubMed

Erickson, L D; Vogel, L A; Cascalho, M; Wong, J; Wabl, M; Durell, B G; Noelle, R J

2000-11-01

This study tracks the fate of antigen-reactive B cells through follicular and extrafollicular responses and addresses the function of CD40 in these processes. The unique feature of this system is the use of transgenic B cells in which the heavy chain locus has been altered by site-directed insertion of a rearranged V(H) DJ(H) exon such that they are able to clonally expand, isotype-switch and follow a normal course of differentiation upon immunization. These Ig transgenic B cells when adoptively transferred into non-transgenic (Tg) mice in measured amounts expanded and differentiated distinctively in response to T cell-independent (TI) or T cell-dependent (TD) antigens. The capacity of these Tg B cells to faithfully recapitulate the humoral immune response to TI and TD antigens provides the means to track clonal B cell behavior in vivo. Challenge with TI antigen in the presence of agonistic anti-CD40 mAb resulted in well-defined alterations of the TI response. In vivo triggering of Tg B cells with TI antigen and CD40 caused an increase in the levels IgG produced and a broadening of the Ig isotype profile, characteristics which partially mimic TD responses. Although some TD characteristics were induced by TI antigen and CD40 triggering, the Tg B cells failed to acquire a germinal center phenotype and failed to generate a memory response. Therefore, TD-like immunity can be only partially reconstituted with CD40 agonists and TI antigens, suggesting that there are additional signals required for germinal center formation and development of memory.

Different Regions of the Malaria Merozoite Surface Protein 1 of Plasmodium chabaudi Elicit Distinct T-Cell and Antibody Isotype Responses

PubMed Central

Quin, Stuart J.; Langhorne, Jean

2001-01-01

In this study we have investigated the antibody and CD4 T-cell responses to the well-characterized malaria vaccine candidate MSP-1 during the course of a primary Plasmodium chabaudi chabaudi (AS) infection. Specific antibody responses can be detected within the first week of infection, and CD4 T cells can be detected after 3 weeks of infection. The magnitude of the CD4 T-cell response elicited during a primary infection depended upon the region of MSP-1. In general, the highest precursor frequencies were obtained when a recombinant MSP-1 fragment corresponding to amino acids 900 to 1507 was used as the antigen in vitro. By contrast, proliferative and cytokine responses against amino acids 1508 to 1766 containing the C-terminal 21-kDa region of the molecule were low. The characteristic interleukin 4 (IL-4) switch that occurs in the CD4 T-cell population after an acute blood stage P. c. chabaudi infection was only consistently observed in the response to the amino acid 900 to 1507 MSP1 fragment. A lower frequency of IL-4-producing cells was seen in response to other regions. Although the magnitudes of the immunoglobulin G antibody responses to the different regions of MSP-1 were similar, the isotype composition of each response was distinct, and there was no obvious relationship with the type of T helper cells generated. Interestingly, a relatively high antibody response to the C-terminal region of MSP-1 was observed, suggesting that T-cell epitopes outside of this region may provide the necessary cognate help for specific antibody production. PMID:11254580

Correlated noise-based switches and stochastic resonance in a bistable genetic regulation system

NASA Astrophysics Data System (ADS)

Wang, Can-Jun; Yang, Ke-Li

2016-07-01

The correlated noise-based switches and stochastic resonance are investigated in a bistable single gene switching system driven by an additive noise (environmental fluctuations), a multiplicative noise (fluctuations of the degradation rate). The correlation between the two noise sources originates from on the lysis-lysogeny pathway system of the λ phage. The steady state probability distribution is obtained by solving the time-independent Fokker-Planck equation, and the effects of noises are analyzed. The effects of noises on the switching time between the two stable states (mean first passage time) is investigated by the numerical simulation. The stochastic resonance phenomenon is analyzed by the power amplification factor. The results show that the multiplicative noise can induce the switching from "on" → "off" of the protein production, while the additive noise and the correlation between the noise sources can induce the inverse switching "off" → "on". A nonmonotonic behaviour of the average switching time versus the multiplicative noise intensity, for different cross-correlation and additive noise intensities, is observed in the genetic system. There exist optimal values of the additive noise, multiplicative noise and cross-correlation intensities for which the weak signal can be optimal amplified.

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks.

PubMed

Shen, Yiwen; Hattink, Maarten H N; Samadi, Payman; Cheng, Qixiang; Hu, Ziyiz; Gazman, Alexander; Bergman, Keren

2018-04-16

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. We present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly network testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 µs control plane latency for data-center and high performance computing platforms.

The generation and selection of single-domain, v region libraries from nurse sharks.

PubMed

Flajnik, Martin F; Dooley, Helen

2009-01-01

The cartilaginous fish (sharks, skates, and rays) are the oldest phylogenetic group in which a human-type adaptive immune system and immunoglobulins (Igs) have been found. In addition to their conventional (heavy-light chain heterodimeric) isotypes, IgM and IgW, sharks produce the novel isotype, IgNAR, a heavy chain homodimer that does not associate with light chains. Instead, its variable (V) regions act as independent, soluble units in order to bind antigen. In this chapter, we detail our immunization protocol in order to raise a humoral IgNAR response in the nurse shark (Ginglymostoma cirratum) and the subsequent cloning of the single-domain V regions from this isotype in order to select antigen-specific binders by phage display.

The influence of genetic factors associated with the immunoglobulin heavy chain locus on the development of benign monoclonal gammapathy in ageing IgH-congenic mice.

PubMed Central

van den Akker, T W; de Glopper-van der Veer, E; Radl, J; Benner, R

1988-01-01

The role of genetic factors associated with the immunoglobulin heavy chain locus (Igh) in the development of benign monoclonal gammapathy (BMG), a benign B-cell proliferative disorder, was investigated in six Igh congenic mouse strains during ageing. The strains used had a C57BL or BALB background: C57BL/6, BALB.Igb and CB-20 carrying the C57BL Igh (Ighb allotype), BALB/c and C57BL/6.Iga carrying the BALB/c Igh (Igha allotype) and BAB-14, that is of BALB/c origin with the exception of the constant part of the Igh, which is of C57BL origin. The frequency of homogeneous immunoglobulins (H-Ig), both single and multiple, was the highest in C57BL/6 mice, followed by C57BL/6.Iga. The frequencies of H-Ig in BALB.Igb and CB-20 mice were higher than those of BALB/c and BAB-14, although somewhat lower than in C57BL/6.Iga mice. Multiple H-Ig were found especially in the sera of C57BL/6 mice. Categorization of the monoclonal gammapathies (MG) on the basis of their origin showed a single transient monoclonal B-cell proliferation in 0-8% of the mice of all strains. Persistent, non-progressive MG, presumably BMG, were detected in 64% of C57BL/6, 30% of C57BL/6.Iga, 22% of BALB.Igb, 17% of CB-20, 13% of BAB-14 and 6% of BALB/c mice. Multiple myeloma or Waldenström-like B-cell lymphoma were found to be responsible for 2-4% of the paraproteinemias in all strains. The remaining H-Ig, varying from 11% of the C57BL/6 to 70% of the BAB-14 mice, could not be evaluated in time. The most frequent isotypes of the BMG within C57BL/6 and C57BL/6.Iga were IgG2a and IgG2b, respectively; IgM was the most frequent isotype within the four BALB congenic strains. The immunoglobulin heavy chain allotypes under investigation appeared to be only partly related to the onset, occurrence, multiplicity and persistence of the BMG developing in these Igh congenic C57BL and BALB strains during ageing. The immunoglobulin heavy chain allotypes, however, were not related to the major isotype of the BMG. The results obtained in CB-20 and BALB.Igb on the one hand, and in BAB-14 on the other hand, may suggest a role for the variable part of the Igh in the development of BMG. Since no absolute influence could be ascribed to the Igh, we assume that primarily other genetic sequences regulating proliferative B-cell functions account for the pathogenesis of BMG. PMID:3141270

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells

PubMed Central

Nguyen, Thuy Vy; Riou, Lydia

2014-01-01

Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca−/− mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. PMID:24799500

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells.

PubMed

Nguyen, Thuy Vy; Riou, Lydia; Aoufouchi, Saïd; Rosselli, Filippo

2014-06-02

Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca(-/-) mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. © 2014 Nguyen et al.

Malondialdehyde-acetaldehyde adducts (MAA) and anti-MAA antibody in rheumatoid arthritis

PubMed Central

Thiele, Geoffrey M.; Duryee, Michael J.; Anderson, Daniel R.; Klassen, Lynell W.; Mohring, Stephen M.; Young, Kathleen A.; Benissan-Messan, Dathe; Sayles, Harlan; Dusad, Anand; Hunter, Carlos D.; Sokolove, Jeremy; Robinson, William; O’Dell, James R.; Nicholas, Anthony P.; Tuma, Dean; Mikuls, Ted R.

2017-01-01

Objective As a product of oxidative stress associated with tolerance loss in other disease states, we investigated the presence of malondialdehyde-acetaldehyde (MAA) adducts and circulating anti-MAA antibody in rheumatoid arthritis (RA). Methods Synovial tissues from RA and osteoarthritis patients were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA cases (n = 1720) and healthy controls (n = 80) by ELISA. Antigen-specific anti-citrullinated protein antibody (ACPA) was measured in RA cases using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of cases (n = 80) and matched controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA, were examined in all RA cases. Results MAA adducts were increased in RA synovial tissues relative to osteoarthritis and co-localized with citrullinated protein. Anti-MAA antibody isotypes were increased in RA cases vs. controls (p < 0.001). Among RA cases, anti-MAA antibody isotypes were associated with ACPA and RF positivity (p < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a higher number of positive antigen-specific ACPA analytes in high titer (p < 0.001) and a higher ACPA score (p < 0.001) independent of other covariates. Conclusion MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPA. These results support speculation that MAA formation may be a co-factor that drives tolerance loss resulting in the autoimmune responses characteristic of RA. PMID:25417811

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

PubMed Central

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

Application of monoclonal antibodies in functional and comparative investigations of heavy-chain immunoglobulins in new world camelids.

PubMed

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

2005-03-01

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 gamma 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.

Requirement of 8-mercaptoguanosine as a costimulus for IL-4-dependent mu to gamma1 class switch recombination in CD38-activated B cells.

PubMed

Tsukamoto, Yumiko; Uehara, Shoji; Mizoguchi, Chieko; Sato, Atsushi; Horikawa, Keisuke; Takatsu, Kiyoshi

2005-10-21

Mature B-2 cells expressing surface IgM and IgD proliferate upon stimulation by CD38, CD40 or lipopolysaccharide (LPS) and differentiate into IgG1-producing plasma cells in the presence of cytokines. The process of class switch recombination (CSR) from IgM to other isotypes is highly regulated by cytokines and activation-induced cytidine deaminase (AID). Blimp-1 and XBP-1 play an essential role in the terminal differentiation of switched B-2 cells to Ig-producing plasma cells. IL-5 induces AID and Blimp-1 expression in CD38- and CD40-activated B-2 cells, leading to mu to gamma1 CSR at DNA level and IgG1 production. IL-4, a well-known IgG1-inducing factor, does not induce mu to gamma1 CSR in CD38-activated B-2 cells or Blimp-1, while IL-4 induces mu to gamma1 CSR, XBP-1 expression, and IgG1 production expression in CD40-activated B-2 cells. Interestingly, the addition of 8-mercaptoguanosine (8-SGuo) with IL-4 to the culture of CD38-activated B cells can induce mu to gamma1 CSR, Blimp-1 expression, and IgG1 production. Intriguingly, 8-SGuo by itself induces AID expression in CD38-activated B cells. However, it does not induce mu to gamma1 CSR. These results imply that the mode of B-cell activation for extracellular stimulation affects the outcome of cytokine stimulation with respect to the efficiency and direction of CSR, and the requirements of the transcriptional regulator and the generation of antibody-secreting cells. Furthermore, our data suggest the requirement of additional molecules in addition to AID for CSR.

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks

DOE PAGES

Shen, Yiwen; Hattink, Maarten; Samadi, Payman; ...

2018-04-13

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. Here, we present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly networkmore » testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 microsecond control plane latency for data-center and high performance computing platforms.« less

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks

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

Shen, Yiwen; Hattink, Maarten; Samadi, Payman

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. Here, we present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly networkmore » testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 microsecond control plane latency for data-center and high performance computing platforms.« less

MuSK induced experimental autoimmune myasthenia gravis does not require IgG1 antibody to MuSK.

PubMed

Küçükerden, Melike; Huda, Ruksana; Tüzün, Erdem; Yılmaz, Abdullah; Skriapa, Lamprini; Trakas, Nikos; Strait, Richard T; Finkelman, Fred D; Kabadayı, Sevil; Zisimopoulou, Paraskevi; Tzartos, Socrates; Christadoss, Premkumar

2016-06-15

Sera of myasthenia gravis (MG) patients with muscle-specific receptor kinase-antibody (MuSK-Ab) predominantly display the non-complement fixing IgG4 isotype. Similarly, mouse IgG1, which is the analog of human IgG4, is the predominant isotype in mice with experimental autoimmune myasthenia gravis (EAMG) induced by MuSK immunization. The present study was performed to determine whether IgG1 anti-MuSK antibody is required for immunized mice to develop EAMG. Results demonstrated a significant correlation between clinical severity of EAMG and levels of MuSK-binding IgG1+, IgG2+ and IgG3+ peripheral blood B cells in MuSK-immunized wild-type (WT) mice. Moreover, MuSK-immunized IgG1 knockout (KO) and WT mice showed similar EAMG severity, serum MuSK-Ab levels, muscle acetylcholine receptor concentrations, neuromuscular junction immunoglobulin and complement deposit ratios. IgG1 and IgG3 were the predominant anti-MuSK isotypes in WT and IgG1 KO mice, respectively. These observations demonstrate that non-IgG1 isotypes can mediate MuSK-EAMG pathogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

A multiple camera tongue switch for a child with severe spastic quadriplegic cerebral palsy.

PubMed

Leung, Brian; Chau, Tom

2010-01-01

The present study proposed a video-based access technology that facilitated a non-contact tongue protrusion access modality for a 7-year-old boy with severe spastic quadriplegic cerebral palsy (GMFCS level 5). The proposed system featured a centre camera and two peripheral cameras to extend coverage of the frontal face view of this user for longer durations. The child participated in a descriptive case study. The participant underwent 3 months of tongue protrusion training while the multiple camera tongue switch prototype was being prepared. Later, the participant was brought back for five experiment sessions where he worked on a single-switch picture matching activity, using the multiple camera tongue switch prototype in a controlled environment. The multiple camera tongue switch achieved an average sensitivity of 82% and specificity of 80%. In three of the experiment sessions, the peripheral cameras were associated with most of the true positive switch activations. These activations would have been missed by a centre-camera-only setup. The study demonstrated proof-of-concept of a non-contact tongue access modality implemented by a video-based system involving three cameras and colour video processing.

Activation of monoamine oxidase isotypes by prolonged intake of aluminum in rat brain.

PubMed

Huh, Jae-Wan; Choi, Myung-Min; Lee, Jang Han; Yang, Seung-Ju; Kim, Mi Jung; Choi, Jene; Lee, Kwan Ho; Lee, Jong Eun; Cho, Sung-Woo

2005-10-01

Rats were fed 100 microM aluminum maltolate for one year in their drinking water. Brain aluminum contents have increased 4.2-fold in the aluminum-treated group, whereas no significant changes in the body weight, brain weight, and brain protein content were observed. Long-term aluminum feeding induced apoptosis as assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and showed activatory effects on the catalytic efficiency (kcat/KM) of monoamine oxidase-A and monoamine oxidase-B up to 1.9- and 3.8-fold, respectively. The expression level of monoamine oxidase isotypes on the Western blot remained unchanged between the two groups, suggesting a change in post-translational regulation of the activities of monoamine oxidase isotypes by long-term aluminum feeding.

Refill Adherence in Relation to Substitution and the Use of Multiple Medications: A Nationwide Population Based Study on New ACE-Inhibitor Users

PubMed Central

Jönsson, Anna K.; Lesén, Eva; Mårdby, Ann-Charlotte; Sundell, Karolina Andersson

2016-01-01

Objective Generic substitution has contributed to economic savings but switching products may affect patient adherence, particularly among those using multiple medications. The aim was to analyse if use of multiple medications influenced the association between switching products and refill adherence to angiotensin-converting-enzyme (ACE) inhibitors in Sweden. Study Design and Setting New users of ACE-inhibitors, starting between 1 July 2006 and 30 June 2007, were identified in the Swedish Prescribed Drug Register. Refill adherence was assessed using the continuous measure of medication acquisition (CMA) and analysed with linear regression and analysis of covariance. Results The study population included 42735 individuals whereof 51.2% were exposed to switching ACE-inhibitor and 39.6% used multiple medications. Refill adherence was higher among those exposed to switching products than those not, but did not vary depending on the use of multiple medications or among those not. Refill adherence varied with age, educational level, household income, country of birth, previous hospitalisation and previous cardiovascular diagnosis. Conclusion The results indicate a positive association between refill adherence and switching products, mainly due to generic substitution, among new users of ACE-inhibitors in Sweden. This association was independent of use of multiple medications. PMID:27192203

Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

PubMed Central

Zheng, Chaogu; Diaz-Cuadros, Margarete; Nguyen, Ken C. Q.; Hall, David H.; Chalfie, Martin

2017-01-01

Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization. PMID:28835377

Output regulation control for switched stochastic delay systems with dissipative property under error-dependent switching

NASA Astrophysics Data System (ADS)

Li, L. L.; Jin, C. L.; Ge, X.

2018-01-01

In this paper, the output regulation problem with dissipative property for a class of switched stochastic delay systems is investigated, based on an error-dependent switching law. Under the assumption that none subsystem is solvable for the problem, a sufficient condition is derived by structuring multiple Lyapunov-Krasovskii functionals with respect to multiple supply rates, via designing error feedback regulators. The condition is also established when dissipative property reduces to passive property. Finally, two numerical examples are given to demonstrate the feasibility and efficiency of the present method.

Quantification of SAA1 and SAA2 in lung cancer plasma using the isotype-specific PRM assays.

PubMed

Kim, Yeoun Jin; Gallien, Sebastien; El-Khoury, Victoria; Goswami, Panchali; Sertamo, Katriina; Schlesser, Marc; Berchem, Guy; Domon, Bruno

2015-09-01

The quantification of plasma proteins using the high resolution and accurate mass (HR/AM)-based parallel reaction monitoring (PRM) method provides an immediate benefit over the conventional SRM-based method in terms of selectivity. In this study, multiplexed PRM assays were developed to analyze isotypes of serum amyloid A (SAA) proteins in human plasma with a focus on SAA1 and SAA2. Elevated plasma levels of these proteins in patients diagnosed with lung cancer have been reported in previous studies. Since SAA1 and SAA2 are highly homologous, the available immunoassays tend to overestimate their concentrations due to cross-reactivity. On the other hand, when mass spectrometry (MS)-based assays are used, the presence of the several allelic variants may result in a problem of underestimation. In the present study, eight peptides that represent the target proteins at three different levels: isotype-specific (SAA1α,  SAA 1β,  SAA1γ,  SAA2α,  SAA2β), protein-specific (SAA1 or SAA2), and pan SAA (SAA1 and SAA2) were chosen to differentiate SAAs in lung cancer plasma samples using a panel of PRM assays. The measurement of specific isotypes, leveraging the analytical performance of PRM, allowed to quantify the allelic variants of both target proteins. The isotypes detected were corroborated with the genetic information obtained from the same samples. The combination of SAA2α and SAA2β assays representing the total SAA2 concentration demonstrated a superior analytical outcome than the previously used assay on the common peptide when applied to the detection of lung cancer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clandestine Transmissions and Operations of Embedded Software on Cellular Mobile Devices

DTIC Science & Technology

2011-09-01

Register EMS Enhanced Message Service FDMA Frequency Division Multiple Access GMT Greenwich Mean Time GMSC Gateway Mobile Switching Center...Message Switching Center SMS-IWMSC SMS-Interworking Mobile-Service Switching Center TCH Traffic Channels TDMA Time Division Multiple Access TP...assume the user will not attempt to re-program the device. Finally, we assume that the owner and user do not have root access and cannot disable any

The evolution of multiple isotypic IgM heavy chain genes in the shark.

PubMed

Lee, Victor; Huang, Jing Li; Lui, Ming Fai; Malecek, Karolina; Ohta, Yuko; Mooers, Arne; Hsu, Ellen

2008-06-01

The IgM H chain gene organization of cartilaginous fishes consists of 15-200 miniloci, each with a few gene segments (V(H)-D1-D2-J(H)) and one C gene. This is a gene arrangement ancestral to the complex IgH locus that exists in all other vertebrate classes. To understand the molecular evolution of this system, we studied the nurse shark, which has relatively fewer loci, and characterized the IgH isotypes for organization, functionality, and the somatic diversification mechanisms that act upon them. Gene numbers differ slightly between individuals ( approximately 15), but five active IgM subclasses are always present. Each gene undergoes rearrangement that is strictly confined within the minilocus; in B cells there is no interaction between adjacent loci located > or =120 kb apart. Without combinatorial events, the shark IgM H chain repertoire is based on junctional diversity and, subsequently, somatic hypermutation. We suggest that the significant contribution by junctional diversification reflects the selected novelty introduced by RAG in the early vertebrate ancestor, whereas combinatorial diversity coevolved with the complex translocon organization. Moreover, unlike other cartilaginous fishes, there are no germline-joined VDJ at any nurse shark mu locus, and we suggest that such genes, when functional, are species-specific and may have specialized roles. With an entire complement of IgM genes available for the first time, phylogenetic analyses were performed to examine how the multiple Ig loci evolved. We found that all domains changed at comparable rates, but V(H) appears to be under strong positive selection for increased amino acid sequence diversity, and surprisingly, so does Cmicro2.

Unprecedented multiplicity of Ig transmembrane and secretory mRNA forms in the cartilaginous fish.

PubMed

Rumfelt, Lynn L; Diaz, Marilyn; Lohr, Rebecca L; Mochon, Evonne; Flajnik, Martin F

2004-07-15

In most jawed vertebrates including cartilaginous fish, membrane-bound IgM is expressed as a five Ig superfamily (Igsf)-domain H chain attached to a transmembrane (Tm) region. Heretofore, bony fish IgM was the one exception with IgM mRNA spliced to produce a four-domain Tm H chain. We now demonstrate that the Tm and secretory (Sec) mRNAs of the novel cartilaginous fish Ig isotypes, IgW and IgNAR, are present in multiple forms, most likely generated by alternative splicing. In the nurse shark, Ginglymostoma cirratum, and horn shark, Heterodontus francisci, alternative splicing of Tm exons to the second or the fourth constant (C(H)) exons produces two distinct IgW Tm cDNAs. Although the seven-domain IgW Sec cDNA form contains a canonical secretory tail shared with IgM, IgNAR, and IgA, we report a three-domain cDNA form of shark IgW (IgW(short)) having an unusual Sec tail, which is orthologous to skate IgX(short) cDNA. The IgW and IgW(short) Sec transcripts are restricted in their tissue distribution and expression levels vary among individual sharks, with all forms expressed early in ontogeny. IgNAR mRNA is alternatively spliced to produce a truncated four-domain Tm cDNA and a second Tm cDNA is expressed identical in Igsf domains as the Sec form. PBL is enriched in the Tm cDNA of these Igs. These molecular data suggest that cartilaginous fish have augmented their humoral immune repertoire by diversifying the sizes of their Ig isotypes. Furthermore, these Tm cDNAs are prototypical and the truncated variants may translate as more stable protein at the cell surface.

Measurement of serum amyloid A1 (SAA1), a major isotype of acute phase SAA.

PubMed

Xu, Yuanyuan; Yamada, Toshiyuki; Satoh, Takahiko; Okuda, Yasuaki

2006-01-01

Serum amyloid A (SAA), a plasma precursor of reactive amyloid deposits, is a multigene product. SAA1 and SAA2, with primary structures that are 93% identical (98 of 104 amino acids), behave as acute phase proteins, as demonstrated by their increasing levels in plasma. Heretofore, it has been understood that SAA1 predominates and functions as an isotype in plasma. However, accurate measurements differentiating the two isotypes have not been reported. In this study, using monoclonal antibodies specific for SAA1, we developed an enzyme-linked immunosorbent assay (ELISA) for SAA1. The levels and ratios of SAA1 in total SAA (TSAA) were investigated in healthy subjects and patients with rheumatoid arthritis (RA). The SAA1/TSAA ratio was 74 +/- 12% and 77 +/- 12% in healthy subjects and RA patients, respectively. In RA patients, the ratios were not influenced by SAA1 genotype, which has been proposed to affect plasma SAA values. The kinetics of SAA1 in inflamed patients undergoing hemodialysis was found to be parallel with total SAA and C-reactive protein. Finally, this study confirmed that SAA1 is a major isotype of acute phase SAA and may determine total SAA values. This specific assay could be used in the evaluation of SAA behavior in several clinical conditions.

In vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor and birth

PubMed Central

Gomez-Lopez, Nardhy; Romero, Roberto; Arenas-Hernandez, Marcia; Ahn, Hyunyoung; Panaitescu, Bogdan; Vadillo-Ortega, Felipe; Sanchez-Torres, Carmen; Salisbury, Katherine S; Hassan, Sonia S.

2016-01-01

PROBLEM Activated/effector T cells seem to play a role in the pathological inflammation associated with preterm labor. The aim of this study was to determine whether in vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor and birth. METHOD OF STUDY Pregnant B6 mice were intraperitoneally injected with a monoclonal αCD3ε antibody or its isotype control. The gestational age and the rates of preterm birth and pup mortality at birth, as well as the fetal heart rate and umbilical artery pulsatility index, were determined. RESULTS Injection of a monoclonal αCD3ε antibody led to preterm labor/birth [αCD3ε 83 ± 16.97% (10/12) vs. isotype 0% (0/8)], and increased the rate of pup mortality at birth [αCD3ε 87.30 ± 8.95% (77/85) vs. isotype 4.91 ± 4.34% (3/59)]. In addition, injection of a monoclonal αCD3ε antibody decreased the fetal heart rate and increased the umbilical artery pulsatility index when compared to isotype controls. CONCLUSION In vivo T-cell activation by a monoclonal αCD3ε antibody in late gestation induces preterm labor and birth. PMID:27658719

An H2A Histone Isotype, H2ac, Associates with Telomere and Maintains Telomere Integrity

PubMed Central

Tzeng, Tsai-Yu; Lin, I-Hsuan; Hsu, Ming-Ta

2016-01-01

Telomeres are capped at the ends of eukaryotic chromosomes and are composed of TTAGGG repeats bound to the shelterin complex. Here we report that a replication-dependent histone H2A isotype, H2ac, was associated with telomeres in human cells and co-immunoprecipitates with telomere repeat factor 2 (TRF2) and protection of telomeres protein 1 (POT1), whereas other histone H2A isotypes and mutations of H2ac did not bind to telomeres or these two proteins. The amino terminal basic domain of TRF2 was necessary for the association with H2ac and for the recruitment of H2ac to telomeres. Depletion of H2ac led to loss of telomeric repeat sequences, the appearance of dysfunctional telomeres, and chromosomal instability, including chromosomal breaks and anaphase bridges, as well as accumulation of telomere-associated DNA damage factors in H2ac depleted cells. Additionally, knockdown of H2ac elicits an ATM-dependent DNA damage response at telomeres and depletion of XPF protects telomeres against H2ac-deficiency-induced G-strand overhangs loss and DNA damage response, and prevents chromosomal instability. These findings suggest that the H2A isotype, H2ac, plays an essential role in maintaining telomere functional integrity. PMID:27228173

Effects of ambient stimuli on measures of behavioral state and microswitch use in adults with profound multiple impairments.

PubMed

Murphy, Kathleen M; Saunders, Muriel D; Saunders, Richard R; Olswang, Lesley B

2004-01-01

The effects of different types and amounts of environmental stimuli (visual and auditory) on microswitch use and behavioral states of three individuals with profound multiple impairments were examined. The individual's switch use and behavioral states were measured under three setting conditions: natural stimuli (typical visual and auditory stimuli in a recreational situation), reduced visual stimuli, and reduced visual and auditory stimuli. Results demonstrated differential switch use in all participants with the varying environmental setting conditions. No consistent effects were observed in behavioral state related to environmental condition. Predominant behavioral state scores and switch use did not systematically covary with any participant. Results suggest the importance of considering environmental stimuli in relationship to switch use when working with individuals with profound multiple impairments.

Multiple acousto-optic q-switch

DOEpatents

Deason, Vance A.

1993-01-01

An improved dynamic moire interferometer comprised of a lasing medium providing a plurality of beams of coherent light, a multiple q-switch producing multiple trains of 100,000 or more pulses per second, a combining means collimating multiple trains of pulses into substantially a single train and directing beams to specimen gratings affixed to a test material, and a controller, triggering and sequencing the emission of the pulses with the occurrence and recording of a dynamic loading event.

Multiple acousto-optic q-switch

DOEpatents

Deason, Vance A.

1993-12-07

An improved dynamic moire interferometer comprised of a lasing medium providing a plurality of beams of coherent light, a multiple q-switch producing multiple trains of 100,000 or more pulses per second, a combining means collimating multiple trains of pulses into substantially a single train and directing beams to specimen gratings affixed to a test material, and a controller, triggering and sequencing the emission of the pulses with the occurrence and recording of a dynamic loading event.

Cytokine Regulation Immunoglobulin Isotype Production

DTIC Science & Technology

1994-11-08

been shown to involve the activation of a newly di scovered subgroup of tyro sine kinases known as the Janus kinases (26 1 -270). Upon binding of IFN-r...indiCated reagents at dosages indiCated in Figure 1 . Culture supernatants were then harvested for determination of Ig isotype concentrations by ELISA ...Ig - immunoglobulin Iy2b - intronic gamma 2b regIOn IL - interleukin IP3 - inositol triphosphate XXlll JAK - Janus kinase LA P latency

Comparative modelling of human β tubulin isotypes and implications for drug binding

NASA Astrophysics Data System (ADS)

Torin Huzil, J.; Ludueña, Richard F.; Tuszynski, Jack

2006-02-01

The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.

Serodiagnosis of parasitic diseases.

PubMed Central

Maddison, S E

1991-01-01

In this review on serodiagnosis of parasitic diseases, antibody detection, antigen detection, use of monoclonal antibodies in parasitic serodiagnosis, molecular biological technology, and skin tests are discussed. The focus at the Centers for Disease Control on developing improved antigens, a truly quantitative FAST-enzyme-linked immunosorbent assay, and the very specific immunoblot assays for antibody detection is highlighted. The last two assays are suitable for field studies. Identification of patient response in terms of immunoglobulin class or immunoglobulin G subclass isotypes or both is discussed. Immunoglobulin isotypes may asist in defining the stage of some diseases. In other instances, use of a particular anti-isotype conjugate may increase the specificity of the assay. Monoclonal antibodies have played important roles in antigen purification and identification, in competitive antibody assays with increased sensitivity and specificity, and in assays for antigen detection in serum, body fluids, or excreta. Molecular biological technology has allowed significant advances in the production of defined parasitic serodiagnostic antigens. PMID:1747862

A generalized functional response for predators that switch between multiple prey species.

PubMed

van Leeuwen, E; Brännström, Å; Jansen, V A A; Dieckmann, U; Rossberg, A G

2013-07-07

We develop a theory for the food intake of a predator that can switch between multiple prey species. The theory addresses empirical observations of prey switching and is based on the behavioural assumption that a predator tends to continue feeding on prey that are similar to the prey it has consumed last, in terms of, e.g., their morphology, defences, location, habitat choice, or behaviour. From a predator's dietary history and the assumed similarity relationship among prey species, we derive a general closed-form multi-species functional response for describing predators switching between multiple prey species. Our theory includes the Holling type II functional response as a special case and makes consistent predictions when populations of equivalent prey are aggregated or split. An analysis of the derived functional response enables us to highlight the following five main findings. (1) Prey switching leads to an approximate power-law relationship between ratios of prey abundance and prey intake, consistent with experimental data. (2) In agreement with empirical observations, the theory predicts an upper limit of 2 for the exponent of such power laws. (3) Our theory predicts deviations from power-law switching at very low and very high prey-abundance ratios. (4) The theory can predict the diet composition of a predator feeding on multiple prey species from diet observations for predators feeding only on pairs of prey species. (5) Predators foraging on more prey species will show less pronounced prey switching than predators foraging on fewer prey species, thus providing a natural explanation for the known difficulties of observing prey switching in the field. Copyright © 2013 Elsevier Ltd. All rights reserved.

In vivo detection of peripherin-specific autoreactive B cells during type 1 diabetes pathogenesis1

PubMed Central

Garabatos, Nahir; Alvarez, Raimon; Carrillo, Jorge; Carrascal, Jorge; Izquierdo, Cristina; Chapman, Harold D.; Presa, Maximiliano; Mora, Conchi; Serreze, David V.; Verdaguer, Joan; Stratmann, Thomas

2014-01-01

Summary Autoreactive B cells are essential for the pathogenesis of type 1 diabetes. The genesis and dynamics of autoreactive B cells remain unknown. Here, we analyzed the immune response in the NOD mouse model to the neuronal protein peripherin (PRPH), a target antigen of islet-infiltrating B cells. PRPH autoreactive B cells recognized a single linear epitope of this protein, in contrast to the multiple epitope recognition commonly observed during autoreactive B cell responses. Autoantibodies to this epitope were also detected in the disease-resistant NOR and C57BL/6 strains. To specifically detect the accumulation of these B cells, we developed a novel approach, octameric peptide display, to follow the dynamics and localization of anti-PRPH B cell during disease progression. Before extended insulitis established, anti-PRPH B cells preferentially accumulated in the peritoneum. Anti-PRPH B cells were likewise detected in C57BL/6 mice, albeit at lower frequencies. As disease unfolded in NOD mice, anti-PRPH B cells invaded the islets and increased in number at the peritoneum of diabetic but not pre-diabetic mice. Isotype switched B cells were only detected in the peritoneum. Anti-PRPH B cells represent a heterogeneous population composed of both B1 and B2 subsets. In the spleen, anti-PRPH B cell were predominantly in the follicular subset. Therefore, anti-PRPH B cells represent a heterogeneous population that is generated early in life but proliferates as diabetes establishes. These findings on the temporal and spatial progression of autoreactive B cells should be relevant for our understanding of B cell function in diabetes pathogenesis. PMID:24610011

Small cell lymphocytic variant of marginal zone lymphoma: A distinct form of marginal zone lymphoma derived from naïve B cells as a cutaneous counterpart to the naïve marginal zone lymphoma of splenic origin.

PubMed

Magro, Cynthia M; Olson, Luke C

2018-02-21

Primary cutaneous marginal zone lymphoma most commonly represents an indolent form of cutaneous B cell lymphoma. However, epidermotropic marginal zone lymphoma, blastic marginal zone lymphoma and B cell dominant variants without isotype switching can be associated with extracutaneous dissemination. The presumptive cell of origin is a post germinal center B cell with plasmacytic features. In the extracutaneous setting, however, a naïve B cell origin has been proposed for a subset of marginal zone lymphomas, notably splenic marginal zone lymphoma. The author encountered 11 cases of atypical lymphocytic infiltration of the skin primarily occurring in older individuals with an upper arm and head and neck localization; there was a reproducible pattern of diffuse and nodular infiltration by small monomorphic-appearing B cells. Phenotypically, the infiltrate was one predominated by B cells exhibiting CD23 and IgD positivity without immunoreactivity for CD38 and there were either no plasma cells or only a few without light chain restriction. In cases presenting with a solitary lesion complete excision and/or radiation led to successful disease remission in all cases without recurrence or metastatic disease. Of three cases with multiple initial lesions, evidence of extracutaneous disease was seen in two cases and recurrence occurred in one case. No patients have died of lymphoma. Longer term follows up and additional cases are needed to determine if this subset of marginal zone lymphoma is associated with a worse prognosis. Copyright © 2018. Published by Elsevier Inc.

Ig synthesis and class switching do not require the presence of the hs4 enhancer in the 3' IgH regulatory region.

PubMed

Vincent-Fabert, Christelle; Truffinet, Véronique; Fiancette, Remi; Cogné, Nadine; Cogné, Michel; Denizot, Yves

2009-06-01

Several studies have reported that regulatory elements located 3' of the IgH locus (namely hs3a, hs1,2, hs3b, and hs4) might play a role during class switch recombination (CSR) and Ig synthesis. While individual deletion of hs3a or hs1,2 had no effect, pairwise deletion of hs3b (an inverted copy of hs3a) and hs4 markedly affected CSR and Ig expression. Among these two elements, hs4 was tentatively presented with the master role due to its unique status within the 3' regulatory region: distal position outside repeated regions, early activation in pre-B cells, strong activity throughout B cell ontogeny. To clarify its role, we generated mice with a clean deletion of the hs4 after replacement with a floxed neo(R) cassette. Surprisingly, and as for previous deletion of hs3a or hs1,2, deletion of hs4 did not affect either in vivo CSR or the secretion level of any Ig isotype. In vitro CSR and Ig secretion in response to LPS and cytokines was not affected either. The only noticeable effects of the hs4 deletion were a decrease in the number of B splenocytes and a decreased membrane IgM expression. In conclusion, while dispensable for CSR and Ig transcription in plasma cells, hs4 mostly appears to contribute to Ig transcription in resting B lymphocytes.

Biased immunoglobulin light chain gene usage in the shark1

PubMed Central

Iacoangeli, Anna; Lui, Anita; Naik, Ushma; Ohta, Yuko; Flajnik, Martin; Hsu, Ellen

2015-01-01

This study of a large family of kappa light (L) chain clusters in nurse shark completes the characterization of its classical immunoglobulin (Ig) gene content (two heavy chain classes, mu and omega, and four L chain isotopes, kappa, lambda, sigma, and sigma-2). The shark kappa clusters are minigenes consisting of a simple VL-JL-CL array, where V to J recombination occurs over a ~500 bp interval, and functional clusters are widely separated by at least 100 kb. Six out of ca. 39 kappa clusters are pre-rearranged in the germline (GL-joined). Unlike the complex gene organization and multistep assembly process of Ig in mammals, each shark Ig rearrangement, somatic or in the germline, appears to be an independent event localized to the minigene. This study examined the expression of functional, non-productive, and sterile transcripts of the kappa clusters compared to the other three L chain isotypes. Kappa cluster usage was investigated in young sharks, and a skewed pattern of split gene expression was observed, one similar in functional and non-productive rearrangements. These results show that the individual activation of the spatially distant kappa clusters is non-random. Although both split and GL-joined kappa genes are expressed, the latter are prominent in young animals and wane with age. We speculate that, in the shark, the differential activation of the multiple isotypes can be advantageously used in receptor editing. PMID:26342033

Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus

PubMed Central

Hawke, Christine G; Painter, Dorothy M; Kirwan, Paul D; Van Driel, Rosemary R; Baxter, Alan G

2003-01-01

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model. PMID:12519305

p-p Heterojunction of Nickel Oxide-Decorated Cobalt Oxide Nanorods for Enhanced Sensitivity and Selectivity toward Volatile Organic Compounds.

PubMed

Suh, Jun Min; Sohn, Woonbae; Shim, Young-Seok; Choi, Jang-Sik; Song, Young Geun; Kim, Taemin L; Jeon, Jong-Myeong; Kwon, Ki Chang; Choi, Kyung Soon; Kang, Chong-Yun; Byun, Hyung-Gi; Jang, Ho Won

2018-01-10

The utilization of p-p isotype heterojunctions is an effective strategy to enhance the gas sensing properties of metal-oxide semiconductors, but most previous studies focused on p-n heterojunctions owing to their simple mechanism of formation of depletion layers. However, a proper choice of isotype semiconductors with appropriate energy bands can also contribute to the enhancement of the gas sensing performance. Herein, we report nickel oxide (NiO)-decorated cobalt oxide (Co 3 O 4 ) nanorods (NRs) fabricated using the multiple-step glancing angle deposition method. The effective decoration of NiO on the entire surface of Co 3 O 4 NRs enabled the formation of numerous p-p heterojunctions, and they exhibited a 16.78 times higher gas response to 50 ppm of C 6 H 6 at 350 °C compared to that of bare Co 3 O 4 NRs with the calculated detection limit of approximately 13.91 ppb. Apart from the p-p heterojunctions, increased active sites owing to the changes in the orientation of the exposed lattice surface and the catalytic effects of NiO also contributed to the enhanced gas sensing properties. The advantages of p-p heterojunctions for gas sensing applications demonstrated in this work will provide a new perspective of heterostructured metal-oxide nanostructures for sensitive and selective gas sensing.

A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?

PubMed

Perwein, Maria K; Smestad, John A; Warrington, Arthur E; Heider, Robin M; Kaczor, Mark W; Maher, Louis J; Wootla, Bharath; Kunbaz, Ahmad; Rodriguez, Moses

2018-05-01

Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions. Areas covered: We discuss the history and development of natural human IgM-isotype immunoglobulins (HIgMs) and recently-identified aptamer-conjugates that have been shown to enhance endogenous myelin repair in animal models of demyelination by acting on myelin-producing oligodendrocytes (OLs) or oligodendrocyte progenitor cells (OPCs) within CNS lesions. We also discuss future development aims and applications for these important novel technologies. Expert opinion: Aptamer conjugate Myaptavin-3064 and recombinant human IgM-isotype antibody rHIgM22 regenerate CNS myelin, thereby reducing axonal degeneration and offering the potential of recovery from MS relapses, reversal of disability and prevention of disease progression. Advancement of these technologies into the clinic for MS treatment is therefore a top priority. It remains unclear to what extent the therapeutic modalities of remyelinating antibodies and aptamers may synergize with other currently-approved therapies to yield enhanced therapeutic effects.

A biotin-drug extraction and acid dissociation (BEAD) procedure to eliminate matrix and drug interference in a protein complex anti-drug antibody (ADA) isotype specific assay.

PubMed

Niu, Hongmei; Klem, Thomas; Yang, Jinsong; Qiu, Yongchang; Pan, Luying

2017-07-01

Monitoring anti-drug antibody (ADA) responses in patients receiving protein therapeutics treatment is an important safety assessment for regulatory agencies, drug manufacturers, clinicians and patients. Recombinant human IGF-1/IGFBP-3 (rhIGF-1/rhIGFBP-3) is a 1:1 formulation of naturally occurring protein complex. The individual IGF-1 and IGFBP-3 proteins have multiple binding partners in serum matrix with high binding affinity to each other, which presents challenges in ADA assay development. We have developed a biotin-drug extraction with acid dissociation (BEAD) procedure followed by an electrochemiluminescence (ECL) direct assay to overcome matrix and drug interference. The method utilizes two step acid dissociation and excess biotin-drug to extract total ADA, which are further captured by soluble biotin-drug and detected in an ECL semi-homogeneous direct assay format. The pre-treatment method effectively eliminates interference by serum matrix and free drug, and enhances assay sensitivity. The assays passed acceptance criteria for all validation parameters, and have been used for clinical sample Ab testing. This method principle exemplifies a new approach for anti-isotype ADA assays, and could be an effective strategy for neutralizing antibody (NAb), pharmacokinetic (PK) and biomarker analysis in need of overcoming interference factors. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of automation and task load on task switching during human supervision of multiple semi-autonomous robots in a dynamic environment.

PubMed

Squire, P N; Parasuraman, R

2010-08-01

The present study assessed the impact of task load and level of automation (LOA) on task switching in participants supervising a team of four or eight semi-autonomous robots in a simulated 'capture the flag' game. Participants were faster to perform the same task than when they chose to switch between different task actions. They also took longer to switch between different tasks when supervising the robots at a high compared to a low LOA. Task load, as manipulated by the number of robots to be supervised, did not influence switch costs. The results suggest that the design of future unmanned vehicle (UV) systems should take into account not simply how many UVs an operator can supervise, but also the impact of LOA and task operations on task switching during supervision of multiple UVs. The findings of this study are relevant for the ergonomics practice of UV systems. This research extends the cognitive theory of task switching to inform the design of UV systems and results show that switching between UVs is an important factor to consider.

Multimodal information Management: Evaluation of Auditory and Haptic Cues for NextGen Communication Displays

NASA Technical Reports Server (NTRS)

Begault, Durand R.; Bittner, Rachel M.; Anderson, Mark R.

2012-01-01

Auditory communication displays within the NextGen data link system may use multiple synthetic speech messages replacing traditional ATC and company communications. The design of an interface for selecting amongst multiple incoming messages can impact both performance (time to select, audit and release a message) and preference. Two design factors were evaluated: physical pressure-sensitive switches versus flat panel "virtual switches", and the presence or absence of auditory feedback from switch contact. Performance with stimuli using physical switches was 1.2 s faster than virtual switches (2.0 s vs. 3.2 s); auditory feedback provided a 0.54 s performance advantage (2.33 s vs. 2.87 s). There was no interaction between these variables. Preference data were highly correlated with performance.

Experimental demonstration of tunable multiple optical orthogonal codes sequences-based optical label for optical packets switching

NASA Astrophysics Data System (ADS)

Zhang, Chongfu; Qiu, Kun; Zhou, Heng; Ling, Yun; Wang, Yawei; Xu, Bo

2010-03-01

In this paper, the tunable multiple optical orthogonal codes sequences (MOOCS)-based optical label for optical packet switching (OPS) (MOOCS-OPS) is experimentally demonstrated for the first time. The tunable MOOCS-based optical label is performed by using fiber Bragg grating (FBG)-based optical en/decoders group and optical switches configured by using Field Programmable Gate Array (FPGA), and the optical label is erased by using Semiconductor Optical Amplifier (SOA). Some waveforms of the MOOCS-based optical label, optical packet including the MOOCS-based optical label and the payloads are obtained, the switching control mechanism and the switching matrix are discussed, the bit error rate (BER) performance of this system is also studied. These experimental results show that the tunable MOOCS-OPS scheme is effective.

A Josephson Junction based SPDT switch

NASA Astrophysics Data System (ADS)

Zhang, Helin; Earnest, Nathan; Lu, Yao; Ma, Ruichao; Chakram, Srivatsan; Schuster, David

RF microwave switches are useful tools in cryogenic experiments, allowing for multiple experiments to be connected to a single cryogenic measurement chain. However, these switches dissipate a substantial amount of heat, preventing fast switching. Josephson junction (JJ) are a promising avenue for realizing millikelvin microwave switching. We present a JJ based single-pole-double throw (SPDT) switch that has fast switching time, no heat dissipation, large on/off contrast, and works over a wide bandwidth. The switch can be used for real-time switching between experiments, routing single photons, or even generating entanglement. We will describe the design of the switch and present experimental characterization of its performance.

Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice.

PubMed Central

Zhou, X; Paulsson, G; Stemme, S; Hansson, G K

1998-01-01

Atherosclerosis is an inflammatory-fibrotic response to accumulation of cholesterol in the artery wall. In hypercholesterolemia, low density lipoproteins (LDL) accumulate and are oxidized to proinflammatory compounds in the arterial intima, leading to activation of endothelial cells, macrophages, and T lymphocytes. We have studied immune cell activation and the autoimmune response to oxidized LDL in atherosclerotic apo E-knockout mice. Autoantibodies to oxidized LDL exhibited subclass specificities indicative of T cell help, and the increase in antibody titers in peripheral blood was associated with increased numbers of cytokine-expressing T cells in the spleen. In addition to T cell-dependent antibodies, IgM antibodies to oxidized LDL were also increased in apo E-knockout mice. This suggests that both T cell-dependent and T cell-independent epitopes may be present on oxidized LDL. In moderate hypercholesterolemia, IgG antibodies were largely of the IgG2a isotype, suggesting that T cell help was provided by proinflammatory T helper (Th) 1 cells, which are prominent components of atherosclerotic lesions. In severe hypercholesterolemia induced by cholesterol feeding of apo E-knockout mice, a switch to Th2-dependent help was evident. It was associated with a loss of IFN-gamma-producing Th1 cells in the spleen, whereas IL-4-producing Th2 cells were more resistant to hypercholesterolemia. IFN-gamma but not IL-4 mRNA was detected in atherosclerotic lesions of moderately hypercholesterolemic apo E-knockout mice, but IL-4 mRNA appeared in the lesions when mice were made severely hypercholesterolemic by cholesterol feeding. These data show that IFN-gamma-producing Th1 cells infiltrate atherosclerotic lesions and provide T cell help for autoimmune responses to oxidized LDL in apo E-knockout mice. However, severe hypercholesterolemia is associated with a switch from Th1 to Th2, which results not only in the formation of IgG1 autoantibodies to oxidized LDL, but also in the appearance of Th2-type cytokines in the atherosclerotic lesions. Since the two subsets of T cells counteract each other, this switch may have important consequences for the inflammatory/immune process in atherosclerosis. PMID:9541503

Molecular analysis of immunoglobulin variable genes supports a germinal center experienced normal counterpart in primary cutaneous diffuse large B-cell lymphoma, leg-type.

PubMed

Pham-Ledard, Anne; Prochazkova-Carlotti, Martina; Deveza, Mélanie; Laforet, Marie-Pierre; Beylot-Barry, Marie; Vergier, Béatrice; Parrens, Marie; Feuillard, Jean; Merlio, Jean-Philippe; Gachard, Nathalie

2017-11-01

Immunophenotype of primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL-LT) suggests a germinal center-experienced B lymphocyte (BCL2+ MUM1+ BCL6+/-). As maturation history of B-cell is "imprinted" during B-cell development on the immunoglobulin gene sequence, we studied the structure and sequence of the variable part of the genes (IGHV, IGLV, IGKV), immunoglobulin surface expression and features of class switching in order to determine the PCLBCL-LT cell of origin. Clonality analysis with BIOMED2 protocol and VH leader primers was done on DNA extracted from frozen skin biopsies on retrospective samples from 14 patients. The clonal DNA IGHV sequence of the tumor was aligned and compared with the closest germline sequence and homology percentage was calculated. Superantigen binding sites were studied. Features of selection pressure were evaluated with the multinomial Lossos model. A functional monoclonal sequence was observed in 14 cases as determined for IGHV (10), IGLV (2) or IGKV (3). IGV mutation rates were high (>5%) in all cases but one (median:15.5%), with superantigen binding sites conservation. Features of selection pressure were identified in 11/12 interpretable cases, more frequently negative (75%) than positive (25%). Intraclonal variation was detected in 3 of 8 tumor specimens with a low rate of mutations. Surface immunoglobulin was an IgM in 12/12 cases. FISH analysis of IGHM locus, deleted during class switching, showed heterozygous IGHM gene deletion in half of cases. The genomic PCR analysis confirmed the deletions within the switch μ region. IGV sequences were highly mutated but functional, with negative features of selection pressure suggesting one or more germinal center passage(s) with somatic hypermutation, but superantigen (SpA) binding sites conservation. Genetic features of class switch were observed, but on the non functional allele and co-existing with primary isotype IgM expression. These data suggest that cell-of origin is germinal center experienced and superantigen driven selected B-cell, in a stage between germinal center B-cell and plasma cell. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Correlated Template-Switching Events during Minus-Strand DNA Synthesis: a Mechanism for High Negative Interference during Retroviral Recombination

PubMed Central

Anderson, Jeffrey A.; Teufel, Ronald J.; Yin, Philip D.; Hu, Wei-Shau

1998-01-01

Two models for the mechanism of retroviral recombination have been proposed: forced copy choice (minus-strand recombination) and strand displacement-assimilation (plus-strand recombination). Each minus-strand recombination event results in one template switch, whereas each plus-strand recombination event results in two template switches. Recombinant proviruses with one and more than one template switches were previously observed. Recombinants with one template switch were generated by minus-strand recombination, while recombinants containing more than one template switch may have been generated by plus-strand recombination or by correlated minus-strand recombination. We recently observed that retroviral recombination exhibits high negative interference whereby the frequency of recombinants containing multiple template-switching events is higher than expected. To delineate the mechanism that generates recombinants with more than one template switch, we devised a system that permits only minus-strand recombination. Two highly homologous vectors, WH204 and WH221, containing eight different restriction site markers were used. The primer binding site (PBS) of WH221 was deleted; although reverse transcription cannot initiate from WH221 RNA, it can serve as a template for DNA synthesis in heterozygotic virions. After one round of retroviral replication, the structures of the recombinant proviruses were examined. Recombinants containing two, three, four, and five template switches were observed at 1.4-, 10-, 65-, and 50-fold-higher frequencies, respectively, than expected. This indicates that minus-strand recombination events are correlated and can generate proviruses with multiple template switches efficiently. The frequencies of recombinants containing multiple template switches were similar to those observed in the previous system, which allowed both minus- and plus-strand recombination. Thus, the previously reported high negative interference during retroviral recombination can be caused by correlated template switches during minus-strand DNA synthesis. In addition, all examined recombinants contained an intact PBS, indicating that most of the plus-strand DNA transfer occurs after completion of the strong-stop DNA. PMID:9445017

Axonal transport of class II and III beta-tubulin: evidence that the slow component wave represents the movement of only a small fraction of the tubulin in mature motor axons

PubMed Central

1992-01-01

Pulse-labeling studies demonstrate that tubulin synthesized in the neuron cell body (soma) moves somatofugally within the axon (at a rate of several millimeters per day) as a well-defined wave corresponding to the slow component of axonal transport. A major goal of the present study was to determine what proportion of the tubulin in mature motor axons is transported in this wave. Lumbar motor neurons in 9-wk-old rats were labeled by injecting [35S]methionine into the spinal cord 2 wk after motor axons were injured (axotomized) by crushing the sciatic nerve. Immunoprecipitation with mAbs which recognize either class II or III beta-tubulin were used to analyze the distributions of radioactivity in these isotypes in intact and axotomized motor fibers 5 d after labeling. We found that both isotypes were associated with the slow component wave, and that the leading edge of this wave was enriched in the class III isotype. Axotomy resulted in significant increases in the labeling and transport rates of both isotypes. Immunohistochemical examination of peripheral nerve fibers demonstrated that nearly all of the class II and III beta-tubulin in nerve fibers is located within axons. Although the amounts of radioactivity per millimeter of nerve in class II and III beta-tubulin were significantly greater in axotomized than in control nerves (with increases of +160% and +58%, respectively), immunoassay revealed no differences in the amounts of these isotypes in axotomized and control motor fibers. We consider several explanations for this paradox; these include the possibility that the total tubulin content is relatively insensitive to changes in the amount of tubulin transported in the slow component wave because this wave represents the movement of only a small fraction of the tubulin in these motor fibers. PMID:1383234

Longitudinal Monitoring of Antibody Responses against Tumor Cells Using Magneto-nanosensors with a Nanoliter of Blood.

PubMed

Lee, Jung-Rok; Chan, Carmel T; Ruderman, Daniel; Chuang, Hui-Yen; Gaster, Richard S; Atallah, Michelle; Mallick, Parag; Lowe, Scott W; Gambhir, Sanjiv S; Wang, Shan X

2017-11-08

Each immunoglobulin isotype has unique immune effector functions. The contribution of these functions in the elimination of pathogens and tumors can be determined by monitoring quantitative temporal changes in isotype levels. Here, we developed a novel technique using magneto-nanosensors based on the effect of giant magnetoresistance (GMR) for longitudinal monitoring of total and antigen-specific isotype levels with high precision, using as little as 1 nL of serum. Combining in vitro serologic measurements with in vivo imaging techniques, we investigated the role of the antibody response in the regression of firefly luciferase (FL)-labeled lymphoma cells in spleen, kidney, and lymph nodes in a syngeneic Burkitt's lymphoma mouse model. Regression status was determined by whole body bioluminescent imaging (BLI). The magneto-nanosensors revealed that anti-FL IgG2a and total IgG2a were elevated and sustained in regression mice compared to non-regression mice (p < 0.05). This platform shows promise for monitoring immunotherapy, vaccination, and autoimmunity.

Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling.

PubMed

Essop, M Faadiel; Razeghi, Peter; McLeod, Chris; Young, Martin E; Taegtmeyer, Heinrich; Sack, Michael N

2004-02-06

Mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) are postulated to contribute to antioxidant defense, nutrient partitioning, and energy efficiency in the heart. To distinguish isotype function in response to metabolic stress we measured cardiac mitochondrial function and cardiac UCP gene expression following chronic hypobaric hypoxia. Isolated mitochondrial O(2) consumption and ATP synthesis rate were reduced but respiratory coupling was unchanged compared to normoxic groups. Concurrently, left ventricular UCP3 mRNA levels were significantly decreased with hypoxia (p<0.05) while UCP2 levels remained unchanged versus controls. Diminished UCP3 expression was associated with coordinate regulation of counter-regulatory metabolic genes. From these data, we propose a role for UCP3 in the regulation of fatty acid oxidation in the heart as opposed to uncoupling of mitochondria. Moreover, the divergent hypoxia-induced regulation of UCP2 and UCP3 supports distinct mitochondrial regulatory functions of these inner mitochondrial membrane proteins in the heart in response to metabolic stress.

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

PubMed Central

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions. PMID:29109730

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection.

PubMed

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

Systemic antibodies administered by passive immunization prevent generalization of the infection by foot-and-mouth disease virus in cattle after oronasal challenge.

PubMed

Barrionuevo, Florencia; Di Giacomo, Sebastián; Bucafusco, Danilo; Ayude, Andrea; Schammas, Juan; Miraglia, M Cruz; Capozzo, Alejandra; Borca, Manuel V; Perez-Filgueira, Mariano

2018-05-01

The role of passively transferred sera in the protection against aerogenous foot-and-mouth disease (FMD) virus infection in cattle was evaluated using vaccine-induced immune serum preparations obtained at 7 and 26 days post-vaccination (dpv). We showed that circulating antibodies were sufficient to prevent disease generalization after oronasal infection in animals passively transferred with 26-dpv serum but not with the 7-dpv serum. Conversely, conventional FMD vaccination provided clinical protection at 7 dpv, promoting fast and robust antibody responses upon challenge and even though antibody titers were similar to those found in animals passively immunized with 7-dpv serum. These results demonstrate that presence of antigen-specific antibodies is critical to prevent the dissemination of the virus within the animal. Conventional FMD vaccination additionally promoted the deployment of rapid, high titer and isotype-switched antibody responses at systemic and mucosal levels after infection, thus conferring protection even in the presence of low pre-challenge antibody titers. Copyright © 2018 Elsevier Inc. All rights reserved.

Transient immune deficiency in patients with acute Epstein-Barr virus infection.

PubMed

Junker, A K; Ochs, H D; Clark, E A; Puterman, M L; Wedgwood, R J

1986-09-01

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage phi X174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying Ia and T8 (CD8) phenotypes was increased and the T helper/suppressor (T4/T8) ratio was decreased (less than 1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage phi X174 both in vivo and in vitro. In vitro coculture experiments indicated that the Ia+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+ lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infectious mononucleosis.

Selective control of multiple ferroelectric switching pathways using a trailing flexoelectric field

NASA Astrophysics Data System (ADS)

Park, Sung Min; Wang, Bo; Das, Saikat; Chae, Seung Chul; Chung, Jin-Seok; Yoon, Jong-Gul; Chen, Long-Qing; Yang, Sang Mo; Noh, Tae Won

2018-05-01

Flexoelectricity is an electromechanical coupling between electrical polarization and a strain gradient1 that enables mechanical manipulation of polarization without applying an electrical bias2,3. Recently, flexoelectricity was directly demonstrated by mechanically switching the out-of-plane polarization of a uniaxial system with a scanning probe microscope tip3,4. However, the successful application of flexoelectricity in low-symmetry multiaxial ferroelectrics and therefore active manipulation of multiple domains via flexoelectricity have not yet been achieved. Here, we demonstrate that the symmetry-breaking flexoelectricity offers a powerful route for the selective control of multiple domain switching pathways in multiaxial ferroelectric materials. Specifically, we use a trailing flexoelectric field that is created by the motion of a mechanically loaded scanning probe microscope tip. By controlling the SPM scan direction, we can deterministically select either stable 71° ferroelastic switching or 180° ferroelectric switching in a multiferroic magnetoelectric BiFeO3 thin film. Phase-field simulations reveal that the amplified in-plane trailing flexoelectric field is essential for this domain engineering. Moreover, we show that mechanically switched domains have a good retention property. This work opens a new avenue for the deterministic selection of nanoscale ferroelectric domains in low-symmetry materials for non-volatile magnetoelectric devices and multilevel data storage.

Regulation of Aicda expression and AID activity

PubMed Central

ZAN, HONG; CASALI, PAOLO

2013-01-01

Activation-induced cytidine deaminase (AID) is expressed in a B cell differentiation stage-specific fashion and is essential for immunoglobulin (Ig) gene class switch DNA recombination (CSR) and somatic hypermutation (SHM). CSR and SHM play a central role in the maturation of antibody and autoantibody responses. AID displays a mutagenic activity by catalyzing targeted deamination of deoxycytidine (dC) residues in DNA resulting in dU:dG mismatches, which are processed into point-mutations in SHM or double-strand breaks (DSBs) in CSR. Although AID specifically targets the Ig gene loci (IgH, Igκ and Igλ), it can also home into a wide array of non-Ig genes in B- and non-B-cell backgrounds. Aberrant expression of AID is associated with multiple diseases such as allergy, inflammation, autoimmunity and cancer. In autoimmune systemic lupus erythematosus, dysregulated AID expression underpins increased CSR, SHM and autoantibody production. As a potent mutator, AID is under stringent transcriptional, post-transcriptional and post-translational regulation. AID is also regulated in its targeting and enzymatic function. In resting naïve or memory B cells, AID transcripts and protein are undetectable. These, however, are readily and significantly upregulated in B cells induced to undergo CSR and/or SHM. Transcription factors, such as HoxC4 and NF-κB, which are upregulated in a B cell lineage- and/or differentiation stage-specific manner, regulate the induction of AID. HoxC4 induces AID expression by directly binding to the AID gene promoter through an evolutionarily conserved 5’-ATTT-3’ motif. HoxC4 is induced by the same stimuli that induce AID and CSR. It is further upregulated by estrogen through three estrogen responsive elements in its promoter region. The targeting of AID to switch (S) regions is mediated by 14-3-3 adaptor proteins, which specifically bind to 5′-AGCT-3′ repeats that are exist at high frequency in S region cores. Like HoxC4, 14-3-3 adaptors are induced by the same stimuli that induce AID. These include “primary” inducing stimuli, that is, those that play a major role in inducing AID, i.e., engagement of CD40 by CD154, engagement of Toll-like receptors (TLRs) by microbial-associated molecular patterns (MAMPs) and cross-linking of the BCR, as synergized by “secondary” inducing stimuli, that is, those that synergize for AID induction and specify CSR to different isotypes, i.e., switch-directing cytokines IL-4, TGF-β or IFN-γ. In this review, we focus on the multi-levels regulation of AID expression and activity. We also discuss the dysregulation or misexpression of AID in autoimmunity and tumorigenesis. PMID:23181381

Metal-Free Multiple Carbon-Carbon and Carbon-Hydrogen Bond Activations via Charge-Switching Mechanism in Unstrained Diindolylmethanes.

PubMed

Challa, Chandrasekhar; Varughese, Sunil; Suresh, Cherumuttathu H; Lankalapalli, Ravi S

2017-08-18

A transformation of the unstrained phenol substituted 3,3'-diindolylmethanes (DIPMs) to 2,3'-diindolylketones (DIKs) by double C-C single bond cleavage with associated rearrangements, triggered by phenyliodine(III) diacetate (PIDA), is reported. Density functional theory studies reveal a mechanism involving multiple "charge-switching" steps by synergistic involvement of the two indole units with overall low activation energy. The indole 'charge-switching' mechanism in DIPMs was further extended toward synthesis of a natural product motif cyclohepta[b]indole from biaryl appended DIBM.

Peruvian Maca: Two Scientific Names Lepidium Meyenii Walpers and Lepidium Peruvianum Chacon – Are They Phytochemically-Synonymous?

PubMed Central

Meissner, Henry O.; Mscisz, Alina; Kedzia, Bogdan; Pisulewski, Pawel; Piatkowska, Ewa

2015-01-01

Using Liquid Chromatography-Mass Spectrometry (LCMS) , profiles of the two isotypes labelled under the same common name Maca deposited in the Medicinal Plant Herbarium, in Australia and Poland, but identified under two different scientific names Lepidium meyenii Walpers (L. meyenii) and Lepidium peruvianum Chacon (L. peruvianum) are presented. The two isotypes correspond to two holotypes of Peruvian medicinal herb known under the same common name “Maca”, as originally deposited in the Herbarium of San Marcos University in Lima, Peru dated back to 1843 and 1990 respectively. The results demonstrate distinct differences in taxonomy, visual appearance, phytochemical profiles and DNA sequences of the two researched Maca isotypes, suggesting that the two Maca specimens are dissimilar and formal use of the term “synonymous” to L. meyenii and L. peruvianum may be misleading. On the basis of presented results the scientific name L. meyenii, used since 1843 up-today for cultivated Peruvian Maca by numerous reference sources worldwide, including Regulatory Bodies in the USA, EU, Australia and most lately in China, appears to be used in error and should be formally revised. It is concluded, that the isotype of cultivated Peruvian Maca labelled under its scientific name Lepidium peruvianum Chacon, provides all the characteristics peculiar to this historically-documented herb grown in Andean highlands, which may be linked to its traditional use and accepted functionality, confirmed in recent clinical study to be relevant to its present day use for expected dietary, therapeutic and health benefits.

Switching Matrix For Optical Signals

NASA Technical Reports Server (NTRS)

Grove, Charles H.

1990-01-01

Proposed matrix of electronically controlled shutters switches signals in optical fibers between multiple input and output channels. Size, weight, and power consumption reduced. Device serves as building block for small, low-power, broad-band television- and data-signal-switching systems providing high isolation between nominally disconnected channels.

Development of a microwave 20 x 20 switch matrix for 30/20 GHz SS-TDMA application

NASA Technical Reports Server (NTRS)

Cory, B. J.; Berkowitz, M.; Wallis, R.; Schiavone, A.; Shieh, D.; Campbell, J.

1982-01-01

The design and fabrication of a 3-8 GHz, 20 x 20 Satellite Switched-Time Division Multiple Access IF switch matrix applicable to a 30/20 GHz communications satellite are described. An assessment of switch architecture in 1980 concluded that the GaAs FET-based coupled crossbar switch matrix, incorporating high speed CMOS LSI logic for switch crosspoint addressing, would be the optimum technology available for communications satellite switching by 1982. This assessment was based on such factors as switching speed, bandwidth, off-state isolation, and reliability, over a 10-year mission life. A proof-of-concept model's construction and testing are presented.

High-power microwave generation using optically activated semiconductor switches

NASA Astrophysics Data System (ADS)

Nunnally, William C.

1990-12-01

The two prominent types of optically controlled switches, the optically controlled linear (OCL) switch and the optically initiated avalanche (OIA) switch, are described, and their operating parameters are characterized. Two transmission line approaches, one using a frozen-wave generator and the other using an injected-wave generator, for generation of multiple cycles of high-power microwave energy using optically controlled switches are discussed. The point design performances of the series-switch, frozen-wave generator and the parallel-switch, injected-wave generator are compared. The operating and performance limitations of the optically controlled switch types are discussed, and additional research needed to advance the development of the optically controlled, bulk, semiconductor switches is indicated.

Packet communications in satellites with multiple-beam antennas and signal processing

NASA Technical Reports Server (NTRS)

Davies, R.; Chethik, F.; Penick, M.

1980-01-01

A communication satellite with a multiple-beam antenna and onboard signal processing is considered for use in a 'message-switched' data relay system. The signal processor may incorporate demodulation, routing, storage, and remodulation of the data. A system user model is established and key functional elements for the signal processing are identified. With the throughput and delay requirements as the controlled variables, the hardware complexity, operational discipline, occupied bandwidth, and overall user end-to-end cost are estimated for (1) random-access packet switching; and (2) reservation-access packet switching. Other aspects of this network (eg, the adaptability to channel switched traffic requirements) are examined. For the given requirements and constraints, the reservation system appears to be the most attractive protocol.

KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry

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

Lu, Jia; Harrison, Rane A.; Li, Lianbo

KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basismore » for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.« less

Proton-Controlled Organic Microlaser Switch.

PubMed

Gao, Zhenhua; Zhang, Wei; Yan, Yongli; Yi, Jun; Dong, Haiyun; Wang, Kang; Yao, Jiannian; Zhao, Yong Sheng

2018-05-25

Microscale laser switches have been playing irreplaceable roles in the development of photonic devices with high integration levels. However, it remains a challenge to switch the lasing wavelengths across a wide range due to relatively fixed energy bands in traditional semiconductors. Here, we report a strategy to switch the lasing wavelengths among multiple states based on a proton-controlled intramolecular charge-transfer (ICT) process in organic dye-doped flexible microsphere resonant cavities. The protonic acids can effectively bind onto the ICT molecules, which thus enhance the ICT strength of the dyes and lead to a red-shifted gain behavior. On this basis, the gain region was effectively modulated by using acids with different proton-donating ability, and as a result, laser switching among multiple wavelengths was achieved. The results will provide guidance for the rational design of miniaturized lasers with performances based on the characteristic of organic optoelectronic materials.

Isotype analysis of the anti-CENP-B anticentromere autoantibody: evidence for restricted clonality.

PubMed

Eisenberg, R A; Earnshaw, W C; Bordwell, B J; Craven, S Y; Cheek, R; Rothfield, N F

1989-10-01

Utilizing the centromere B fusion protein (CENP-B) and specific, matched monoclonal antiisotype reagents in an enzyme-linked immunosorbent assay, we found that anti-CENP-B autoantibodies were skewed to the IgG1 isotype. The overall kappa:lambda light chain ratio was 2:1, although several individual sera showed a strong predominance of one of the light chains. Isoelectric focusing of light chain-skewed sera showed polyclonal patterns. Our findings are consistent with the anti-CENP-B autoantibody response being a chronic, antigen-driven response.

Optimization of micromachined membrane switches

NASA Astrophysics Data System (ADS)

Hiltmann, Kai; Lang, Walter

1997-09-01

We have determined the minimum dimensions for micromachined membrane switches in several experiments, both regarding the strength of the membranes themselves and the elongations required for safe switching performance. Based on these data, pressure switches for voltages of 10 - 100 V were made as single and multiple elements and tested. Test results, with scatter of pressure threshold data in the ten per cent range, prove very encouraging for further development.

Adaptive Backstepping-Based Neural Tracking Control for MIMO Nonlinear Switched Systems Subject to Input Delays.

PubMed

Niu, Ben; Li, Lu

2018-06-01

This brief proposes a new neural-network (NN)-based adaptive output tracking control scheme for a class of disturbed multiple-input multiple-output uncertain nonlinear switched systems with input delays. By combining the universal approximation ability of radial basis function NNs and adaptive backstepping recursive design with an improved multiple Lyapunov function (MLF) scheme, a novel adaptive neural output tracking controller design method is presented for the switched system. The feature of the developed design is that different coordinate transformations are adopted to overcome the conservativeness caused by adopting a common coordinate transformation for all subsystems. It is shown that all the variables of the resulting closed-loop system are semiglobally uniformly ultimately bounded under a class of switching signals in the presence of MLF and that the system output can follow the desired reference signal. To demonstrate the practicability of the obtained result, an adaptive neural output tracking controller is designed for a mass-spring-damper system.

Next generation communications satellites: Multiple access and network studies

NASA Technical Reports Server (NTRS)

Stern, T. E.; Schwartz, M.; Meadows, H. E.; Ahmadi, H. K.; Gadre, J. G.; Gopal, I. S.; Matsmo, K.

1980-01-01

Following an overview of issues involved in the choice of promising system architectures for efficient communication with multiple small inexpensive Earth stations serving hetergeneous user populations, performance evaluation via analysis and simulation for six SS/TDMA (satellite-switched/time-division multiple access) system architectures is discussed. These configurations are chosen to exemplify the essential alternatives available in system design. Although the performance evaluation analyses are of fairly general applicability, whenever possible they are considered in the context of NASA's 30/20 GHz studies. Packet switched systems are considered, with the assumption that only a part of transponder capacit is devoted to packets, the integration of circuit and packet switched traffic being reserved for further study. Three types of station access are distinguished: fixed (FA), demand (DA), and random access (RA). Similarly, switching in the satellite can be assigned on a fixed (FS) or demand (DS) basis, or replaced by a buffered store-and-forward system (SF) onboard the satellite. Since not all access/switching combinations are practical, six systems are analyzed in detail: three FS SYSTEMS, FA/FS, DA/ES, RA/FS; one DS system, DA/DS; and two SF systems, FA/SF, DA/SF. Results are presented primarily in terms of delay-throughput characteristics.

Megavolt, Multigigawatt Pulsed Plasma Switch

NASA Technical Reports Server (NTRS)

Lee, Ja H.; Choi, Sang H.; Song, Kyo D.

1996-01-01

Plasma switch proposed for use in high-voltage, high-current pulse power system. Designed not only to out-perform conventional spark-gap switch but also relatively compact and lightweight. Features inverse-pinch configuration to prevent constriction of current sheets into filaments, plus multiple-ring-electrode structure to resist high-voltage breakdown.

Multi-megavolt low jitter multistage switch

DOEpatents

Humphreys, D.R.; Penn, K.J. Jr.

1985-06-19

It is one object of the present invention to provide a multistage switch capable of holding off numerous megavolts, until triggered, from a particle beam accelerator of the type used for inertial confinement fusion. The invention provides a multistage switch having low timing jitter and capable of producing multiple spark channels for spreading current over a wider area to reduce electrode damage and increase switch lifetime. The switch has fairly uniform electric fields and a short spark gap for laser triggering and is engineered to prevent insulator breakdowns.

The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms.

PubMed

Risinger, April L; Jackson, Evelyn M; Polin, Lisa A; Helms, Gregory L; LeBoeuf, Desiree A; Joe, Patrick A; Hopper-Borge, Elizabeth; Ludueña, Richard F; Kruh, Gary D; Mooberry, Susan L

2008-11-01

The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein (Pgp), multidrug resistance protein 7 (MRP7), and the betaIII isotype of tubulin. The ability of four taccalonolides, A, E, B, and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B, and N were effective in vitro against cell lines that overexpress Pgp and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel-resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the betaIII isotype of tubulin was generated to evaluate the effect of betaIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the betaIII-tubulin-overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine. In striking contrast, the betaIII-tubulin-overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential.

Smoldering Multiple Myeloma

PubMed Central

Gao, Minjie; Yang, Guang; Kong, Yuanyuan; Wu, Xiaosong; Shi, Jumei

2015-01-01

Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage of multiple myeloma (MM) characterized by clonal bone marrow plasma cells (BMPC) ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC) ratio, peripheral blood plasma cells (PBPC), pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI), cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population. PMID:26000300

The Roles of Relative Linguistic Proficiency and Modality Switching in Language Switch Cost: Evidence from Chinese Visual Unimodal and Bimodal Bilinguals.

PubMed

Lu, Aitao; Wang, Lu; Guo, Yuyang; Zeng, Jiahong; Zheng, Dongping; Wang, Xiaolu; Shao, Yulan; Wang, Ruiming

2017-09-01

The current study investigated the mechanism of language switching in unbalanced visual unimodal bilinguals as well as balanced and unbalanced bimodal bilinguals during a picture naming task. All three groups exhibited significant switch costs across two languages, with symmetrical switch cost in balanced bimodal bilinguals and asymmetrical switch cost in unbalanced unimodal bilinguals and bimodal bilinguals. Moreover, the relative proficiency of the two languages but not their absolute proficiency had an effect on language switch cost. For the bimodal bilinguals the language switch cost also arose from modality switching. These findings suggest that the language switch cost might originate from multiple sources from both outside (e.g., modality switching) and inside (e.g., the relative proficiency of the two languages) the linguistic lexicon.

IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate

PubMed Central

Noviski, Mark; Mueller, James L; Satterthwaite, Anne; Garrett-Sinha, Lee Ann; Brombacher, Frank

2018-01-01

Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only Lyn−/− B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1+ SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells. PMID:29521626

PWM-switching pattern-based diagnosis scheme for single and multiple open-switch damages in VSI-fed induction motor drives.

PubMed

Trabelsi, Mohamed; Boussak, Mohamed; Gossa, Moncef

2012-03-01

This paper deals with a fault detection technique for insulated-gate bipolar transistors (IGBTs) open-circuit faults in voltage source inverter (VSI)-fed induction motor drives. The novelty of this idea consists in analyzing the pulse-width modulation (PWM) switching signals and the line-to-line voltage levels during the switching times, under both healthy and faulty operating conditions. The proposed method requires line-to-line voltage measurement, which provides information about switching states and is not affected by the load. The fault diagnosis scheme is achieved using simple hardware and can be included in the existing inverter system without any difficulty. In addition, it allows not only accurate single and multiple faults diagnosis but also minimization of the fault detection time to a maximum of one switching period (T(c)). Simulated and experimental results on a 3-kW squirrel-cage induction motor drive are displayed to validate the feasibility and the effectiveness of the proposed strategy. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Self-Induced Switchings between Multiple Space-Time Patterns on Complex Networks of Excitable Units

NASA Astrophysics Data System (ADS)

Ansmann, Gerrit; Lehnertz, Klaus; Feudel, Ulrike

2016-01-01

We report on self-induced switchings between multiple distinct space-time patterns in the dynamics of a spatially extended excitable system. These switchings between low-amplitude oscillations, nonlinear waves, and extreme events strongly resemble a random process, although the system is deterministic. We show that a chaotic saddle—which contains all the patterns as well as channel-like structures that mediate the transitions between them—is the backbone of such a pattern-switching dynamics. Our analyses indicate that essential ingredients for the observed phenomena are that the system behaves like an inhomogeneous oscillatory medium that is capable of self-generating spatially localized excitations and that is dominated by short-range connections but also features long-range connections. With our findings, we present an alternative to the well-known ways to obtain self-induced pattern switching, namely, noise-induced attractor hopping, heteroclinic orbits, and adaptation to an external signal. This alternative way can be expected to improve our understanding of pattern switchings in spatially extended natural dynamical systems like the brain and the heart.

A random Q-switched fiber laser

PubMed Central

Tang, Yulong; Xu, Jianqiu

2015-01-01

Extensive studies have been performed on random lasers in which multiple-scattering feedback is used to generate coherent emission. Q-switching and mode-locking are well-known routes for achieving high peak power output in conventional lasers. However, in random lasers, the ubiquitous random cavities that are formed by multiple scattering inhibit energy storage, making Q-switching impossible. In this paper, widespread Rayleigh scattering arising from the intrinsic micro-scale refractive-index irregularities of fiber cores is used to form random cavities along the fiber. The Q-factor of the cavity is rapidly increased by stimulated Brillouin scattering just after the spontaneous emission is enhanced by random cavity resonances, resulting in random Q-switched pulses with high brightness and high peak power. This report is the first observation of high-brightness random Q-switched laser emission and is expected to stimulate new areas of scientific research and applications, including encryption, remote three-dimensional random imaging and the simulation of stellar lasing. PMID:25797520

Interacting Multiple Model (IMM) Fifth-Degree Spherical Simplex-Radial Cubature Kalman Filter for Maneuvering Target Tracking

PubMed Central

Liu, Hua; Wu, Wen

2017-01-01

For improving the tracking accuracy and model switching speed of maneuvering target tracking in nonlinear systems, a new algorithm named the interacting multiple model fifth-degree spherical simplex-radial cubature Kalman filter (IMM5thSSRCKF) is proposed in this paper. The new algorithm is a combination of the interacting multiple model (IMM) filter and the fifth-degree spherical simplex-radial cubature Kalman filter (5thSSRCKF). The proposed algorithm makes use of Markov process to describe the switching probability among the models, and uses 5thSSRCKF to deal with the state estimation of each model. The 5thSSRCKF is an improved filter algorithm, which utilizes the fifth-degree spherical simplex-radial rule to improve the filtering accuracy. Finally, the tracking performance of the IMM5thSSRCKF is evaluated by simulation in a typical maneuvering target tracking scenario. Simulation results show that the proposed algorithm has better tracking performance and quicker model switching speed when disposing maneuver models compared with the interacting multiple model unscented Kalman filter (IMMUKF), the interacting multiple model cubature Kalman filter (IMMCKF) and the interacting multiple model fifth-degree cubature Kalman filter (IMM5thCKF). PMID:28608843

Interacting Multiple Model (IMM) Fifth-Degree Spherical Simplex-Radial Cubature Kalman Filter for Maneuvering Target Tracking.

PubMed

Liu, Hua; Wu, Wen

2017-06-13

For improving the tracking accuracy and model switching speed of maneuvering target tracking in nonlinear systems, a new algorithm named the interacting multiple model fifth-degree spherical simplex-radial cubature Kalman filter (IMM5thSSRCKF) is proposed in this paper. The new algorithm is a combination of the interacting multiple model (IMM) filter and the fifth-degree spherical simplex-radial cubature Kalman filter (5thSSRCKF). The proposed algorithm makes use of Markov process to describe the switching probability among the models, and uses 5thSSRCKF to deal with the state estimation of each model. The 5thSSRCKF is an improved filter algorithm, which utilizes the fifth-degree spherical simplex-radial rule to improve the filtering accuracy. Finally, the tracking performance of the IMM5thSSRCKF is evaluated by simulation in a typical maneuvering target tracking scenario. Simulation results show that the proposed algorithm has better tracking performance and quicker model switching speed when disposing maneuver models compared with the interacting multiple model unscented Kalman filter (IMMUKF), the interacting multiple model cubature Kalman filter (IMMCKF) and the interacting multiple model fifth-degree cubature Kalman filter (IMM5thCKF).

Spacecraft IF switch matrix for wideband service applications in 30/20 GHz communications satellite systems: Proof-of-concept model, executive summary

NASA Technical Reports Server (NTRS)

Ho, P. T.; Coban, E.; Pelose, J.

1983-01-01

The design and development of a unique coupler crossbar 20 x 20 microwave switch matrix are described. The test results of the proof of concept model that meets the requirements for a high speed satellite switched, time division multiple access (SS-TDMA) system are presented.

Measuring technical and mathematical investigation of multiple reignitions at the switching of a motor using vacuum circuit breakers

NASA Astrophysics Data System (ADS)

Luxa, Andreas

The necessary conditions in switching system and vacuum circuit breaker for the occurrence of multiple re-ignitions and accompanying effects were examined. The shape of the occurring voltages was determined in relationship to other types of overvoltage. A phenomenological model of the arc, based on an extension of the Mayr equation for arcs was used with the simulation program NETOMAC for the switching transients. Factors which affect the arc parameters were analyzed. The results were statistically verified by 3000 three-phase switching tests on 3 standard vacuum circuit breakers under realistic systems conditions; the occurring overvoltage level was measured. Dimensioning criteria for motor simulation circuits in power plants were formulated on the basis of a theoretical equivalence analysis and experimental studies. The simulation model allows a sufficiently correct estimation of all effects.

Task switching costs in preschool children and adults.

PubMed

Peng, Anna; Kirkham, Natasha Z; Mareschal, Denis

2018-08-01

Past research investigating cognitive flexibility has shown that preschool children make many perseverative errors in tasks that require switching between different sets of rules. However, this inflexibility might not necessarily hold with easier tasks. The current study investigated the developmental differences in cognitive flexibility using a task-switching procedure that compared reaction times and accuracy in 4- and 6-year-olds with those in adults. The experiment involved simple target detection tasks and was intentionally designed in a way that the stimulus and response conflicts were minimal together with a long preparation window. Global mixing costs (performance costs when multiple tasks are relevant in a context), and local switch costs (performance costs due to switching to an alternative task) are typically thought to engage endogenous control processes. If this is the case, we should observe developmental differences with both of these costs. Our results show, however, that when the accuracy was good, there were no age differences in cognitive flexibility (i.e., the ability to manage multiple tasks and to switch between tasks) between children and adults. Even though preschool children had slower reaction times and were less accurate, the mixing and switch costs associated with task switching were not reliably larger for preschool children. Preschool children did, however, show more commission errors and greater response repetition effects than adults, which may reflect differences in inhibitory control. Copyright © 2018 Elsevier Inc. All rights reserved.

Concurrent detection of secreted products from human lymphocytes by microengraving: cytokines and antigen-reactive antibodies

PubMed Central

Bradshaw, Elizabeth M.; Kent, Sally C.; Tripuraneni, Vinay; Orban, Tihamer; Ploegh, Hidde L.; Hafler, David A.; Love, J. Christopher

2008-01-01

Cell surface determinants, cytokines and antibodies secreted by hematopoietic cells are used to classify their lineage and function. Currently available techniques are unable to elucidate multiple secreted proteins while also assigning phenotypic surface-displayed markers to the individual living cells. Here, a soft lithographic method, microengraving, was adapted for the multiplexed interrogation of populations of individual human peripheral blood mononuclear cells for secreted cytokines (IFN-γ and IL-6), antigen-specific antibodies, and lineage-specific surface-expressed markers. Application of the method to a clinical sample from a recent onset Type 1 diabetic subject with a positive titer of anti-insulin antibodies showed that ~0.58% of circulating CD19+ B cells secreted proinsulin-reactive antibodies of the IgG isotype and 2–3% of circulating cells secreted IL-6. These data demonstrate the utility of microengraving for interrogating multiple phenotypes of single human cells concurrently and for detecting rare populations of cells by their secreted products. PMID:18675591

A molecular-sized optical logic circuit for digital modulation of a fluorescence signal

NASA Astrophysics Data System (ADS)

Nishimura, Takahiro; Tsuchida, Karin; Ogura, Yusuke; Tanida, Jun

2018-03-01

Fluorescence measurement allows simultaneous detection of multiple molecular species by using spectrally distinct fluorescence probes. However, due to the broad spectra of fluorescence emission, the multiplicity of fluorescence measurement is generally limited. To overcome this limitation, we propose a method to digitally modulate fluorescence output signals with a molecular-sized optical logic circuit by using optical control of fluorescence resonance energy transfer (FRET). The circuit receives a set of optical inputs represented with different light wavelengths, and then it switches high and low fluorescence intensity from a reporting molecule according to the result of the logic operation. By using combinational optical inputs in readout of fluorescence signals, the number of biomolecular species that can be identified is increased. To implement the FRET-based circuits, we designed two types of basic elements, YES and NOT switches. An YES switch produces a high-level output intensity when receiving a designated light wavelength input and a low-level intensity without the light irradiation. A NOT switch operates inversely to the YES switch. In experiments, we investigated the operation of the YES and NOT switches that receive a 532-nm light input and modulate the fluorescence intensity of Alexa Fluor 488. The experimental result demonstrates that the switches can modulate fluorescence signals according to the optical input.

Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris autoantibodies.

PubMed

Hacker, Mary K; Janson, Marleen; Fairley, Janet A; Lin, Mong-Shang

2002-10-01

In this study we systematically characterized isotype profiles and antigenic and tissue specificity of antidesmoglein autoantibodies from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) using enzyme-linked immunoabsorbent assays (ELISA), indirect immunofluorescence (IIF) staining, and immunoblotting (IB). In PF, we found that IgG1 antidesmoglein-1 (Dsg1) reacts with a linear epitope(s) on the ectodomain of Dsg1, while its IgG4 counterpart recognizes a conformational epitope(s). These two subclasses of anti-Dsg1 are both capable of recognizing tissues from monkey esophagus and adult human skin, but IgG1 is not able to react with mouse skin, which may explain why this isotype of anti-Dsg1 failed to induce PF-like lesions in the passive transfer animal model. In mucosal PV patients, we found that both IgG1 and IgG4 only recognized monkey esophagus tissue by IIF, except in one patient, indicating that these antibodies react with a unique conformational epitope(s) that is present in mucosal but not skin tissue. In generalized PV, IgG1 anti-Dsg3 autoantibodies appeared to recognize a linear epitope(s) on the Dsg3 ectodomain. In contrast, IgG4 anti-Dsg3 antibodies recognized both linear and conformational epitopes on the Dsg3 molecule. Interestingly, the IgG1 anti-Dsg3 antibodies failed to react with human and mouse skin tissues, suggesting that this subclass of autoantibodies may not play an essential role in the development of PV suprabasilar lesions. In summary, we conclude that this study further elucidates the pathological mechanisms of PF and PV autoantibodies by revealing their distinct isotype and antigenic profiles. This information may help us to better understand the autoimmune mechanisms underlying the development of pemphigus.

An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.

PubMed Central

Caccamo, D. V.; Herman, M. M.; Frankfurter, A.; Katsetos, C. D.; Collins, V. P.; Rubinstein, L. J.

1989-01-01

Approximately one third of the female mice of the LTXBO strain develop spontaneous ovarian teratomas. These tumors contain a large neuroepithelial component, which includes primitive neural structures resembling embryonic neural tubes (medulloepithelial rosettes), ependymoblastic and ependymal rosettes, neuroblasts, mature ganglionic neurons, myelinated neurites, and astrocytes. The purpose of this study was to characterize these tumors according to the immunohistochemical location of some well-characterized trophic and regulatory neuropeptides and neurotransmitters, several neuronal-associated cytoskeletal proteins, and other proteins indicative of neuronal and glial differentiation. Medulloepithelial rosettes showed focal serotonin-like, opioid peptide-like and gamma-amino butyric acid-like immunoreactivity, and displayed immunostaining for the neuron-associated class III beta-tubulin isotype. The mature ganglion cells were also immunoreactive for these markers, and, in addition, for somatostatin, cholecystokinin, bombesin, glucagon, vasoactive intestinal peptide, and neuropeptide Y. Mature ganglion cells were also immunoreactive for proteins associated with the neuronal cytoskeleton (including microtubule-associated proteins, MAP2 and tau, and higher molecular weight phosphorylated and non-phosphorylated neurofilament subunits), neuron-specific enolase, and synaptophysin. Undifferentiated stem cells, ependymoblastic and ependymal rosettes, and astroglia all stained with a monoclonal antibody that recognizes all mammalian beta-tubulin isotypes, but did not react with antibodies to neuronal-associated cytoskeletal proteins or neuropeptides. Neuropeptide-like immunoreactivity and demonstration of the class III beta-tubulin isotype indicate early neuronal commitment in neoplastic primitive neuroepithelium. These patterns of immunoreactivity closely follow those encountered in the normal neurocytogenesis of the mammalian and avian forebrain, and increase the precision with which the early stages of progressive neuroepithelial differentiation can be analyzed in human embryonal tumors of the CNS. Images Figure 1 Figure 2 Figure 3 PMID:2817080

Detection of total and PRRSV-specific antibodies in oral fluids collected with different rope types from PRRSV-vaccinated and experimentally infected pigs.

PubMed

Decorte, Inge; Van Breedam, Wander; Van der Stede, Yves; Nauwynck, Hans J; De Regge, Nick; Cay, Ann Brigitte

2014-06-17

Oral fluid collected by means of ropes has the potential to replace serum for monitoring and surveillance of important swine pathogens. Until now, the most commonly used method to collect oral fluid is by hanging a cotton rope in a pen. However, concerns about the influence of rope material on subsequent immunological assays have been raised. In this study, we evaluated six different rope materials for the collection of oral fluid and the subsequent detection of total and PRRSV-specific antibodies of different isotypes in oral fluid collected from PRRSV-vaccinated and infected pigs. An initial experiment showed that IgA is the predominant antibody isotype in porcine saliva. Moreover, it was found that synthetic ropes may yield higher amounts of IgA, whereas all rope types seemed to be equally suitable for IgG collection. Although IgA is the predominant antibody isotype in porcine oral fluid, the PRRSV-specific IgA-based IPMA and ELISA tests were clearly not ideal for sensitive detection of PRRSV-specific IgA antibodies. In contrast, PRRSV-specific IgG in oral fluids was readily detected in PRRSV-specific IgG-based IPMA and ELISA tests, indicating that IgG is a more reliable isotype for monitoring PRRSV-specific antibody immunity in vaccinated/infected animals via oral fluids with the currently available tests. Since PRRSV-specific IgG detection seems more reliable than PRRSV-specific IgA detection for monitoring PRRSV-specific antibody immunity via oral fluids, and since all rope types yield equal amounts of IgG, it seems that the currently used cotton ropes are an appropriate choice for sample collection in PRRSV monitoring.

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients.

PubMed

Trivedi, Sumita; Srivastava, Raghvendra M; Concha-Benavente, Fernando; Ferrone, Soldano; Garcia-Bates, Tatiana M; Li, Jing; Ferris, Robert L

2016-11-01

EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8 + T cells in patients treated with cetuximab compared with those treated with panitumumab. Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. ©2016 AACR. ©2016 American Association for Cancer Research.

Hybrid colored noise process with space-dependent switching rates

NASA Astrophysics Data System (ADS)

Bressloff, Paul C.; Lawley, Sean D.

2017-07-01

A fundamental issue in the theory of continuous stochastic process is the interpretation of multiplicative white noise, which is often referred to as the Itô-Stratonovich dilemma. From a physical perspective, this reflects the need to introduce additional constraints in order to specify the nature of the noise, whereas from a mathematical perspective it reflects an ambiguity in the formulation of stochastic differential equations (SDEs). Recently, we have identified a mechanism for obtaining an Itô SDE based on a form of temporal disorder. Motivated by switching processes in molecular biology, we considered a Brownian particle that randomly switches between two distinct conformational states with different diffusivities. In each state, the particle undergoes normal diffusion (additive noise) so there is no ambiguity in the interpretation of the noise. However, if the switching rates depend on position, then in the fast switching limit one obtains Brownian motion with a space-dependent diffusivity of the Itô form. In this paper, we extend our theory to include colored additive noise. We show that the nature of the effective multiplicative noise process obtained by taking both the white-noise limit (κ →0 ) and fast switching limit (ɛ →0 ) depends on the order the two limits are taken. If the white-noise limit is taken first, then we obtain Itô, and if the fast switching limit is taken first, then we obtain Stratonovich. Moreover, the form of the effective diffusion coefficient differs in the two cases. The latter result holds even in the case of space-independent transition rates, where one obtains additive noise processes with different diffusion coefficients. Finally, we show that yet another form of multiplicative noise is obtained in the simultaneous limit ɛ ,κ →0 with ɛ /κ2 fixed.

Interprocessor bus switching system for simultaneous communication in plural bus parallel processing system

DOEpatents

Atac, R.; Fischler, M.S.; Husby, D.E.

1991-01-15

A bus switching apparatus and method for multiple processor computer systems comprises a plurality of bus switches interconnected by branch buses. Each processor or other module of the system is connected to a spigot of a bus switch. Each bus switch also serves as part of a backplane of a modular crate hardware package. A processor initiates communication with another processor by identifying that other processor. The bus switch to which the initiating processor is connected identifies and secures, if possible, a path to that other processor, either directly or via one or more other bus switches which operate similarly. If a particular desired path through a given bus switch is not available to be used, an alternate path is considered, identified and secured. 11 figures.

Interprocessor bus switching system for simultaneous communication in plural bus parallel processing system

DOEpatents

Atac, Robert; Fischler, Mark S.; Husby, Donald E.

1991-01-01

A bus switching apparatus and method for multiple processor computer systems comprises a plurality of bus switches interconnected by branch buses. Each processor or other module of the system is connected to a spigot of a bus switch. Each bus switch also serves as part of a backplane of a modular crate hardware package. A processor initiates communication with another processor by identifying that other processor. The bus switch to which the initiating processor is connected identifies and secures, if possible, a path to that other processor, either directly or via one or more other bus switches which operate similarly. If a particular desired path through a given bus switch is not available to be used, an alternate path is considered, identified and secured.

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses.

PubMed

Tay, Matthew Zirui; Liu, Pinghuang; Williams, LaTonya D; McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T; Dennison, S Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S Munir; Moody, M Anthony; Hope, Thomas J; Haynes, Barton F; Tomaras, Georgia D

2016-08-01

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

PubMed Central

McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T.; Dennison, S. Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S. Munir; Haynes, Barton F.; Tomaras, Georgia D.

2016-01-01

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo. PMID:27579713

The DDN (Defense Data Network) Course,

DTIC Science & Technology

1986-04-01

devices will share the same node-to-node channels. * Simultaneous availability of source and destination is not required. * Speed and code conversion can...address multiple addresses simultaneously 3) Disadvantages of Message Switching Systems Not suited to real time or interactive use * Long and highly...transmission b) Unlike message switching, packet switching requires the -. simultaneous availability of source and destination. 64 -4 ) ..xa...e s

Design Method of Digital Optimal Control Scheme and Multiple Paralleled Bridge Type Current Amplifier for Generating Gradient Magnetic Fields in MRI Systems

NASA Astrophysics Data System (ADS)

Watanabe, Shuji; Takano, Hiroshi; Fukuda, Hiroya; Hiraki, Eiji; Nakaoka, Mutsuo

This paper deals with a digital control scheme of multiple paralleled high frequency switching current amplifier with four-quadrant chopper for generating gradient magnetic fields in MRI (Magnetic Resonance Imaging) systems. In order to track high precise current pattern in Gradient Coils (GC), the proposal current amplifier cancels the switching current ripples in GC with each other and designed optimum switching gate pulse patterns without influences of the large filter current ripple amplitude. The optimal control implementation and the linear control theory in GC current amplifiers have affinity to each other with excellent characteristics. The digital control system can be realized easily through the digital control implementation, DSPs or microprocessors. Multiple-parallel operational microprocessors realize two or higher paralleled GC current pattern tracking amplifier with optimal control design and excellent results are given for improving the image quality of MRI systems.

A Comparison of High-Voltage Switches

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

Chu, K.W.; Scott, G.L.

1999-02-01

This report summarizes our work on high-voltage switches during the past few years. With joint funding from the Department of Energy (DOE) and the Department of Defense (DOD), we tested a wide variety of switches to a common standard. This approach permitted meaningful comparisons between disparate switches. Most switches were purchased from commercial sources, though some were experimental devices. For the purposes of this report, we divided the switches into three generic types (gas, vacuum, and semiconductor) and selected data that best illustrates important strengths and weaknesses of each switch type. Test techniques that indicate the state of health ofmore » the switches are emphasized. For example, a good indicator of residual gas in a vacuum switch is the systematic variation of the switching delay in response to changes in temperature and/or operating conditions. We believe that the presentation of this kind of information will help engineers to select and to test switches for their particular applications. Our work was limited to switches capable of driving slappers. Also known as exploding-foil initiators, slappers are detonators that initiate a secondary explosive by direct impact with a small piece of matter moving at the detonation velocity (several thousands of meters per second). A slapper is desirable for enhanced safety (no primary explosive), but it also places extra demands on the capacitor-discharge circuit to deliver a fast-rising current pulse (greater than 10 A/ns) of several thousand amperes. The required energy is substantially less than one joule; but this energy is delivered in less than one microsecond, taking the peak power into the megawatt regime. In our study, the switches operated in the 1 kV to 3 kV range and were physically small, roughly 1 cm{sup 3} or less. Although a fuze functions only once in actual use, multiple-shot capability is important for production testing and for research work. For this reason, we restricted this report to multiple-shot switches. Furthermore, our work included only switches with submicrosecond timing precision, thereby excluding mechanical switches.« less

Quantitative regulation of B cell division destiny by signal strength.

PubMed

Turner, Marian L; Hawkins, Edwin D; Hodgkin, Philip D

2008-07-01

Differentiation to Ab secreting and isotype-switched effector cells is tightly linked to cell division and therefore the degree of proliferation strongly influences the nature of the immune response. The maximum number of divisions reached, termed the population division destiny, is stochastically distributed in the population and is an important parameter in the quantitative outcome of lymphocyte responses. In this study, we further assessed the variables that regulate B cell division destiny in vitro in response to T cell- and TLR-dependent stimuli. Both the concentration and duration of stimulation were able to regulate the average maximum number of divisions undergone for each stimulus. Notably, a maximum division destiny was reached during provision of repeated saturating stimulation, revealing that an intrinsic limit to proliferation exists even under these conditions. This limit was linked directly to division number rather than time of exposure to stimulation and operated independently of the survival regulation of the cells. These results demonstrate that a B cell population's division destiny is regulable by the stimulatory conditions up to an inherent maximum value. Division destiny is a crucial parameter in regulating the extent of B cell responses and thereby also the nature of the immune response mounted.

STAT4 and T-bet control follicular helper T cell development in viral infections.

PubMed

Weinstein, Jason S; Laidlaw, Brian J; Lu, Yisi; Wang, Jessica K; Schulz, Vincent P; Li, Ningcheng; Herman, Edward I; Kaech, Susan M; Gallagher, Patrick G; Craft, Joe

2018-01-02

Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response. T-bet is important for Tfh cell production of IFN-γ, but not IL-21, and for a robust GC reaction. STAT4, phosphorylated in Tfh cells upon infection, is required for expression of T-bet and Bcl6 and for IFN-γ and IL-21. These data indicate that T-bet is expressed with Bcl6 in Tfh cells and is required alongside STAT4 to coordinate Tfh cell IL-21 and IFN-γ production and for promotion of the GC response after acute viral challenge. © 2018 Weinstein et al.

Nanopore extended field-effect transistor for selective single-molecule biosensing.

PubMed

Ren, Ren; Zhang, Yanjun; Nadappuram, Binoy Paulose; Akpinar, Bernice; Klenerman, David; Ivanov, Aleksandar P; Edel, Joshua B; Korchev, Yuri

2017-09-19

There has been a significant drive to deliver nanotechnological solutions to biosensing, yet there remains an unmet need in the development of biosensors that are affordable, integrated, fast, capable of multiplexed detection, and offer high selectivity for trace analyte detection in biological fluids. Herein, some of these challenges are addressed by designing a new class of nanoscale sensors dubbed nanopore extended field-effect transistor (nexFET) that combine the advantages of nanopore single-molecule sensing, field-effect transistors, and recognition chemistry. We report on a polypyrrole functionalized nexFET, with controllable gate voltage that can be used to switch on/off, and slow down single-molecule DNA transport through a nanopore. This strategy enables higher molecular throughput, enhanced signal-to-noise, and even heightened selectivity via functionalization with an embedded receptor. This is shown for selective sensing of an anti-insulin antibody in the presence of its IgG isotype.Efficient detection of single molecules is vital to many biosensing technologies, which require analytical platforms with high selectivity and sensitivity. Ren et al. combine a nanopore sensor and a field-effect transistor, whereby gate voltage mediates DNA and protein transport through the nanopore.

T cell-independent and T cell-dependent immunoglobulin G responses to polyomavirus infection are impaired in complement receptor 2-deficient mice.

PubMed

Szomolanyi-Tsuda, Eva; Seedhom, Mina O; Carroll, Michael C; Garcea, Robert L

2006-08-15

Polyomavirus (PyV) infection induces protective T cell-independent (TI) IgM and IgG antibody responses in T cell-deficient mice, but these responses are not generated by immunization with viral proteins or virus like particles. We hypothesized that innate signals contribute to the generation of isotype-switched antiviral antibody responses. We studied the role of complement receptor (CR2) engagement in TI and T cell-dependent (TD) antibody responses to PyV using CR2-deficient mice. Antiviral IgG responses were reduced by 80-40% in CR2-/- mice compared to wild type. Adoptive transfer experiments demonstrated the need for CR2 not only in TD, but also in TI IgG responses to PyV. Transfer of CR2-/- B lymphocytes to SCID mice resulted in TI antiviral IgG responses that corresponded to 10% of that seen in wild-type B cell-reconstituted mice. Thus, our studies revealed a profound dependence of TI and TD antiviral antibody responses on CR2-mediated signals in PyV-infected mice, where the viral antigen is abundant and persistent.

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

Chen, Dong; Heidelberger, Philip; Sugawara, Yutaka

An apparatus and method for extending the scalability and improving the partitionability of networks that contain all-to-all links for transporting packet traffic from a source endpoint to a destination endpoint with low per-endpoint (per-server) cost and a small number of hops. An all-to-all wiring in the baseline topology is decomposed into smaller all-to-all components in which each smaller all-to-all connection is replaced with star topology by using global switches. Stacking multiple copies of the star topology baseline network creates a multi-planed switching topology for transporting packet traffic. Point-to-point unified stacking method using global switch wiring methods connects multiple planes ofmore » a baseline topology by using the global switches to create a large network size with a low number of hops, i.e., low network latency. Grouped unified stacking method increases the scalability (network size) of a stacked topology.« less

Fault detection for singular switched linear systems with multiple time-varying delay in finite frequency domain

NASA Astrophysics Data System (ADS)

Zhai, Ding; Lu, Anyang; Li, Jinghao; Zhang, Qingling

2016-10-01

This paper deals with the problem of the fault detection (FD) for continuous-time singular switched linear systems with multiple time-varying delay. In this paper, the actuator fault is considered. Besides, the systems faults and unknown disturbances are assumed in known frequency domains. Some finite frequency performance indices are initially introduced to design the switched FD filters which ensure that the filtering augmented systems under switching signal with average dwell time are exponentially admissible and guarantee the fault input sensitivity and disturbance robustness. By developing generalised Kalman-Yakubovic-Popov lemma and using Parseval's theorem and Fourier transform, finite frequency delay-dependent sufficient conditions for the existence of such a filter which can guarantee the finite-frequency H- and H∞ performance are derived and formulated in terms of linear matrix inequalities. Four examples are provided to illustrate the effectiveness of the proposed finite frequency method.

[Use of new immunoglobulin isotype-specific ELISA-systems to detect Salmonella infections in pigs].

PubMed

Ehlers, Joachim; Alt, Michael; Trepnau, Daniela; Lehmann, Jörg

2006-01-01

In Germany, the program for controlling salmonella infections in pigs is based on tests detecting salmonella-lipopolysaccharide (LPS) induced antibodies in meat-juice or blood. These conventional tests which are based on the technology of enzyme-linked immunosorbent assay (ELISA) detect exclusively or mainly immunoglobulin(lg)G antibodies. Meanwhile, novel ELISA systems (WCE-ELISA, 3-Isotype-Screening-ELISA) have been developed, which additionally detect the antibody classes IgM and IgA.This fact enables the registration of fresh salmonella infections (starting with day 5 p.i.) and thus, the distinction between early and older infections. The results show that animals with early salmonella infections appear significantly more often in herds with a high than with a low prevalence. With the newly developed tests this group of animals can be detected much more efficiently and precisely than with the tests used so far. Due to their clearly improved sensitivity the application of the WCE-ELISA and the 3-Isotype-Screening-ELISA in terms of the QS-Salmonella-Monitoring program can therefore significantly improve the selection of farms with potential salmonella excretors. Additionally, the WCE-ELISA can be applied very suitable for the examination of individual animals.

Differential expression of largemouth bass (Micropterus salmoides) estrogen receptor isotypes alpha, beta, and gamma by estradiol.

PubMed

Sabo-Attwood, Tara; Kroll, Kevin J; Denslow, Nancy D

2004-04-15

The expression levels of three estrogen receptor (ER) isotypes alpha, beta, and gamma were quantified in female largemouth bass (Micropterus salmoides) (LMB) liver, ovary, brain, and pituitary tissues. ER alpha and beta expression predominated in the liver, while ERs beta and gamma predominated in the other tissues. Temporally in females, ER alpha was highly up-regulated, ER gamma was slightly up-regulated, and ER beta levels remained unchanged in the liver when plasma 17-beta estradiol (E2) and vitellogenin (Vtg) levels were elevated in the spring. In ovarian tissue from these same fish, all three ERs were maximally expressed in the fall, during early oocyte development and prior to peak plasma E2 levels. When males were injected with E2, ER alpha was highly inducible, ER gamma was moderately up-regulated, and ER beta levels were not affected. None of the ER isotypes were induced by E2 in gonadal tissues. These results combined suggest that the ERs themselves are not regulated in the same manner by E2, and furthermore, do not contribute equally to the transcriptional regulation of genes involved in fish reproduction such as Vtg.

Quantification of α-tubulin isotypes by sandwich ELISA with signal amplification through biotinyl-tyramide or immuno-PCR.

PubMed

Dráberová, Eduarda; Stegurová, Lucie; Sulimenko, Vadym; Hájková, Zuzana; Dráber, Petr; Dráber, Pavel

2013-09-30

Microtubules formed by αβ-tubulin dimers represent cellular structures that are indispensable for the maintenance of cell morphology and for cell motility generation. Microtubules in intact cells are in highly regulated equilibrium with cellular pools of soluble tubulin dimers. Sensitive, reproducible and rapid assays are necessary to monitor tubulin changes in cytosolic pools after treatment with anti-mitotic drugs, during the cell cycle or activation and differentiation events. Here we describe new assays for α-tubulin quantification. The assays are based on sandwich ELISA, and the signal is amplified with biotinyl-tyramide or immuno-PCR. Matching monoclonal antibody pair recognizes phylogenetically highly conserved epitopes localized outside the C-terminal isotype-defining region. This makes it possible to detect α-tubulin isotypes in different cell types of various species. Biotinyl-tyramide amplification and immuno-PCR amplification enable detection of tubulin at concentrations 2.5ng/ml and 0.086ng/ml, respectively. Immuno-PCR detection shows enhanced sensitivity and wider dynamic range when compared to ELISA with biotinyl-tyramide detection. Our results on taxol-treated and activated bone marrow-derived mast cells demonstrate, that the assays allow sensitive quantification of tubulin in complex biological fluids. © 2013.

Immunoglobulin isotypes in Atlantic salmon, Salmo salar.

PubMed

Hordvik, Ivar

2015-02-27

There are three major immunoglobulin (Ig) isotypes in salmonid fish: IgM, IgD and IgT, defined by the heavy chains μ, δ and τ, respectively. As a result of whole genome duplication in the ancestor of the salmonid fish family, Atlantic salmon (Salmo salar) possess two highly similar Ig heavy chain gene complexes (A and B), comprising two μ genes, two δ genes, three intact τ genes and five τ pseudogenes. The μA and μB genes correspond to two distinct sub-populations of serum IgM. The IgM-B sub-variant has a characteristic extra cysteine near the C-terminal part of the heavy chain and exhibits a higher degree of polymer disulfide cross-linking compared to IgM-A. The IgM-B:IgM-A ratio in serum is typically 60:40, but skewed ratios are also observed. The IgT isotype appears to be specialized to mucosal immune responses in salmonid fish. The concentration of IgT in serum is 100 to 1000 times lower than IgM. Secreted forms of IgD have been detected in rainbow trout, but not yet in Atlantic salmon.

Distributed parallel messaging for multiprocessor systems

DOEpatents

Chen, Dong; Heidelberger, Philip; Salapura, Valentina; Senger, Robert M; Steinmacher-Burrow, Burhard; Sugawara, Yutaka

2013-06-04

A method and apparatus for distributed parallel messaging in a parallel computing system. The apparatus includes, at each node of a multiprocessor network, multiple injection messaging engine units and reception messaging engine units, each implementing a DMA engine and each supporting both multiple packet injection into and multiple reception from a network, in parallel. The reception side of the messaging unit (MU) includes a switch interface enabling writing of data of a packet received from the network to the memory system. The transmission side of the messaging unit, includes switch interface for reading from the memory system when injecting packets into the network.

A sweep algorithm for massively parallel simulation of circuit-switched networks

NASA Technical Reports Server (NTRS)

Gaujal, Bruno; Greenberg, Albert G.; Nicol, David M.

1992-01-01

A new massively parallel algorithm is presented for simulating large asymmetric circuit-switched networks, controlled by a randomized-routing policy that includes trunk-reservation. A single instruction multiple data (SIMD) implementation is described, and corresponding experiments on a 16384 processor MasPar parallel computer are reported. A multiple instruction multiple data (MIMD) implementation is also described, and corresponding experiments on an Intel IPSC/860 parallel computer, using 16 processors, are reported. By exploiting parallelism, our algorithm increases the possible execution rate of such complex simulations by as much as an order of magnitude.

Structural and functional properties of antibodies to the superantigen TSST-1 and their relationship to menstrual toxic shock syndrome.

PubMed

Kansal, Rita; Davis, Catherine; Hansmann, Melanie; Seymour, Jon; Parsonnet, Jeffrey; Modern, Paul; Gilbert, Steve; Kotb, Malak

2007-05-01

Menstrual toxic shock syndrome (mTSS) is an acute febrile disease accompanied by hypotension and multiple organ involvement. Infection with Staphylococcus aureus producing the superantigen toxic shock syndrome toxin-1 (TSST-1) vaginally is necessary; however, only a small fraction of those infected with TSST-1 producing bacteria actually develop mTSS, suggesting that host factors modulate disease susceptibility. Serum antibodies to the toxin protect against development of the syndrome, but not all antibodies can neutralize the toxin. We set out to determine whether risk of developing the syndrome is related to the absence of neutralizing antibody and if antibody isotypes influence the neutralization capacity. In healthy subjects, TSST-1-binding serum antibodies were exclusively of the IgG and IgM classes; however, toxin-neutralizing capacity was correlated to the TSST-1-specific IgG1 and IgG4 antibodies (r (2)=0.88, p<0.0001 and 0.33, p<0.0086, respectively) but not with IgM antibodies. Specific IgA was not detectable. Compared to healthy matched controls who were colonized vaginally with S. aureus, IgG1 anti-TSST-1 antibodies and toxin neutralizing activity was lacking in all of the acute phases and in the majority of convalescent sera, suggesting that these patients may be incapable of generating TSST-1 neutralizing antibodies. These new findings support the hypothesis that host factors are important in the development of mTSS and that the anti-toxin isotype impacts antibody functionality.

Genetic stability of gene targeted immunoglobulin loci. I. Heavy chain isotype exchange induced by a universal gene replacement vector.

PubMed Central

Kardinal, C; Selmayr, M; Mocikat, R

1996-01-01

Gene targeting at the immunoglobulin loci of B cells is an efficient tool for studying immunoglobulin expression or generating chimeric antibodies. We have shown that vector integration induced by human immunoglobulin G1 (IgG1) insertion vectors results in subsequent vector excision mediated by the duplicated target sequence, whereas replacement events which could be induced by the same constructs remain stable. We could demonstrate that the distribution of the vector homology strongly influences the genetic stability obtained. To this end we developed a novel type of a heavy chain replacement vector making use of the heavy chain class switch recombination sequence. Despite the presence of a two-sided homology this construct is universally applicable irrespective of the constant gene region utilized by the B cell. In comparison to an integration vector the frequency of stable incorporation was strongly increased, but we still observed vector excision, although at a markedly reduced rate. The latter events even occurred with circular constructs. Linearization of the construct at various sites and the comparison with an integration vector that carries the identical homology sequence, but differs in the distribution of homology, revealed the following features of homologous recombination of immunoglobulin genes: (i) the integration frequency is only determined by the length of the homology flank where the cross-over takes place; (ii) a 5' flank that does not meet the minimum requirement of homology length cannot be complemented by a sufficient 3' flank; (iii) free vector ends play a role for integration as well as for replacement targeting; (iv) truncating recombination events are suppressed in the presence of two flanks. Furthermore, we show that the switch region that was used as 3' flank is non-functional in an inverted orientation. Images Figure 2 PMID:8958041

Genetic stability of gene targeted immunoglobulin loci. I. Heavy chain isotype exchange induced by a universal gene replacement vector.

PubMed

Kardinal, C; Selmayr, M; Mocikat, R

1996-11-01

Gene targeting at the immunoglobulin loci of B cells is an efficient tool for studying immunoglobulin expression or generating chimeric antibodies. We have shown that vector integration induced by human immunoglobulin G1 (IgG1) insertion vectors results in subsequent vector excision mediated by the duplicated target sequence, whereas replacement events which could be induced by the same constructs remain stable. We could demonstrate that the distribution of the vector homology strongly influences the genetic stability obtained. To this end we developed a novel type of a heavy chain replacement vector making use of the heavy chain class switch recombination sequence. Despite the presence of a two-sided homology this construct is universally applicable irrespective of the constant gene region utilized by the B cell. In comparison to an integration vector the frequency of stable incorporation was strongly increased, but we still observed vector excision, although at a markedly reduced rate. The latter events even occurred with circular constructs. Linearization of the construct at various sites and the comparison with an integration vector that carries the identical homology sequence, but differs in the distribution of homology, revealed the following features of homologous recombination of immunoglobulin genes: (i) the integration frequency is only determined by the length of the homology flank where the cross-over takes place; (ii) a 5' flank that does not meet the minimum requirement of homology length cannot be complemented by a sufficient 3' flank; (iii) free vector ends play a role for integration as well as for replacement targeting; (iv) truncating recombination events are suppressed in the presence of two flanks. Furthermore, we show that the switch region that was used as 3' flank is non-functional in an inverted orientation.

Functional magnetic resonance imaging examination of two modular architectures for switching multiple internal models.

PubMed

Imamizu, Hiroshi; Kuroda, Tomoe; Yoshioka, Toshinori; Kawato, Mitsuo

2004-02-04

An internal model is a neural mechanism that can mimic the input-output properties of a controlled object such as a tool. Recent research interests have moved on to how multiple internal models are learned and switched under a given context of behavior. Two representative computational models for task switching propose distinct neural mechanisms, thus predicting different brain activity patterns in the switching of internal models. In one model, called the mixture-of-experts architecture, switching is commanded by a single executive called a "gating network," which is different from the internal models. In the other model, called the MOSAIC (MOdular Selection And Identification for Control), the internal models themselves play crucial roles in switching. Consequently, the mixture-of-experts model predicts that neural activities related to switching and internal models can be temporally and spatially segregated, whereas the MOSAIC model predicts that they are closely intermingled. Here, we directly examined the two predictions by analyzing functional magnetic resonance imaging activities during the switching of one common tool (an ordinary computer mouse) and two novel tools: a rotated mouse, the cursor of which appears in a rotated position, and a velocity mouse, the cursor velocity of which is proportional to the mouse position. The switching and internal model activities temporally and spatially overlapped each other in the cerebellum and in the parietal cortex, whereas the overlap was very small in the frontal cortex. These results suggest that switching mechanisms in the frontal cortex can be explained by the mixture-of-experts architecture, whereas those in the cerebellum and the parietal cortex are explained by the MOSAIC model.

Neuro-Oscillatory Mechanisms of Intersensory Selective Attention and Task Switching in School-Aged Children, Adolescents and Young Adults

ERIC Educational Resources Information Center

Murphy, Jeremy W.; Foxe, John J.; Molholm, Sophie

2016-01-01

The ability to attend to one among multiple sources of information is central to everyday functioning. Just as central is the ability to switch attention among competing inputs as the task at hand changes. Such processes develop surprisingly slowly, such that even into adolescence, we remain slower and more error prone at switching among tasks…

Phase-plane analysis of the totally asymmetric simple exclusion process with binding kinetics and switching between antiparallel lanes

PubMed Central

Kuan, Hui-Shun; Betterton, Meredith D.

2016-01-01

Motor protein motion on biopolymers can be described by models related to the totally asymmetric simple exclusion process (TASEP). Inspired by experiments on the motion of kinesin-4 motors on antiparallel microtubule overlaps, we analyze a model incorporating the TASEP on two antiparallel lanes with binding kinetics and lane switching. We determine the steady-state motor density profiles using phase-plane analysis of the steady-state mean field equations and kinetic Monte Carlo simulations. We focus on the density-density phase plane, where we find an analytic solution to the mean field model. By studying the phase-space flows, we determine the model’s fixed points and their changes with parameters. Phases previously identified for the single-lane model occur for low switching rate between lanes. We predict a multiple coexistence phase due to additional fixed points that appear as the switching rate increases: switching moves motors from the higher-density to the lower-density lane, causing local jamming and creating multiple domain walls. We determine the phase diagram of the model for both symmetric and general boundary conditions. PMID:27627345

Modelling and stability analysis of switching impulsive power systems with multiple equilibria

NASA Astrophysics Data System (ADS)

Zhu, Liying; Qiu, Jianbin; Chadli, Mohammed

2017-12-01

This paper tries to model power systems accompanied with a series of faults in the form of switched impulsive Hamiltonian systems (SIHSs) with multiple equilibria (ME) and unstable subsystems (US), and then analyze long-term stability issues of the power systems from the viewpoint of mathematics. According to the complex phenomena of switching actions of stages and generators, impulses of state, and existence of multiple equilibria, this paper first introduces an SIHS with ME and US to formulate a switching impulsive power system composed of an active generator, a standby generator, and an infinite load. Then, based on special system structures, a unique compact region containing all ME is determined, and novel stability concepts of region stability (RS), asymptotic region stability (ARS), and exponential region stability (ERS) are defined for such SIHS with respect to the region. Third, based on the introduced stability concepts, this paper proposes a necessary and sufficient condition of RS and ARS and a sufficient condition of ERS for the power system with respect to the region via the maximum energy function method. Finally, numerical simulations are carried out for a power system to show the effectiveness and practicality of the obained novel results.

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

PubMed Central

van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Time and spatial evolution of spin-orbit torque-induced magnetization switching in W/CoFeB/MgO structures with various sizes

NASA Astrophysics Data System (ADS)

Zhang, Chaoliang; Fukami, Shunsuke; DuttaGupta, Samik; Sato, Hideo; Ohno, Hideo

2018-04-01

We study spin-orbit torque (SOT) switching in W/CoFeB/MgO structures with various dot sizes (120-3500 nm) using pulsed current of various widths τ (800 ps-100 ms) to examine the time and spatial evolution of magnetization switching. We show that the switching behavior and the resultant threshold switching current density J th strongly depend on device size and pulse width. The switching mode in a 3500 nm dot device changes from probabilistic switching to reproducible partial switching as τ decreases. At τ = 800 ps, J th becomes more than 3 times larger than that in the long-pulse regime. A decrease in dot size to 700 nm does not significantly change the switching characteristics, suggesting that domain-wall propagation among the nucleated multiple domains governs switching. In contrast, devices with further reduced size (120 nm) show normal full switching with increasing probability with current and insignificant dependence of J th on τ, indicating that nucleation governs switching.

Photo-induced micro-mechanical optical switch

DOEpatents

Rajic, Slobodan; Datskos, Panagiotis George; Egert, Charles M.

2002-01-01

An optical switch is formed by introducing light lengthwise to a microcantilever waveguide directed toward a second waveguide. The microcantilever is caused to bend by light emitted from a laser diode orthogonal to the microcantilever and at an energy above the band gap, which induces stress as a result of the generation of free carriers. The bending of the waveguide directs the carrier frequency light to a second receptor waveguide or to a non-responsive surface. The switch may be combined in an array to perform multiple switching functions rapidly and at low energy losses.

MULTIPLE SPARK GAP SWITCH

DOEpatents

Schofield, A.E.

1958-07-22

A multiple spark gap switch of unique construction is described which will permit controlled, simultaneous discharge of several capacitors into a load. The switch construction includes a disc electrode with a plurality of protuberances of generally convex shape on one surface. A firing electrode is insulatingly supponted In each of the electrode protuberances and extends substantially to the apex thereof. Individual electrodes are disposed on an insulating plate parallel with the disc electrode to form a number of spark gaps with the protuberances. These electrodes are each connected to a separate charged capacitor and when a voltage ls applied simultaneously between the trigger electrodes and the dlsc electrode, each spark gap fires to connect its capacitor to the disc electrode and a subsequent load.

Multiple host-switching of Haemosporidia parasites in bats

PubMed Central

Duval, Linda; Robert, Vincent; Csorba, Gabor; Hassanin, Alexandre; Randrianarivelojosia, Milijaona; Walston, Joe; Nhim, Thy; Goodman, Steve M; Ariey, Frédéric

2007-01-01

Background There have been reported cases of host-switching in avian and lizard species of Plasmodium (Apicomplexa, Haemosporidia), as well as in those infecting different primate species. However, no evidence has previously been found for host-swapping between wild birds and mammals. Methods This paper presents the results of the sampling of blood parasites of wild-captured bats from Madagascar and Cambodia. The presence of Haemosporidia infection in these animals is confirmed and cytochrome b gene sequences were used to construct a phylogenetic analysis. Results Results reveal at least three different and independent Haemosporidia evolutionary histories in three different bat lineages from Madagascar and Cambodia. Conclusion Phylogenetic analysis strongly suggests multiple host-switching of Haemosporidia parasites in bats with those from avian and primate hosts. PMID:18045505

Controllability of multi-agent systems with periodically switching topologies and switching leaders

NASA Astrophysics Data System (ADS)

Tian, Lingling; Zhao, Bin; Wang, Long

2018-05-01

This paper considers controllability of multi-agent systems with periodically switching topologies and switching leaders. The concept of m-periodic controllability is proposed, and a criterion for m-periodic controllability is established. The effect of the duration of subsystems on controllability is analysed by utilising a property of analytic functions. In addition, the influence of switching periods on controllability is investigated, and an algorithm is proposed to search for the fewest periods to ensure controllability. A necessary condition for m-periodic controllability is obtained from the perspective of eigenvectors of the subsystems' Laplacian matrices. For a system with switching leaders, it is proved that switching-leader controllability is equivalent to multiple-leader controllability. Furthermore, both the switching order and the tenure of agents being leaders have no effect on the controllability. Some examples are provided to illustrate the theoretical results.

Switched Systems With Multiple Invariant Sets

DTIC Science & Technology

2015-05-06

LaSalle’s invariant set theorem [10] allow us to analyze asymptotic stability of this larger class of systems . LaSalle’s theorem and much of the... Stability and conver- gence for systems with switching equilibria, in: Proc. of the 46th IEEE Conference on Decision and Control , 2007. [8] X. Xu, G...Champaign, Urbana, Illinois 61801 Abstract This paper explores dwell time constraints on switched systems with mul- tiple, possibly disparate

Observation of ambipolar switching in a silver nanoparticle single-electron transistor with multiple molecular floating gates

NASA Astrophysics Data System (ADS)

Yamamoto, Makoto; Shinohara, Shuhei; Tamada, Kaoru; Ishii, Hisao; Noguchi, Yutaka

2016-03-01

Ambipolar switching behavior was observed in a silver nanoparticle (AgNP)-based single-electron transistor (SET) with tetra-tert-butyl copper phthalocyanine (ttbCuPc) as a molecular floating gate. Depending on the wavelength of the incident light, the stability diagram shifted to the negative and positive directions along the gate voltage axis. These results were explained by the photoinduced charging of ttbCuPc molecules in the vicinity of AgNPs. Moreover, multiple device states were induced by the light irradiation at a wavelength of 600 nm, suggesting that multiple ttbCuPc molecules individually worked as a floating gate.

Study of advanced communications satellite systems based on SS-FDMA

NASA Technical Reports Server (NTRS)

Kiesling, J.

1980-01-01

A satellite communication system based on the use of a multiple, contiguous beam satellite antenna and frequency division multiple access (FDMA) is studied. Emphasis is on the evaluation of the feasibility of SS (satellite switching) FDMA technology, particularly the multiple, contiguous beam antenna, the onboard switch and channelization, and on methods to overcome the effects of severe Ka band fading caused by precipitation. This technology is evaluated and plans for technology development and evaluation are given. The application of SS-FDMA to domestic satellite communications is also evaluated. Due to the potentially low cost Earth stations, SS-FDMA is particularly attractive for thin route applications up to several hundred kilobits per second, and offers the potential for competing with terrestrial facilities at low data rates and over short routes. The onboard switch also provides added route flexibility for heavy route systems. The key beneficial SS-FDMA strategy is to simplify and thus reduce the cost of the direct access Earth station at the expense of increased satellite complexity.

Multirate parallel distributed compensation of a cluster in wireless sensor and actor networks

NASA Astrophysics Data System (ADS)

Yang, Chun-xi; Huang, Ling-yun; Zhang, Hao; Hua, Wang

2016-01-01

The stabilisation problem for one of the clusters with bounded multiple random time delays and packet dropouts in wireless sensor and actor networks is investigated in this paper. A new multirate switching model is constructed to describe the feature of this single input multiple output linear system. According to the difficulty of controller design under multi-constraints in multirate switching model, this model can be converted to a Takagi-Sugeno fuzzy model. By designing a multirate parallel distributed compensation, a sufficient condition is established to ensure this closed-loop fuzzy control system to be globally exponentially stable. The solution of the multirate parallel distributed compensation gains can be obtained by solving an auxiliary convex optimisation problem. Finally, two numerical examples are given to show, compared with solving switching controller, multirate parallel distributed compensation can be obtained easily. Furthermore, it has stronger robust stability than arbitrary switching controller and single-rate parallel distributed compensation under the same conditions.

Design Sketches For Optical Crossbar Switches Intended For Large-Scale Parallel Processing Applications

NASA Astrophysics Data System (ADS)

Hartmann, Alfred; Redfield, Steve

1989-04-01

This paper discusses design of large-scale (1000x 1000) optical crossbar switching networks for use in parallel processing supercom-puters. Alternative design sketches for an optical crossbar switching network are presented using free-space optical transmission with either a beam spreading/masking model or a beam steering model for internodal communications. The performances of alternative multiple access channel communications protocol-unslotted and slotted ALOHA and carrier sense multiple access (CSMA)-are compared with the performance of the classic arbitrated bus crossbar of conventional electronic parallel computing. These comparisons indicate an almost inverse relationship between ease of implementation and speed of operation. Practical issues of optical system design are addressed, and an optically addressed, composite spatial light modulator design is presented for fabrication to arbitrarily large scale. The wide range of switch architecture, communications protocol, optical systems design, device fabrication, and system performance problems presented by these design sketches poses a serious challenge to practical exploitation of highly parallel optical interconnects in advanced computer designs.

Tubulin C-terminal Post-translational Modifications Do Not Occur in Wood Forming Tissue of Populus

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

Hu, Hao; Gu, Xi; Xue, Liang-Jiao

Cortical microtubules (MTs) are evolutionarily conserved cytoskeletal components with specialized roles in plants, including regulation of cell wall biogenesis. MT functions and dynamics are dictated by the composition of their monomeric subunits, α- (TUA) and β-tubulins (TUB), which in animals and protists are subject to both transcriptional regulation and post-translational modifications (PTM). While spatiotemporal regulation of tubulin gene expression has been reported in plants, whether and to what extent tubulin PTMs occur in these species remain poorly understood. We chose the woody perennial Populus for investigation of tubulin PTMs in this study, with a particular focus on developing xylem wheremore » high tubulin transcript levels support MT-dependent secondary cell wall deposition. Mass spectrometry and immunodetection concurred that detyrosination, non-tyrosination and glutamylation were essentially absent in tubulins isolated from wood-forming tissues of P. deltoides and P. tremula ×alba. Label-free quantification of tubulin isotypes and RNA-Seq estimation of tubulin transcript abundance were largely consistent with transcriptional regulation. However, two TUB isotypes were detected at noticeably lower levels than expected based on RNA-Seq transcript abundance in both Populus species. These findings led us to conclude that MT composition during wood formation depends exclusively on transcriptional and, to a lesser extent, translational regulation of tubulin isotypes.« less

Trithallium hydrogen bis(sulfate), Tl(3)H(SO(4))(2), in the super-ionic phase by X-ray powder diffraction.

PubMed

Matsuo, Yasumitsu; Kawachi, Shinya; Shimizu, Yuya; Ikehata, Seiichiro

2002-07-01

The structure of trithallium hydrogen bis(sulfate), Tl(3)H(SO(4))(2), in the super-ionic phase has been analyzed by Rietveld analysis of the X-ray powder diffraction pattern. Atomic parameters based on the isotypic Rb(3)H(SeO(4))(2) crystal in space group R3m in the super-ionic phase were used as the starting model, because it has been shown from the comparison of thermal and electric properties in Tl(3)H(SO(4))(2) and M(3)H(SO(4))(2) type crystals (M = Rb, Cs or NH(4)) that the room-temperature Tl(3)H(SO(4))(2) phase is isostructural with the high-temperature R3m-symmetry M(3)H(SO(4))(2) crystals. The structure was determined in the trigonal space group R3m and the Rietveld refinement shows that an hydrogen-bond O-H...O separation is slightly shortened compared with O-H...O separations in isotypic M(3)H(SeO(4))(2) crystals. In addition, it was found that the distortion of the SO(4) tetrahedra in Tl(3)H(SO(4))(2) is less than that in isotypic crystals.

Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and Semiquantitation

PubMed Central

2016-01-01

Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug antibodies that can pose problems for both patient safety and product efficacy. During drug development immunogenicity is usually examined by risk-based approach along with specific strategies for developing “fit-for-purpose” bioanalytical approaches. Enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays are the most widely used platform for ADA detection due to their high sensitivity and throughput. During the past decade, LC/MS has emerged as a promising technology for quantitation of biotherapeutics and protein biomarkers in biological matrices, mainly owing to its high specificity, selectivity, multiplexing, and wide dynamic range. In fully taking these advantages, we describe here an immunocapture-LC/MS methodology for simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly, ADA and/or drug-ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on streptavidin magnetic beads, and separated from human plasma by a magnet. ADA is then released from the beads and subjected to trypsin digestion followed by LC/MS detection of specific universal peptides for each ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve. The proof-of-concept of this methodology is demonstrated by detecting preexisting ADA in human plasma. PMID:27034966

Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and Semiquantitation.

PubMed

Chen, Lin-Zhi; Roos, David; Philip, Elsy

2016-01-01

Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug antibodies that can pose problems for both patient safety and product efficacy. During drug development immunogenicity is usually examined by risk-based approach along with specific strategies for developing "fit-for-purpose" bioanalytical approaches. Enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays are the most widely used platform for ADA detection due to their high sensitivity and throughput. During the past decade, LC/MS has emerged as a promising technology for quantitation of biotherapeutics and protein biomarkers in biological matrices, mainly owing to its high specificity, selectivity, multiplexing, and wide dynamic range. In fully taking these advantages, we describe here an immunocapture-LC/MS methodology for simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly, ADA and/or drug-ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on streptavidin magnetic beads, and separated from human plasma by a magnet. ADA is then released from the beads and subjected to trypsin digestion followed by LC/MS detection of specific universal peptides for each ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve. The proof-of-concept of this methodology is demonstrated by detecting preexisting ADA in human plasma.

Tubulin C-terminal Post-translational Modifications Do Not Occur in Wood Forming Tissue of Populus

DOE PAGES

Hu, Hao; Gu, Xi; Xue, Liang-Jiao; ...

2016-10-13

Cortical microtubules (MTs) are evolutionarily conserved cytoskeletal components with specialized roles in plants, including regulation of cell wall biogenesis. MT functions and dynamics are dictated by the composition of their monomeric subunits, α- (TUA) and β-tubulins (TUB), which in animals and protists are subject to both transcriptional regulation and post-translational modifications (PTM). While spatiotemporal regulation of tubulin gene expression has been reported in plants, whether and to what extent tubulin PTMs occur in these species remain poorly understood. We chose the woody perennial Populus for investigation of tubulin PTMs in this study, with a particular focus on developing xylem wheremore » high tubulin transcript levels support MT-dependent secondary cell wall deposition. Mass spectrometry and immunodetection concurred that detyrosination, non-tyrosination and glutamylation were essentially absent in tubulins isolated from wood-forming tissues of P. deltoides and P. tremula ×alba. Label-free quantification of tubulin isotypes and RNA-Seq estimation of tubulin transcript abundance were largely consistent with transcriptional regulation. However, two TUB isotypes were detected at noticeably lower levels than expected based on RNA-Seq transcript abundance in both Populus species. These findings led us to conclude that MT composition during wood formation depends exclusively on transcriptional and, to a lesser extent, translational regulation of tubulin isotypes.« less

Optical zero-differential pressure switch and its evaluation in a multiple pressure measuring system

NASA Technical Reports Server (NTRS)

Powell, J. A.

1977-01-01

The design of a clamped-diaphragm pressure switch is described in which diaphragm motion is detected by a simple fiber-optic displacement sensor. The switch was evaluated in a pressure measurement system where it detected the zero crossing of the differential pressure between a static test pressure and a tank pressure that was periodically ramped from near zero to fullscale gage pressure. With a ramping frequency of 1 hertz and a full-scale tank pressure of 69 N/sq cm gage (100 psig), the switch delay was as long as 2 milliseconds. Pressure measurement accuracies were 0.25 to 0.75 percent of full scale. Factors affecting switch performance are also discussed.

Global exponential stability for switched memristive neural networks with time-varying delays.

PubMed

Xin, Youming; Li, Yuxia; Cheng, Zunshui; Huang, Xia

2016-08-01

This paper considers the problem of exponential stability for switched memristive neural networks (MNNs) with time-varying delays. Different from most of the existing papers, we model a memristor as a continuous system, and view switched MNNs as switched neural networks with uncertain time-varying parameters. Based on average dwell time technique, mode-dependent average dwell time technique and multiple Lyapunov-Krasovskii functional approach, two conditions are derived to design the switching signal and guarantee the exponential stability of the considered neural networks, which are delay-dependent and formulated by linear matrix inequalities (LMIs). Finally, the effectiveness of the theoretical results is demonstrated by two numerical examples. Copyright © 2016 Elsevier Ltd. All rights reserved.

Photonic Switching Devices Using Light Bullets

NASA Technical Reports Server (NTRS)

Goorjian, Peter M. (Inventor)

1999-01-01

A unique ultra-fast, all-optical switching device or switch is made with readily available, relatively inexpensive, highly nonlinear optical materials. which includes highly nonlinear optical glasses, semiconductor crystals and/or multiple quantum well semiconductor materials. At the specified wavelengths. these optical materials have a sufficiently negative group velocity dispersion and high nonlinear index of refraction to support stable light bullets. The light bullets counter-propagate through, and interact within the waveguide to selectively change each others' directions of propagation into predetermined channels. In one embodiment, the switch utilizes a rectangularly planar slab waveguide. and further includes two central channels and a plurality of lateral channels for guiding the light bullets into and out of the waveguide. An advantage of the present all-optical switching device lies in its practical use of light bullets, thus preventing the degeneration of the pulses due to dispersion and diffraction at the front and back of the pulses. Another advantage of the switching device is the relative insensitivity of the collision process to the time difference in which the counter-propagating pulses enter the waveguide. since. contrary to conventional co-propagating spatial solitons, the relative phase of the colliding pulses does not affect the interaction of these pulses. Yet another feature of the present all-optical switching device is the selection of the light pulse parameters which enables the generation of light bullets in nonlinear optical materials. including highly nonlinear optical glasses and semiconductor materials such as semiconductor crystals and/or multiple quantum well semiconductor materials.

Input and output constraints-based stabilisation of switched nonlinear systems with unstable subsystems and its application

NASA Astrophysics Data System (ADS)

Chen, Chao; Liu, Qian; Zhao, Jun

2018-01-01

This paper studies the problem of stabilisation of switched nonlinear systems with output and input constraints. We propose a recursive approach to solve this issue. None of the subsystems are assumed to be stablisable while the switched system is stabilised by dual design of controllers for subsystems and a switching law. When only dealing with bounded input, we provide nested switching controllers using an extended backstepping procedure. If both input and output constraints are taken into consideration, a Barrier Lyapunov Function is employed during operation to construct multiple Lyapunov functions for switched nonlinear system in the backstepping procedure. As a practical example, the control design of an equilibrium manifold expansion model of aero-engine is given to demonstrate the effectiveness of the proposed design method.

Integration of GaN/AlN all-optical switch with SiN/AlN waveguide utilizing spot-size conversion.

PubMed

Iizuka, Norio; Yoshida, Haruhiko; Managaki, Nobuto; Shimizu, Toshimasa; Hassanet, Sodabanlu; Cumtornkittikul, Chiyasit; Sugiyama, Masakazu; Nakano, Yoshiaki

2009-12-07

Spot-size converters for an all-optical switch utilizing the intersubband transition in GaN/AlN multiple quantum wells are studied with the purpose of reducing operation power by improving the coupling efficiency between the input fiber and the switch. With a stair-like spot-size converter, the absorption saturation of 5 dB is achieved with a pulse energy of 25 pJ. The switch is integrated with a SiN/AlN waveguide and spot-size converters, and the structure provides the possibility of an integration of the switch with other functional devices. To further improve the coupling loss between the waveguide and the switch, triangular-shaped converters are investigated, demonstrating losses as low as 2 dB/facet.

Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice

PubMed Central

1991-01-01

Antigens and infectious agents that stimulate interferon alpha(IFN- alpha) production in mice induce antibody responses that are predominantly of the immunoglobulin (Ig)G2a isotype and contain little or no IgE. This suggested the possibility that IFN-alpha might have a role in directing Ig isotype selection. Consistent with this possibility, we have found that injection of mice with recombinant mouse IFN-alpha suppresses IgE secretion, enhances IgG2a secretion, and has no independent effect on IgG1 secretion in mice stimulated with a foreign anti-IgD antibody. Injection of mice with polyinosinic acid.polycytidylic acid (poly I.C), an inducer of macrophage IFN-alpha production, also suppresses the anti-IgD antibody-induced IgE response and stimulates the IgG2a response; these effects are blocked by a sheep antibody that neutralizes mouse IFN-alpha/beta. Both recombinant IFN- alpha and poly I.C have maximum IgE suppressive and IgG2a stimulatory effects when injected early in the anti-IgD antibody-induced immune response. Addition of IFN-alpha to mouse B cells cultured with lipopolysaccharide (LPS) + interleukin 4 (IL-4) suppresses both IgG1 and IgE production, but much less potently than IFN-gamma. IFN-alpha suppresses anti-IgD antibody-induced increases in the level of splenic IL-4 mRNA, but enhances the anti-IgD antibody-induced increase in the splenic level of IFN-gamma mRNA. These results are consistent with the effect of IFN-alpha on Ig isotype expression in mice, as IL-4 stimulates IgE and suppresses IgG2a secretion while IFN-gamma exerts opposite effects. These observations suggest that antigen presenting cells, by secreting IFN-alpha early in the course of an immune response, can influence the nature of that response both through direct effects on B cells and by influencing the differentiation of T cells. PMID:1940796

Serum antibody responses in pigs trickle-infected with Ascaris and Trichuris: Heritabilities and associations with parasitological findings.

PubMed

Kringel, Helene; Thamsborg, Stig Milan; Petersen, Heidi Huus; Göring, Harald Heinz Herbert; Skallerup, Per; Nejsum, Peter

2015-07-30

A humoral immune response following helminth infection in pigs is well documented. However, it has been difficult to confirm the existence of antibody mediated resistance against the large roundworm, Ascaris suum, and whipworm, Trichuris suis, in experimental settings by correlating worm burdens or egg excretion with specific antibody levels. We set out to investigate the association between worm load and T. suis and A. suum specific serum antibody levels (IgG1, IgG2 and IgA) against excretory-secretory products of adults and third stage larvae, respectively, measured at 0, 7 and 14 weeks p.i. in a trickle-infected F1-resource-population of crossbred pigs (n=195). Furthermore, we wanted to determine the heritability of these antibody isotypes during the course of infection. Most pigs remained infected with A. suum throughout the experiment while they expelled T. suis between 7 and 14 weeks post infection (p.i.). Parasite specific IgG1 and IgA were significantly (P<0.001) elevated after 7 and 14 weeks of infection, whereas parasite specific IgG2 levels only changed slightly at 14 weeks p.i.. However, the observed association between specific antibody isotype levels and faecal egg counts and macroscopic worm load was weak. The relative heritabilities of the different parasite specific isotypes were assessed and resulted in significant heritability estimates for parasite specific IgG1 and IgA. The highest heritabilities were found for A. suum specific IgG1 (h(2)=0.41 and 0.46 at 7 and 14 weeks p.i., respectively). Thus, the present study demonstrates that host genetic factors influence the IgG1 and IgA antibody isotype responses specific to two of the most common gastrointestinal nematodes of swine whereas specific antibody levels were poorly associated with egg excretion and the presence of macroscopic worms. Copyright © 2015. Published by Elsevier B.V.

Stable scalable control of soliton propagation in broadband nonlinear optical waveguides

NASA Astrophysics Data System (ADS)

Peleg, Avner; Nguyen, Quan M.; Huynh, Toan T.

2017-02-01

We develop a method for achieving scalable transmission stabilization and switching of N colliding soliton sequences in optical waveguides with broadband delayed Raman response and narrowband nonlinear gain-loss. We show that dynamics of soliton amplitudes in N-sequence transmission is described by a generalized N-dimensional predator-prey model. Stability and bifurcation analysis for the predator-prey model are used to obtain simple conditions on the physical parameters for robust transmission stabilization as well as on-off and off-on switching of M out of N soliton sequences. Numerical simulations for single-waveguide transmission with a system of N coupled nonlinear Schrödinger equations with 2 ≤ N ≤ 4 show excellent agreement with the predator-prey model's predictions and stable propagation over significantly larger distances compared with other broadband nonlinear single-waveguide systems. Moreover, stable on-off and off-on switching of multiple soliton sequences and stable multiple transmission switching events are demonstrated by the simulations. We discuss the reasons for the robustness and scalability of transmission stabilization and switching in waveguides with broadband delayed Raman response and narrowband nonlinear gain-loss, and explain their advantages compared with other broadband nonlinear waveguides.

Alternatives for reducing relapse rate when switching from natalizumab to fingolimod in multiple sclerosis.

PubMed

Fragoso, Yara Dadalti; Adoni, Tarso; Alves-Leon, Soniza Vieira; Apostolos-Pereira, Samira Luisa; Araujo, Yuna Ribeiro de; Becker, Jefferson; Brooks, Joseph Bruno Bidin; Correa, Eber Castro; Damasceno, Alfredo; Damasceno, Carlos Augusto de Albuquerque; Ferreira, Maria Lucia B; Gama, Paulo Diniz da; Gama, Rodrigo Assad Diniz da; Gomes, Sidney; Goncalves, Marcus Vinicius Magno; Grzesiuk, Anderson Kuntz; Machado, Suzana Costa Nunes; Matta, Andre Palma da Cunha; Mendes, Maria Fernanda; Ribeiro, Taysa Alexandrino Goncalves Jube; Rocha, Cristiane Franklin da; Ruocco, Heloisa Helena; Sato, Henry; Simm, Renata Faria; Tauil, Carlos Bernardo; Vasconcelos, Claudia Cristina Ferreira; Vieira, Vera Lucia Ferreira

2016-02-21

Natalizumab is a therapeutic option for treating multiple sclerosis (MS) and is particularly efficacious for patients with highly active disease. A long washout period has been recommended between withdrawal of natalizumab and start of fingolimod (another option for treating MS). This long washout period has been associated with a significant increase in MS activity. In the present study, a group of 96 patients who were switched from natalizumab to fingolimod had short washout periods between drugs, or monthly corticosteroid pulse therapy if longer washout periods were recommended. This therapeutic approach led to the lowest reported relapse rate so far, among patients with MS switching from natalizumab to fingolimod (8.3%). No complications from short withdrawal were observed in this group of patients.

Multiple beam antenna/switch system study

NASA Technical Reports Server (NTRS)

1989-01-01

In the study of the Multiple Beam Antenna/Switch for the space to ground link (SGL) uplink and downlink services, several issues related to system engineering, antenna, transmit/receive, and switch systems were addressed and the results are provided. Bandwidth allocation at Ku band is inadequate to serve the data rate requirements for the forward and return services. Rain and depolarization effects at EHF, especially at Ka band, pose a significant threat to the link availabilities at heavy rain areas. Hardware induced effects such as the nonlinear characteristics of the power amplifier may necessitate the use of linearizers and limiters. It is also important to identify the components that are susceptible to the space radiation effects and shield or redesign them with rad-hard technologies for meeting the requirements of the space environment.

Coactivation of cognitive control networks during task switching.

PubMed

Yin, Shouhang; Deák, Gedeon; Chen, Antao

2018-01-01

The ability to flexibly switch between tasks is considered an important component of cognitive control that involves frontal and parietal cortical areas. The present study was designed to characterize network dynamics across multiple brain regions during task switching. Functional magnetic resonance images (fMRI) were captured during a standard rule-switching task to identify switching-related brain regions. Multiregional psychophysiological interaction (PPI) analysis was used to examine effective connectivity between these regions. During switching trials, behavioral performance declined and activation of a generic cognitive control network increased. Concurrently, task-related connectivity increased within and between cingulo-opercular and fronto-parietal cognitive control networks. Notably, the left inferior frontal junction (IFJ) was most consistently coactivated with the 2 cognitive control networks. Furthermore, switching-dependent effective connectivity was negatively correlated with behavioral switch costs. The strength of effective connectivity between left IFJ and other regions in the networks predicted individual differences in switch costs. Task switching was supported by coactivated connections within cognitive control networks, with left IFJ potentially acting as a key hub between the fronto-parietal and cingulo-opercular networks. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Mixed isotype class II antigen expression. A novel class II molecule is expressed on a murine B cell lymphoma

PubMed Central

1989-01-01

The structures of Ia molecules expressed by two BALB/c B cell lymphoma lines, A20-1.11 (A20) and 2PK3, were analyzed in an effort to explain the differences in antigen-presenting capacity displayed by these cells. Alloreactive T cell hybridomas specific for I-Ad and antigen- specific, I-Ad-restricted T cells responded well to A20 as the APC. The same alloreactive T cell hybridomas responded weakly or not at all to 2PK3 and the responses of the antigen-specific, I-Ad-restricted T cells were consistently lower to antigen presented by 2PK3 as compared with A20. T cells restricted to I-Ed responded equally well to either A20 or 2PK3 as APC. Additionally 2PK3, but not A20, stimulated a strong syngeneic mixed lymphocyte response. Structural analyses of the Ia antigens revealed that I-A and I-E molecules were expressed by A20, whereas an I-E and a novel I-A-like molecule were expressed by 2PK3. The novel class II molecule was affinity purified from 2PK3 cells using an mAb specific for Ad beta (MK-D6), and this molecule was subsequently shown by an RIA to react with an E alpha-specific mAb (14-4-4S) as well. Chain-specific polyclonal antisera raised against I-A and I-E alpha and beta chains indicated that the 2PK3 "I-A" alpha chain reacted in immunoblot with E alpha-specific and not A alpha-specific antisera, whereas the beta chain reacted with A beta- and not E beta-specific antisera. Peptide map and partial amino acid sequence analyses indicated that the "I-A" molecule expressed by 2PK3 represented a mixed isotype structure resulting from the pairing of Ed alpha with Ad beta. By immunofluorescence staining analysis, 2PK3 did not react with an mAb specific for Ad alpha. 2PK3 was capable of limited antigen presentation through the mixed isotype molecule to I-Ad-restricted OVA-specific T cell hybridomas, although the responses induced were low compared with presentation through I-A on A20. Previous descriptions of the expression of mixed isotype class II molecules in the mouse have resulted primarily from DNA-mediated gene transfer experiments. The results presented indicate that a mixed isotype class II molecule can be expressed naturally. PMID:2647893

Real-time associative memory with photorefractive crystal KNSBN and liquid-crystal optical switches

NASA Astrophysics Data System (ADS)

Xu, Haiying; Yuan, Yang Y.; Yu, Youlong; Xu, Kebin; Xu, Yuhuan; Zhu, De-Rui

1990-05-01

We present a real-time holographic associative memory implemented with photorefractive KNSBN : Co crystal as memory element and liquid crystal electrooptical switches as reflective thresholding device. The experimental results show that the system has real-time multiple-image storage and recall function.

Computer Access. Tech Use Guide: Using Computer Technology.

ERIC Educational Resources Information Center

Council for Exceptional Children, Reston, VA. Center for Special Education Technology.

One of nine brief guides for special educators on using computer technology, this guide focuses on access including adaptations in input devices, output devices, and computer interfaces. Low technology devices include "no-technology" devices (usually modifications to existing devices), simple switches, and multiple switches. High technology input…

Decomposing task-switching costs with the diffusion model.

PubMed

Schmitz, Florian; Voss, Andreas

2012-02-01

In four experiments, task-switching processes were investigated with variants of the alternating runs paradigm and the explicit cueing paradigm. The classical diffusion model for binary decisions (Ratcliff, 1978) was used to dissociate different components of task-switching costs. Findings can be reconciled with the view that task-switching processes take place in successive phases as postulated by multiple-components models of task switching (e.g., Mayr & Kliegl, 2003; Ruthruff, Remington, & Johnston, 2001). At an earlier phase, task-set reconfiguration (Rogers & Monsell, 1995) or cue-encoding (Schneider & Logan, 2005) takes place, at a later phase, the response is selected in accord with constraints set in the first phase. Inertia effects (Allport, Styles, & Hsieh, 1994; Allport & Wylie, 2000) were shown to affect this later stage. Additionally, findings support the notion that response caution contributes to both global as well as to local switching costs when task switches are predictable.

Further evidence for a deficit in switching attention in schizophrenia.

PubMed

Smith, G L; Large, M M; Kavanagh, D J; Karayanidis, F; Barrett, N A; Michie, P T; O'Sullivan, B T

1998-08-01

In this study, sustained, selective, divided, and switching attention, and reloading of working memory were investigated in schizophrenia by using a newly developed Visual Attention Battery (VAB). Twenty-four outpatients with schizophrenia and 24 control participants were studied using the VAB. Performance on VAB components was correlated with performance of standard tests. Patients with schizophrenia were significantly impaired on VAB tasks that required switching of attention and reloading of working memory but had normal performance on tasks involving sustained attention or attention to multiple stimulus features. Switching attention and reloading of working memory were highly correlated with Trails (B-A) score for patients. The decline in performance on the switching-attention task in patients with schizophrenia met criteria for a differential deficit in switching attention. Future research should examine the neurophysiological basis of the switching deficit and its sensitivity and specificity to schizophrenia.

A single CD4 test with 250 cells/mm3 threshold predicts viral suppression in HIV-infected adults failing first-line therapy by clinical criteria.

PubMed

Gilks, Charles F; Walker, A Sarah; Munderi, Paula; Kityo, Cissy; Reid, Andrew; Katabira, Elly; Goodall, Ruth L; Grosskurth, Heiner; Mugyenyi, Peter; Hakim, James; Gibb, Diana M

2013-01-01

In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable. 3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm(3)) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants. Overall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm(3); only 7 (2%) switched with CD4≥250 cells/mm(3), four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66%) CDM participants failed with WHO 4 events, and 77(25%)/30(10%) with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4≥250 cells/mm(3) (28/77; 36%) (p = 0.0002). CD4 monitoring reduced switching with viral suppression: 23/187 (12%) LCM versus 49/181 (27%) CDM had VL<400 copies/ml at failure/switch (p<0.0001). Amongst CDM participants with CD4<250 cells/mm(3) only 11/133 (8%) had VL<400 copies/ml, compared with 38/48 (79%) with CD4≥250 cells/mm(3) (p<0.0001). Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold 'tiebreaker' of ≥250 cells/mm(3) for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 'clinical failures' would particularly avoid premature, costly switch to second-line ART.

A Single CD4 Test with 250 Cells/Mm3 Threshold Predicts Viral Suppression in HIV-Infected Adults Failing First-Line Therapy by Clinical Criteria

PubMed Central

Munderi, Paula; Kityo, Cissy; Reid, Andrew; Katabira, Elly; Goodall, Ruth L.; Grosskurth, Heiner; Mugyenyi, Peter; Hakim, James; Gibb, Diana M.

2013-01-01

Background In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable. Methods 3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm3) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants. Results Overall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm3; only 7 (2%) switched with CD4≥250 cells/mm3, four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66%) CDM participants failed with WHO 4 events, and 77(25%)/30(10%) with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4≥250 cells/mm3 (28/77; 36%) (p = 0.0002). CD4 monitoring reduced switching with viral suppression: 23/187 (12%) LCM versus 49/181 (27%) CDM had VL<400 copies/ml at failure/switch (p<0.0001). Amongst CDM participants with CD4<250 cells/mm3 only 11/133 (8%) had VL<400copies/ml, compared with 38/48 (79%) with CD4≥250 cells/mm3 (p<0.0001). Conclusion Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold ‘tiebreaker’ of ≥250 cells/mm3 for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 ‘clinical failures’ would particularly avoid premature, costly switch to second-line ART. PMID:23437399

Solar-Blind Photodetector with High Avalanche Gains and Bias-Tunable Detecting Functionality Based on Metastable Phase α-Ga2O3/ZnO Isotype Heterostructures.

PubMed

Chen, Xuanhu; Xu, Yang; Zhou, Dong; Yang, Sen; Ren, Fang-Fang; Lu, Hai; Tang, Kun; Gu, Shulin; Zhang, Rong; Zheng, Youdou; Ye, Jiandong

2017-10-25

The metastable α-phase Ga 2 O 3 is an emerging material for developing solar-blind photodetectors and power electronic devices toward civil and military applications. Despite its superior physical properties, the high quality epitaxy of metastable phase α-Ga 2 O 3 remains challenging. To this end, single crystalline α-Ga 2 O 3 epilayers are achieved on nonpolar ZnO (112̅0) substrates for the first time and a high performance Au/α-Ga 2 O 3 /ZnO isotype heterostructure-based Schottky barrier avalanche diode is demonstrated. The device exhibits self-powered functions with a dark current lower than 1 pA, a UV/visible rejection ratio of 10 3 and a detectivity of 9.66 × 10 12 cm Hz 1/2 W -1 . Dual responsivity bands with cutoff wavelengths at 255 and 375 nm are observed with their peak responsivities of 0.50 and 0.071 A W -1 at -5 V, respectively. High photoconductive gain at low bias is governed by a barrier lowing effect at the Au/Ga 2 O 3 and Ga 2 O 3 /ZnO heterointerfaces. The device also allows avalanche multiplication processes initiated by pure electron and hole injections under different illumination conditions. High avalanche gains over 10 3 and a low ionization coefficient ratio of electrons and holes are yielded, leading to a total gain over 10 5 and a high responsivity of 1.10 × 10 4 A W -1 . Such avalanche heterostructures with ultrahigh gains and bias-tunable UV detecting functionality hold promise for developing high performance solar-blind photodetectors.

Enabling Resiliency Operations across Multiple Microgrids with Grid Friendly Appliance Controllers

DOE PAGES

Schneider, Kevin P.; Tuffner, Frank K.; Elizondo, Marcelo A.; ...

2017-02-16

Changes in economic, technological, and environmental policies are resulting in a re-evaluation of the dependence on large central generation facilities and their associated transmission networks. Emerging concepts of smart communities/cities are examining the potential to leverage cleaner sources of generation, as well as integrating electricity generation with other municipal functions. When grid connected, these generation assets can supplement the existing interconnections with the bulk transmission system, and in the event of an extreme event, they can provide power via a collection of microgrids. To achieve the highest level of resiliency, it may be necessary to conduct switching operations to interconnectmore » individual microgrids. While the interconnection of multiple microgrids can increase the resiliency of the system, the associated switching operations can cause large transients in low inertia microgrids. The combination of low system inertia and IEEE 1547 and 1547a-compliant inverters can prevent multiple microgrids from being interconnected during extreme weather events. This study will present a method of using end-use loads equipped with Grid Friendly™ Appliance controllers to facilitate the switching operations between multiple microgrids; operations that are necessary for optimal operations when islanded for resiliency.« less

Enabling Resiliency Operations across Multiple Microgrids with Grid Friendly Appliance Controllers

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

Schneider, Kevin P.; Tuffner, Frank K.; Elizondo, Marcelo A.

Changes in economic, technological, and environmental policies are resulting in a re-evaluation of the dependence on large central generation facilities and their associated transmission networks. Emerging concepts of smart communities/cities are examining the potential to leverage cleaner sources of generation, as well as integrating electricity generation with other municipal functions. When grid connected, these generation assets can supplement the existing interconnections with the bulk transmission system, and in the event of an extreme event, they can provide power via a collection of microgrids. To achieve the highest level of resiliency, it may be necessary to conduct switching operations to interconnectmore » individual microgrids. While the interconnection of multiple microgrids can increase the resiliency of the system, the associated switching operations can cause large transients in low inertia microgrids. The combination of low system inertia and IEEE 1547 and 1547a-compliant inverters can prevent multiple microgrids from being interconnected during extreme weather events. This study will present a method of using end-use loads equipped with Grid Friendly™ Appliance controllers to facilitate the switching operations between multiple microgrids; operations that are necessary for optimal operations when islanded for resiliency.« less

Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores

NASA Astrophysics Data System (ADS)

Bell, Nicholas A. W.; Keyser, Ulrich F.

2016-07-01

The simultaneous detection of a large number of different analytes is important in bionanotechnology research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, we show that highly multiplexed sensing of single molecules can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, we designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signalled by the presence or absence of multiple DNA dumbbell hairpins. We show that a 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows us to simultaneously detect four different antibodies of the same isotype at nanomolar concentration levels.

Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores.

PubMed

Bell, Nicholas A W; Keyser, Ulrich F

2016-07-01

The simultaneous detection of a large number of different analytes is important in bionanotechnology research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, we show that highly multiplexed sensing of single molecules can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, we designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signalled by the presence or absence of multiple DNA dumbbell hairpins. We show that a 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows us to simultaneously detect four different antibodies of the same isotype at nanomolar concentration levels.

Overview of recent trends in diagnosis and management of leptomeningeal multiple myeloma.

PubMed

Yellu, Mahender R; Engel, Jessica M; Ghose, Abhimanyu; Onitilo, Adedayo A

2016-03-01

Neurological complications related to multiple myeloma (MM) are not uncommon; however, direct involvement of the central nervous system (CNS) is extremely rare and represents a diagnostic and therapeutic challenge. Significant survival difference has been noted with the introduction of novel therapy in patients with MM, but their effect on the incidence and their use for management of leptomeningeal myeloma (LMM) is uncertain. Analysis of published data demonstrates its recent increased incidence, median time to CNS presentation, and slight improvement in median survival after diagnosis of LMM. Less common MM isotypes have been overrepresented in LMM. CNS relapse occurred mostly in patients with Durie-Salmon stage III MM. Despite treatments, standard or experimental, the survival rates of LMM remain dismal. Monitoring high risk patients closely, even after achieving complete remission, may be useful in early detection of LMM. As we gain better understanding of LMM, we recommend that future research and clinical care focus on earlier diagnosis and development of more efficient CNS-directed therapy to improve survival in this patient population. Copyright © 2014 John Wiley & Sons, Ltd.

CMOS imager for pointing and tracking applications

NASA Technical Reports Server (NTRS)

Sun, Chao (Inventor); Pain, Bedabrata (Inventor); Yang, Guang (Inventor); Heynssens, Julie B. (Inventor)

2006-01-01

Systems and techniques to realize pointing and tracking applications with CMOS imaging devices. In general, in one implementation, the technique includes: sampling multiple rows and multiple columns of an active pixel sensor array into a memory array (e.g., an on-chip memory array), and reading out the multiple rows and multiple columns sampled in the memory array to provide image data with reduced motion artifact. Various operation modes may be provided, including TDS, CDS, CQS, a tracking mode to read out multiple windows, and/or a mode employing a sample-first-read-later readout scheme. The tracking mode can take advantage of a diagonal switch array. The diagonal switch array, the active pixel sensor array and the memory array can be integrated onto a single imager chip with a controller. This imager device can be part of a larger imaging system for both space-based applications and terrestrial applications.

Stackable Form-Factor Peripheral Component Interconnect Device and Assembly

NASA Technical Reports Server (NTRS)

Somervill, Kevin M. (Inventor); Ng, Tak-kwong (Inventor); Torres-Pomales, Wilfredo (Inventor); Malekpour, Mahyar R. (Inventor)

2013-01-01

A stackable form-factor Peripheral Component Interconnect (PCI) device can be configured as a host controller or a master/target for use on a PCI assembly. PCI device may comprise a multiple-input switch coupled to a PCI bus, a multiplexor coupled to the switch, and a reconfigurable device coupled to one of the switch and multiplexor. The PCI device is configured to support functionality from power-up, and either control function or add-in card function.

Optical Circuit Switched Protocol

NASA Technical Reports Server (NTRS)

Monacos, Steve P. (Inventor)

2000-01-01

The present invention is a system and method embodied in an optical circuit switched protocol for the transmission of data through a network. The optical circuit switched protocol is an all-optical circuit switched network and includes novel optical switching nodes for transmitting optical data packets within a network. Each optical switching node comprises a detector for receiving the header, header detection logic for translating the header into routing information and eliminating the header, and a controller for receiving the routing information and configuring an all optical path within the node. The all optical path located within the node is solely an optical path without having electronic storage of the data and without having optical delay of the data. Since electronic storage of the header is not necessary and the initial header is eliminated by the first detector of the first switching node. multiple identical headers are sent throughout the network so that subsequent switching nodes can receive and read the header for setting up an optical data path.

Antibodies and Their Receptors: Different Potential Roles in Mucosal Defense

PubMed Central

Horton, Rachel E.; Vidarsson, Gestur

2013-01-01

Over recent years it has become increasingly apparent that mucosal antibodies are not only restricted to the IgM and IgA isotypes, but that also other isotypes and particularly IgG can be found in significant quantities at some mucosal surfaces, such as in the genital tract. Their role is more complex than traditionally believed with, among other things, the discovery of novel function of mucosal immunoglobulin receptors. A thorough knowledge in the source and function and mucosal immunoglobulins is particularly important in development of vaccines providing mucosal immunity, and also in the current climate of microbicide development, to combat major world health issues such as HIV. We present here a comprehensive review of human antibody mediated mucosal immunity. PMID:23882268

The PI3K p110delta is required for down-regulation of RAG expression in immature B cells.

PubMed

Llorian, Miriam; Stamataki, Zania; Hill, Susan; Turner, Martin; Mårtensson, Inga-Lill

2007-02-15

At the immature B cell stage the BCR signals the down-regulation of the RAG genes and Ig L chain (LC) allelic and isotype exclusion. The signaling pathway that regulates these events is poorly characterized. We demonstrate that immature B cells from mice deficient in the PI3K catalytic subunit p110delta fail to suppress RAG expression and inappropriately recombine kappa and lambda LC loci. In addition, in the presence of the autoantigen, clonal deletion and receptor editing still takes place, demonstrating that these processes are independent of p110delta. These results demonstrate a role for p110delta in the regulation of RAG gene expression and thereby LC allelic/isotype exclusion.

Immunoglobulins drive terminal maturation of splenic dendritic cells

PubMed Central

Ziętara, Natalia; Łyszkiewicz, Marcin; Puchałka, Jacek; Pei, Gang; Gutierrez, Maximiliano Gabriel; Lienenklaus, Stefan; Hobeika, Elias; Reth, Michael; Martins dos Santos, Vitor A. P.; Krueger, Andreas; Weiss, Siegfried

2013-01-01

Nature and physiological status of antigen-presenting cells, such as dendritic cells DCs, are decisive for the immune reactions elicited. Multiple factors and cell interactions have been described that affect maturation of DCs. Here, we show that DCs arising in the absence of immunoglobulins (Ig) in vivo are impaired in cross-presentation of soluble antigen. This deficiency was due to aberrant cellular targeting of antigen to lysosomes and its rapid degradation. Function of DCs could be restored by transfer of Ig irrespective of antigen specificity and isotype. Modulation of cross-presentation by Ig was inhibited by coapplication of mannan and, thus, likely to be mediated by C-type lectin receptors. This unexpected dependency of splenic DCs on Ig to cross-present antigen provides insights into the interplay between cellular and humoral immunity and the immunomodulatory capacity of Ig. PMID:23345431

Treatment patterns in disease-modifying therapy for patients with multiple sclerosis in the United States.

PubMed

Bonafede, Machaon M; Johnson, Barbara H; Wenten, Madé; Watson, Crystal

2013-10-01

Patients with multiple sclerosis (MS) whose disease activity is inadequately controlled with a platform therapy (interferon beta or glatiramer acetate [GA]) may switch to another platform therapy or escalate therapy to natalizumab or fingolimod, which were approved in the US in 2006 and 2010, respectively. The objective of this study was to describe treatment patterns in patients with multiple sclerosis (MS) in the United States who were followed for 2 years after initiating a disease-modifying therapy (DMT). A retrospective observational cohort study was conducted to examine treatment patterns of initial DMT use (on initial therapy for 2 years with and without gaps of ≥ 60 days, medication switching, and discontinuation) among patients with MS who initiated a platform therapy (interferon-β or glatiramer acetate) or natalizumab between January 1, 2007, and September 30, 2009; the first DMT claim was the index. Eligible patients were identified in the MarketScan Commercial and Medicare Supplemental databases based on continuous enrollment for 6 months before (preindex period) and 24 months after their index date, with a diagnosis of MS and no claim for a previous DMT in the 6-month preindex period. Demographics at index and clinical characteristics during the preindex period were also analyzed. A total of 6181 MS patients were included, with 5735 (92.8%) starting on platform therapy. Natalizumab initiators were more likely to stay on index therapy (32.3% vs 16.9%, P < 0.001) and have fewer treatment gaps of ≥ 60 days (44.8% vs 55.3%, P < 0.001) compared with platform initiators. In addition, natalizumab initiators were less likely to switch treatment (13.9% vs 19.1%, P = 0.007) and took longer to switch (400.9 days vs 330.7 days, P < 0.001) compared with platform initiators. Nearly 79% of platform initiators who switched went to another platform therapy. Approximately two thirds of patients who switched to a third DMT (n = 130) switched to another platform therapy. A total of 9% of natalizumab and platform initiators discontinued DMT within the 2 years. Most MS patients initiating DMT started on platform therapy. Natalizumab initiators tended to stay on index therapy, have fewer treatment gaps, and switch less than platform initiators in the 2 years after treatment initiation. Switching between platform therapies is common despite evidence that MS patients on platform therapy may benefit from switching to natalizumab. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Micromachined mirrors for raster-scanning displays and optical fiber switches

NASA Astrophysics Data System (ADS)

Hagelin, Paul Merritt

Micromachines and micro-optics have the potential to shrink the size and cost of free-space optical systems, enabling a new generation of high-performance, compact projection displays and telecommunications equipment. In raster-scanning displays and optical fiber switches, a free-space optical beam can interact with multiple tilt- up micromirrors fabricated on a single substrate. The size, rotation angle, and flatness of the mirror surfaces determine the number of pixels in a raster-display or ports in an optical switch. Single-chip and two-chip optical raster display systems demonstrate static mirror curvature correction, an integrated electronic driver board, and dynamic micromirror performance. Correction for curvature caused by a stress gradient in the micromirror leads to resolution of 102 by 119 pixels in the single-chip display. The optical design of the two-chip display features in-situ mirror curvature measurement and adjustable image magnification with a single output lens. An electronic driver board synchronizes modulation of the optical source with micromirror actuation for the display of images. Dynamic off-axis mirror motion is shown to have minimal influence on resolution. The confocal switch, a free-space optical fiber cross- connect, incorporates micromirrors having a design similar to the image-refresh scanner. Two micromirror arrays redirect optical beams from an input fiber array to the output fibers. The switch architecture supports simultaneous switching of multiple wavelength channels. A 2x2 switch configuration, using single-mode optical fiber at 1550 mn, is demonstrated with insertion loss of -4.2 dB and cross-talk of -50.5 dB. The micromirrors have sufficient size and angular range for scaling to a 32x32 cross-connect switch that has low insertion-loss and low cross-talk.

Switching LPV Control for High Performance Tactical Aircraft

NASA Technical Reports Server (NTRS)

Lu, Bei; Wu, Fen; Kim, SungWan

2004-01-01

This paper examines a switching Linear Parameter-Varying (LPV) control approach to determine if it is practical to use for flight control designs within a wide angle of attack region. The approach is based on multiple parameter-dependent Lyapunov functions. The full parameter space is partitioned into overlapping subspaces and a family of LPV controllers are designed, each suitable for a specific parameter subspace. The hysteresis switching logic is used to accomplish the transition among different parameter subspaces. The proposed switching LPV control scheme is applied to an F-16 aircraft model with different actuator dynamics in low and high angle of attack regions. The nonlinear simulation results show that the aircraft performs well when switching among different angle of attack regions.

Predictors of switch from depression to mania in bipolar disorder.

PubMed

Niitsu, Tomihisa; Fabbri, Chiara; Serretti, Alessandro

2015-01-01

Manic switch is a relevant issue when treating bipolar depression. Some risk factors have been suggested, but unequivocal findings are lacking. We therefore investigated predictors of switch from depression to mania in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) sample. Manic switch was defined as a depressive episode followed by a (hypo)manic or mixed episode within the following 12 weeks. We assessed possible predictors of switch using generalized linear mixed models (GLMM). 8403 episodes without switch and 512 episodes with switch (1720 subjects) were included in the analysis. Several baseline variables were associated with a higher risk of switch. They were younger age, previous history of: rapid cycling, severe manic symptoms, suicide attempts, amphetamine use and some pharmacological and psychotherapeutic treatments. During the current depressive episode, the identified risk factors were: any possible mood elevation, multiple mania-associated symptoms with at least moderate severity, and comorbid panic attacks. In conclusion, our study suggests that both characteristics of the disease history and clinical features of the current depressive episode may be risk factors for manic switch. Copyright © 2015 Elsevier Ltd. All rights reserved.

An Improved Interacting Multiple Model Filtering Algorithm Based on the Cubature Kalman Filter for Maneuvering Target Tracking.

PubMed

Zhu, Wei; Wang, Wei; Yuan, Gannan

2016-06-01

In order to improve the tracking accuracy, model estimation accuracy and quick response of multiple model maneuvering target tracking, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) is proposed in this paper. In the proposed algorithm, the interacting multiple models (IMM) algorithm processes all the models through a Markov Chain to simultaneously enhance the model tracking accuracy of target tracking. Then a five degree cubature Kalman filter (5CKF) evaluates the surface integral by a higher but deterministic odd ordered spherical cubature rule to improve the tracking accuracy and the model switch sensitivity of the IMM algorithm. Finally, the simulation results demonstrate that the proposed algorithm exhibits quick and smooth switching when disposing different maneuver models, and it also performs better than the interacting multiple models cubature Kalman filter (IMMCKF), interacting multiple models unscented Kalman filter (IMMUKF), 5CKF and the optimal mode transition matrix IMM (OMTM-IMM).

Programmable resistive-switch nanowire transistor logic circuits.

PubMed

Shim, Wooyoung; Yao, Jun; Lieber, Charles M

2014-09-10

Programmable logic arrays (PLA) constitute a promising architecture for developing increasingly complex and functional circuits through nanocomputers from nanoscale building blocks. Here we report a novel one-dimensional PLA element that incorporates resistive switch gate structures on a semiconductor nanowire and show that multiple elements can be integrated to realize functional PLAs. In our PLA element, the gate coupling to the nanowire transistor can be modulated by the memory state of the resistive switch to yield programmable active (transistor) or inactive (resistor) states within a well-defined logic window. Multiple PLA nanowire elements were integrated and programmed to yield a working 2-to-4 demultiplexer with long-term retention. The well-defined, controllable logic window and long-term retention of our new one-dimensional PLA element provide a promising route for building increasingly complex circuits with nanoscale building blocks.

Virus-specific antibody secreting cell, memory B-cell, and sero-antibody responses in the human influenza challenge model.

PubMed

Huang, Kuan-Ying Arthur; Li, Chris Ka-Fai; Clutterbuck, Elizabeth; Chui, Cecilia; Wilkinson, Tom; Gilbert, Anthony; Oxford, John; Lambkin-Williams, Rob; Lin, Tzou-Yien; McMichael, Andrew J; Xu, Xiao-Ning

2014-05-01

 Antibodies play a major role in the protection against influenza virus in human. However, the antibody level is usually short-lived and the cellular mechanisms underlying influenza virus-specific antibody response to acute infection remain unclear.  We studied the kinetics and magnitude of influenza virus-specific B-cell and serum antibody responses in relation to virus replication during the course of influenza infection in healthy adult volunteers who were previously seronegative and experimentally infected with seasonal influenza H1N1 A/Brisbane/59/07 virus.  Our data demonstrated a robust expansion of the virus-specific antibody-secreting cells (ASCs) and memory B cells in the peripheral blood, which correlated with both the throat viral load and the duration of viral shedding. The ASC response was obviously detected on day 7 post-infection when the virus was completely cleared from nasal samples, and serum hemagglutination-inhibition antibodies were still undetectable. On day 28 postinfection, influenza virus-specific B cells were further identified from the circulating compartment of isotype-switched B cells. Virus-specific ASCs could be the earliest marker of B-cell response to a new flu virus infection, such as H7N9 in humans.

Immunologic Memory Induced by a Glycoconjugate Vaccine in a Murine Adoptive Lymphocyte Transfer Model

PubMed Central

Guttormsen, Hilde-Kari; Wetzler, Lee M.; Finberg, Robert W.; Kasper, Dennis L.

1998-01-01

We have developed an adoptive cell transfer model in mice to study the ability of a glycoprotein conjugate vaccine to induce immunologic memory for the polysaccharide moiety. We used type III capsular polysaccharide from the clinically relevant pathogen group B streptococci conjugated to tetanus toxoid (GBSIII-TT) as our model vaccine. GBS are a major cause of neonatal infections in humans, and type-specific antibodies to the capsular polysaccharide protect against invasive disease. Adoptive transfer of splenocytes from mice immunized with the GBSIII-TT conjugate vaccine conferred anti-polysaccharide immunologic memory to naive recipient mice. The transfer of memory occurred in a dose-dependent manner. The observed anamnestic immune response was characterized by (i) more rapid kinetics, (ii) isotype switching from immunoglobulin M (IgM) to IgG, and (iii) 10-fold-higher levels of type III-specific IgG antibody than for the primary response in animals with cells transferred from placebo-immunized mice. The adoptive cell transfer model described in this paper can be used for at least two purposes: (i) to evaluate conjugate vaccines with different physicochemical properties for their ability to induce immunologic memory and (ii) to study the cellular interactions required for an immune response to these molecules. PMID:9573085

Aberrant antibody affinity selection in SHIP-deficient B cells.

PubMed

Leung, Wai-Hang; Tarasenko, Tatiana; Biesova, Zuzana; Kole, Hemanta; Walsh, Elizabeth R; Bolland, Silvia

2013-02-01

The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5'-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of the Immunomodulatory Properties of Streptococcus suis and Group B Streptococcus Capsular Polysaccharides on the Humoral Response

PubMed Central

Calzas, Cynthia; Taillardet, Morgan; Fourati, Insaf Salem; Roy, David; Gottschalk, Marcelo; Soudeyns, Hugo; Defrance, Thierry; Segura, Mariela

2017-01-01

Streptococcus suis and group B Streptococcus (GBS) are encapsulated streptococci causing septicemia and meningitis. Antibodies (Abs) against capsular polysaccharides (CPSs) have a crucial protective role, but the structure/composition of the CPS, including the presence of sialic acid, may interfere with the generation of anti-CPS Ab responses. We investigated the features of the CPS-specific Ab response directed against S. suis serotypes 2 and 14 and GBS serotypes III and V after infection or immunization with purified native or desialylated CPSs in mice. Whereas S. suis-infected mice developed a very low/undetectable CPS-specific IgM response, significant anti-CPS IgM titers were measured in GBS-infected animals (especially for type III GBS). No isotype switching was detected in S. suis- or GBS-infected mice. While the expression of sialic acid was essential for the immunogenicity of purified GBS type III CPS, this sugar was not responsible for the inability of purified S. suis types 2, 14 and GBS type V CPSs to induce a specific Ab response. Thus, other biochemical criteria unrelated to the presence of sialic acid may be responsible for the inaptitude of the host immune system to mount an effective response against certain S. suis and GBS CPS types. PMID:28425925

Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy

PubMed Central

Levin, Mattias; King, Jasmine J.; Glanville, Jacob; Jackson, Katherine J. L.; Looney, Timothy J.; Hoh, Ramona A.; Mari, Adriano; Andersson, Morgan; Greiff, Lennart; Fire, Andrew Z.; Boyd, Scott D.; Ohlin, Mats

2016-01-01

Background Specific immunotherapy (SIT) is the only treatment with proven long-term curative potential in allergic disease. Allergen-specific IgE is the causative agent of allergic disease, and antibodies contribute to SIT, but the effects of SIT on aeroallergen-specific B cell repertoires are not well understood. Objective To characterize the IgE sequences expressed by allergen-specific B cells, and track the fate of these B cell clones during SIT. Methods We have used high-throughput antibody gene sequencing and identification of allergen-specific IgE using combinatorial antibody fragment library technology to analyze immunoglobulin repertoires of blood and nasal mucosa of aeroallergen-sensitized individuals before and during the first year of subcutaneous SIT. Results Of 52 distinct allergen-specific IgE heavy chains from eight allergic donors, 37 were also detected by high-throughput antibody gene sequencing of blood, nasal mucosa, or both sample types. The allergen-specific clones had increased persistence, higher likelihood of belonging to clones expressing other switched isotypes, and possibly larger clone size than the rest of the IgE repertoire. Clone members in nasal tissue showed close mutational relationships. Conclusion Combining functional binding studies, deep antibody repertoire sequencing, and information on clinical outcomes in larger studies may in the future aid assessment of SIT mechanisms and efficacy. PMID:26559321

Mangifera indica L. extract (Vimang) and mangiferin modulate mouse humoral immune responses.

PubMed

García, D; Leiro, J; Delgado, R; Sanmartín, M L; Ubeira, F M

2003-12-01

The present study investigated the effects of orally administered Vimang (an aqueous extract of Mangifera indica) and mangiferin (the major polyphenol present in Vimang) on mouse antibody responses induced by inoculation with spores of microsporidian parasites. Inoculation induced specific antibody production with an exponential timecourse, peaking after about one month. Vimang significantly inhibited this antibody production from about three weeks post-inoculation, and most markedly by four weeks post-inoculation; by contrast, mangiferin had no significant effect. Determination of Ig isotypes showed that the IgM to IgG switch began about four weeks post-inoculation, with IgG2a predominating. Vimang significantly inhibited IgG production, but had no effect on IgM. Mangiferin did no affect either IgM or IgG2a, but significantly enhanced production of IgG1 and IgG2b. Neither Vimang nor mangiferin enhanced specific antibody secretion by splenic plasma cells from mice inoculated with microsporidian spores, whether administered in vivo before serum extraction or in vitro to the culture medium. Inoculation with spores induced splenomegaly, which was significantly reduced by Vimang and significantly enhanced by mangiferin. These results suggest that components of Mangifera indica extracts may be of potential value for modulating the humoral response in different immunopathological disorders. Copyright 2003 John Wiley & Sons, Ltd.

High-Sequence Diversity and Rapid Virus Turnover Contribute to Higher Rates of Coreceptor Switching in Treatment-Experienced Subjects with HIV-1 Viremia.

PubMed

Nedellec, Rebecca; Herbeck, Joshua T; Hunt, Peter W; Deeks, Steven G; Mullins, James I; Anton, Elizabeth D; Reeves, Jacqueline D; Mosier, Donald E

2017-03-01

Coreceptor switching from CCR5 to CXCR4 is common during chronic HIV-1 infection, but is even more common in individuals who have failed antiretroviral therapy (ART). Prior studies have suggested rapid mutation and/or recombination of HIV-1 envelope (env) genes during coreceptor switching. We compared the functional and genotypic changes in env of viruses from viremic subjects who had failed ART just before and after coreceptor switching and compared those to viruses from matched subjects without coreceptor switching. Analysis of multiple unique functional env clones from each subject revealed extensive diversity at both sample time points and rapid diversification of sequences during the 4-month interval in viruses from both 9 subjects with coreceptor switching and 15 control subjects. Only two subjects had envs with evidence of recombination. Three findings distinguished env clones from subjects with coreceptor switching from controls: (1) lower entry efficiency via CCR5; (2) longer V1/V2 regions; and (3), lower nadir CD4 T cell counts during prior years of infection. Most of these subjects harbored virus with lower replicative capacity associated with protease (PR) and/or reverse transcriptase inhibitor resistance mutations, and the extensive diversification tended to lead either to improved entry efficiency via CCR5 or the gain of entry function via CXCR4. These results suggest that R5X4 or X4 variants emerge from a diverse, low-fitness landscape shaped by chronic infection, multiple ART resistance mutations, the availability of target cells, and reduced entry efficiency via CCR5.

Memristive switching of MgO based magnetic tunnel junctions

NASA Astrophysics Data System (ADS)

Krzysteczko, Patryk; Reiss, Günter; Thomas, Andy

2009-09-01

Here we demonstrate that both, tunnel magnetoresistance (TMR) and resistive switching (RS), can be observed simultaneously in nanoscale magnetic tunnel junctions. The devices show bipolar RS of 6% and TMR ratios of about 100%. For each magnetic state, multiple resistive states are created depending on the bias history, which provides a method for multibit data storage and logic. The electronic transport measurements are discussed in the framework of a memristive system. Differently prepared MgO barriers are compared to gain insight into the switching mechanism.

Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells

PubMed Central

St. George, Marc; Ayoub, Ahmed T.; Banerjee, Asok; Churchill, Cassandra D. M.; Winter, Philip; Klobukowski, Mariusz; Cass, Carol E.; Ludueña, Richard F.; Tuszynski, Jack A.; Damaraju, Sambasivarao

2015-01-01

Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives of paclitaxel designed to bind to this intermediate site differentially depending on the isotype of β-tubulin. Since β-tubulin isotypes have tissue-dependent expression—specifically, the βIII isotype is very abundant in aggressive tumors and much less common in normal tissues—this is expected to lead to tubulin targeted drugs that are more efficacious and have less side effects. Seven derivatives of paclitaxel were designed and four of these were amenable for synthesis in sufficient purity and yield for further testing in breast cancer model cell lines. None of the derivatives studied were superior to currently used taxanes, however computer simulations provided insights into the activity of the derivatives. Our results suggest that neither binding to the intermediate binding site nor the final binding site is sufficient to explain the activities of the derivative taxanes studied. These findings highlight the need to iteratively improve on the design of taxanes based on their activity in model systems. Knowledge gained on the ability of the engineered drugs to bind to targets and bring about activity in a predictable manner is a step towards personalizing therapies. PMID:26052950

MFI ratio estimation of ZAP-70 in B-CLL by flow cytometry can be improved by considering the isotype-matched antibody signal.

PubMed

Marquez, M-E; Deglesne, P-A; Suarez, G; Romano, E

2011-04-01

The IgV(H) mutational status of B-cell chronic lymphocytic leukemia (B-CLL) is of prognostic value. Expression of ZAP-70 in B-CLL is a surrogate marker for IgV(H) unmutated (UM). As determination of IgV(H) mutational status involves a methodology currently unavailable for most clinical laboratories, it is important to have available a reliable technique for ZAP-70 estimation in B-CLL. Flow cytometry (FC) is a convenient technique for this purpose. However, there is still no adequate way for data analysis, which would prevent the assignment of false positive or negative expression. We have modified the currently most accepted technique, which uses the ratio of the mean fluorescent index (MFI) of B-CLL to T cells. The MFI for parallel antibody isotype staining is subtracted from the ZAP-70 MFI of both B-CLL and T cells. We validated this technique comparing the results obtained for ZAP-70 expression by FC with those obtained with quantitative PCR for the same patients. We applied the technique in a series of 53 patients. With this modification, a better correlation between ZAP-70 expression and IgV(H) UM was obtained. Thus, the MFI ratio B-CLL/T cell corrected by isotype is a reliable analysis technique to estimate ZAP-70 expression in B-CLL. © 2010 Blackwell Publishing Ltd.

Detection of Bovine IgG Isotypes in a PPA-ELISA for Johne's Disease Diagnosis in Infected Herds

PubMed Central

Fernández, Bárbara; Gilardoni, Liliana Rosa; Jolly, Ana; Colavecchia, Silvia Beatriz; Paolicchi, Fernando Alberto; Mundo, Silvia Leonor

2012-01-01

Johne's Disease or Paratuberculosis is a chronic granulomatous enteritis disease affecting ruminants. Detection of subclinically infected animals is difficult, hampering the control of this disease. The aim of this work was to evaluate the performance of detection of IgG isotypes in a PPA-ELISA to improve the recognition of cattle naturally infected with Map in different stages. A total of 108 animals from Tuberculosis-free herds were grouped as follows: exposed (n = 30), subclinically infected (n = 26), clinically infected (n = 14), and healthy controls (n = 38). Receiver-operating characteristic (ROC) curves of isotypes/PPA-ELISAs were constructed and areas under the curves were compared to evaluate the performance of each test. Our study demonstrated that the conventional PPA-ELISA (detecting IgG) is the best to identify clinically infected animals with high sensitivity (92.9%) and specificity (100%). Meanwhile, IgG2/PPA-ELISA improved the number of subclinically infected cattle detected as compared with conventional IgG/PPA-ELISA (53.8 versus 23.1%). In addition, it had the maximum sensitivity (65.0%, taking into account all Map-infected cattle). In conclusion, the combination of IgG and IgG2/PPA-ELISAs may improve the identification of Map-infected cattle in different stages of disease. The usefulness of IgG2 detection in serological tests for Johne's Disease diagnosis should be further evaluated. PMID:22792511

Detection of Bovine IgG Isotypes in a PPA-ELISA for Johne's Disease Diagnosis in Infected Herds.

PubMed

Fernández, Bárbara; Gilardoni, Liliana Rosa; Jolly, Ana; Colavecchia, Silvia Beatriz; Paolicchi, Fernando Alberto; Mundo, Silvia Leonor

2012-01-01

Johne's Disease or Paratuberculosis is a chronic granulomatous enteritis disease affecting ruminants. Detection of subclinically infected animals is difficult, hampering the control of this disease. The aim of this work was to evaluate the performance of detection of IgG isotypes in a PPA-ELISA to improve the recognition of cattle naturally infected with Map in different stages. A total of 108 animals from Tuberculosis-free herds were grouped as follows: exposed (n = 30), subclinically infected (n = 26), clinically infected (n = 14), and healthy controls (n = 38). Receiver-operating characteristic (ROC) curves of isotypes/PPA-ELISAs were constructed and areas under the curves were compared to evaluate the performance of each test. Our study demonstrated that the conventional PPA-ELISA (detecting IgG) is the best to identify clinically infected animals with high sensitivity (92.9%) and specificity (100%). Meanwhile, IgG2/PPA-ELISA improved the number of subclinically infected cattle detected as compared with conventional IgG/PPA-ELISA (53.8 versus 23.1%). In addition, it had the maximum sensitivity (65.0%, taking into account all Map-infected cattle). In conclusion, the combination of IgG and IgG2/PPA-ELISAs may improve the identification of Map-infected cattle in different stages of disease. The usefulness of IgG2 detection in serological tests for Johne's Disease diagnosis should be further evaluated.

Perceptual and Conceptual Priming of Cue Encoding in Task Switching

ERIC Educational Resources Information Center

Schneider, Darryl W.

2016-01-01

Transition effects in task-cuing experiments can be partitioned into task switching and cue repetition effects by using multiple cues per task. In the present study, the author shows that cue repetition effects can be partitioned into perceptual and conceptual priming effects. In 2 experiments, letters or numbers in their uppercase/lowercase or…

Video signal processing system uses gated current mode switches to perform high speed multiplication and digital-to-analog conversion

NASA Technical Reports Server (NTRS)

Gilliland, M. G.; Rougelot, R. S.; Schumaker, R. A.

1966-01-01

Video signal processor uses special-purpose integrated circuits with nonsaturating current mode switching to accept texture and color information from a digital computer in a visual spaceflight simulator and to combine these, for display on color CRT with analog information concerning fading.

Experimental study of switching in a rho-i(MQW)-eta vertical coupler

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

Cavailles, J.A.; Erman, M.; Woodbridge, K.

1989-11-01

Electrically controlled switching in a vertically arranged directional coupler with GaAs/GaAIAs multiple quantum well waveguides is demonstrated. Coupling lengths and extinction parameters are determined by using a sample processed in such a way that injection conditions are well defined and that the coupler length can be varied continuously.

Mid-infrared passively switched pulsed dual wavelength Ho3+-doped fluoride fiber laser at 3 μm and 2 μm

PubMed Central

Li, Jianfeng; Luo, Hongyu; Wang, Lele; Liu, Yong; Yan, Zhijun; Zhou, Kaiming; Zhang, Lin; Turistsyn, Sergei K.

2015-01-01

Cascade transitions of rare earth ions involved in infrared host fiber provide the potential to generate dual or multiple wavelength lasing at mid-infrared region. In addition, the fast development of saturable absorber (SA) towards the long wavelengths motivates the realization of passively switched mid-infrared pulsed lasers. In this work, by combing the above two techniques, a new phenomenon of passively Q-switched ~3 μm and gain-switched ~2 μm pulses in a shared cavity was demonstrated with a Ho3+-doped fluoride fiber and a specifically designed semiconductor saturable absorber (SESAM) as the SA. The repetition rate of ~2 μm pulses can be tuned between half and same as that of ~3 μm pulses by changing the pump power. The proposed method here will add new capabilities and more flexibility for generating mid-infrared multiple wavelength pulses simultaneously that has important potential applications for laser surgery, material processing, laser radar, and free-space communications, and other areas. PMID:26041105

Study on multiple-hops performance of MOOC sequences-based optical labels for OPS networks

NASA Astrophysics Data System (ADS)

Zhang, Chongfu; Qiu, Kun; Ma, Chunli

2009-11-01

In this paper, we utilize a new study method that is under independent case of multiple optical orthogonal codes to derive the probability function of MOOCS-OPS networks, discuss the performance characteristics for a variety of parameters, and compare some characteristics of the system employed by single optical orthogonal code or multiple optical orthogonal codes sequences-based optical labels. The performance of the system is also calculated, and our results verify that the method is effective. Additionally it is found that performance of MOOCS-OPS networks would, negatively, be worsened, compared with single optical orthogonal code-based optical label for optical packet switching (SOOC-OPS); however, MOOCS-OPS networks can greatly enlarge the scalability of optical packet switching networks.

A tweaking principle for executive control: neuronal circuit mechanism for rule-based task switching and conflict resolution.

PubMed

Ardid, Salva; Wang, Xiao-Jing

2013-12-11

A hallmark of executive control is the brain's agility to shift between different tasks depending on the behavioral rule currently in play. In this work, we propose a "tweaking hypothesis" for task switching: a weak rule signal provides a small bias that is dramatically amplified by reverberating attractor dynamics in neural circuits for stimulus categorization and action selection, leading to an all-or-none reconfiguration of sensory-motor mapping. Based on this principle, we developed a biologically realistic model with multiple modules for task switching. We found that the model quantitatively accounts for complex task switching behavior: switch cost, congruency effect, and task-response interaction; as well as monkey's single-neuron activity associated with task switching. The model yields several testable predictions, in particular, that category-selective neurons play a key role in resolving sensory-motor conflict. This work represents a neural circuit model for task switching and sheds insights in the brain mechanism of a fundamental cognitive capability.

Channel and Timeslot Co-Scheduling with Minimal Channel Switching for Data Aggregation in MWSNs

PubMed Central

Yeoum, Sanggil; Kang, Byungseok; Lee, Jinkyu; Choo, Hyunseung

2017-01-01

Collision-free transmission and efficient data transfer between nodes can be achieved through a set of channels in multichannel wireless sensor networks (MWSNs). While using multiple channels, we have to carefully consider channel interference, channel and time slot (resources) optimization, channel switching delay, and energy consumption. Since sensor nodes operate on low battery power, the energy consumed in channel switching becomes an important challenge. In this paper, we propose channel and time slot scheduling for minimal channel switching in MWSNs, while achieving efficient and collision-free transmission between nodes. The proposed scheme constructs a duty-cycled tree while reducing the amount of channel switching. As a next step, collision-free time slots are assigned to every node based on the minimal data collection delay. The experimental results demonstrate that the validity of our scheme reduces the amount of channel switching by 17.5%, reduces energy consumption for channel switching by 28%, and reduces the schedule length by 46%, as compared to the existing schemes. PMID:28471416

Channel and Timeslot Co-Scheduling with Minimal Channel Switching for Data Aggregation in MWSNs.

PubMed

Yeoum, Sanggil; Kang, Byungseok; Lee, Jinkyu; Choo, Hyunseung

2017-05-04

Collision-free transmission and efficient data transfer between nodes can be achieved through a set of channels in multichannel wireless sensor networks (MWSNs). While using multiple channels, we have to carefully consider channel interference, channel and time slot (resources) optimization, channel switching delay, and energy consumption. Since sensor nodes operate on low battery power, the energy consumed in channel switching becomes an important challenge. In this paper, we propose channel and time slot scheduling for minimal channel switching in MWSNs, while achieving efficient and collision-free transmission between nodes. The proposed scheme constructs a duty-cycled tree while reducing the amount of channel switching. As a next step, collision-free time slots are assigned to every node based on the minimal data collection delay. The experimental results demonstrate that the validity of our scheme reduces the amount of channel switching by 17.5%, reduces energy consumption for channel switching by 28%, and reduces the schedule length by 46%, as compared to the existing schemes.

Do users of risperidone who switch brands because of generic reference pricing fare better or worse than non-switchers? A New Zealand natural experiment.

PubMed

Lessing, Charon; Ashton, Toni; Davis, Peter

2015-11-01

This study evaluated patient health outcomes and any impact on healthcare costs consequent to the implementation of generic reference-pricing of risperidone in New Zealand using national datasets. Reference pricing risperidone reduced the price of the originator brand by 50 % as well as overall expenditure on risperidone tablets. Half of all patients made a single switch to generic risperidone, with the remainder making multiple switches between brands. 1.5 % made a switch-back to the originator brand. No difference was found in use of healthcare services between switchers and non-switchers of the originator brand or versus the comparator group. This refutes the available literature on brand-to-generic and generic-to-generic switching.

New paradigm for task switching strategies while performing multiple tasks: entropy and symbolic dynamics analysis of voluntary patterns.

PubMed

Guastello, Stephen J; Gorin, Hillary; Huschen, Samuel; Peters, Natalie E; Fabisch, Megan; Poston, Kirsten

2012-10-01

It has become well established in laboratory experiments that switching tasks, perhaps due to interruptions at work, incur costs in response time to complete the next task. Conditions are also known that exaggerate or lessen the switching costs. Although switching costs can contribute to fatigue, task switching can also be an adaptive response to fatigue. The present study introduces a new research paradigm for studying the emergence of voluntary task switching regimes, self-organizing processes therein, and the possibly conflicting roles of switching costs and minimum entropy. Fifty-four undergraduates performed 7 different computer-based cognitive tasks producing sets of 49 responses under instructional conditions requiring task quotas or no quotas. The sequences of task choices were analyzed using orbital decomposition to extract pattern types and lengths, which were then classified and compared with regard to Shannon entropy, topological entropy, number of task switches involved, and overall performance. Results indicated that similar but different patterns were generated under the two instructional conditions, and better performance was associated with lower topological entropy. Both entropy metrics were associated with the amount of voluntary task switching. Future research should explore conditions affecting the trade-off between switching costs and entropy, levels of automaticity between task elements, and the role of voluntary switching regimes on fatigue.

An Alternative to the Stay/Switch Equation Assessed When Using a Changeover-Delay

PubMed Central

MacDonall, James S.

2015-01-01

An alternative to the generalized matching equation for understanding concurrent performances is the stay/switch model. For the stay/switch model, the important events are the contingencies and behaviors at each alternative. The current experiment compares the descriptions by two stay/switch equations, the original, empirically derived stay/switch equation and a more theoretically derived equation based on ratios of stay to switch responses matching ratios of stay to switch reinforcers. The present experiment compared descriptions by the original stay/switch equation when using and not using a changeover delay. It also compared descriptions by the more theoretical equation with and without a changeover delay. Finally, it compared descriptions of the concurrent performances by these two equations. Rats were trained in 15 conditions on identical concurrent random-interval schedules in each component of a multiple schedule. A COD operated in only one component. There were no consistent differences in the variance accounted for by each equation of concurrent performances whether or not a COD was used. The simpler equation found greater sensitivity to stay than to switch reinforcers. It also found a COD eliminated the influence of switch reinforcers. Because estimates of parameters were more meaningful when using the more theoretical stay/switch equation it is preferred. PMID:26299548

An alternative to the stay/switch equation assessed when using a changeover-delay.

PubMed

MacDonall, James S

2015-11-01

An alternative to the generalized matching equation for understanding concurrent performances is the stay/switch model. For the stay/switch model, the important events are the contingencies and behaviors at each alternative. The current experiment compares the descriptions by two stay/switch equations, the original, empirically derived stay/switch equation and a more theoretically derived equation based on ratios of stay to switch responses matching ratios of stay to switch reinforcers. The present experiment compared descriptions by the original stay/switch equation when using and not using a changeover delay. It also compared descriptions by the more theoretical equation with and without a changeover delay. Finally, it compared descriptions of the concurrent performances by these two equations. Rats were trained in 15 conditions on identical concurrent random-interval schedules in each component of a multiple schedule. A COD operated in only one component. There were no consistent differences in the variance accounted for by each equation of concurrent performances whether or not a COD was used. The simpler equation found greater sensitivity to stay than to switch reinforcers. It also found a COD eliminated the influence of switch reinforcers. Because estimates of parameters were more meaningful when using the more theoretical stay/switch equation it is preferred. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel Colchicine Derivatives and their Anti-cancer Activity.

PubMed

Johnson, Lorelei; Goping, Ing Swie; Rieger, Aja; Mane, Jonathan Y; Huzil, Torin; Banerjee, Asok; Luduena, Richard; Hassani, Bashar; Winter, Philip; Tuszynski, Jack A

2017-01-01

In this paper we provide an overview of the status of various colchicine derivatives in preclinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin β isotypes, especially in regard to βIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes overexpressed in cancer and decreasing it for normal cells thereby widening the therapeutic window. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

PubMed

Teter, Barbara; Agashivala, Neetu; Kavak, Katelyn; Chouhfeh, Lynn; Hashmonay, Ron; Weinstock-Guttman, Bianca

2014-06-01

Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation. © The Author(s) 2013.

Next generation communications satellites: multiple access and network studies

NASA Technical Reports Server (NTRS)

Meadows, H. E.; Schwartz, M.; Stern, T. E.; Ganguly, S.; Kraimeche, B.; Matsuo, K.; Gopal, I.

1982-01-01

Efficient resource allocation and network design for satellite systems serving heterogeneous user populations with large numbers of small direct-to-user Earth stations are discussed. Focus is on TDMA systems involving a high degree of frequency reuse by means of satellite-switched multiple beams (SSMB) with varying degrees of onboard processing. Algorithms for the efficient utilization of the satellite resources were developed. The effect of skewed traffic, overlapping beams and batched arrivals in packet-switched SSMB systems, integration of stream and bursty traffic, and optimal circuit scheduling in SSMB systems: performance bounds and computational complexity are discussed.

Multiple-stage integrating accelerometer

DOEpatents

Devaney, H.F.

1984-06-27

An accelerometer assembly is provided for use in activating a switch in response to multiple acceleration pulses in series. The accelerometer includes a housing forming a chamber. An inertial mass or piston is slidably disposed in the chamber and spring biased toward a first or reset position. A damping system is also provided to damp piston movement in response to first and subsequent acceleration pulses. Additionally, a cam, including a Z-shaped slot, and cooperating follower pin slidably received therein are mounted to the piston and the housing. The middle or cross-over leg of the Z-shaped slot cooperates with the follower pin to block or limit piston movement and prevent switch activation in response to a lone acceleration pulse. The switch of the assembly is only activated after two or more separate acceleration pulses are sensed and the piston reaches the end of the chamber opposite the reset position.

Patterns of Treatment Switching in Multiple Sclerosis Therapies in US Patients Active on Social Media: Application of Social Media Content Analysis to Health Outcomes Research.

PubMed

Risson, Valéry; Saini, Deepanshu; Bonzani, Ian; Huisman, Alice; Olson, Melvin

2016-03-17

Social media analysis has rarely been applied to the study of specific questions in outcomes research. The aim was to test the applicability of social media analysis to outcomes research using automated listening combined with filtering and analysis of data by specialists. After validation, the process was applied to the study of patterns of treatment switching in multiple sclerosis (MS). A comprehensive listening and analysis process was developed that blended automated listening with filtering and analysis of data by life sciences-qualified analysts and physicians. The population was patients with MS from the United States. Data sources were Facebook, Twitter, blogs, and online forums. Sources were searched for mention of specific oral, injectable, and intravenous (IV) infusion treatments. The representativeness of the social media population was validated by comparison with community survey data and with data from three large US administrative claims databases: MarketScan, PharMetrics Plus, and Department of Defense. A total of 10,260 data points were sampled for manual review: 3025 from Twitter, 3771 from Facebook, 2773 from Internet forums, and 691 from blogs. The demographics of the social media population were similar to those reported from community surveys and claims databases. Mean age was 39 (SD 11) years and 14.56% (326/2239) of the population was older than 50 years. Women, patients aged 30 to 49 years, and those diagnosed for more than 10 years were represented by more data points than other patients were. Women also accounted for a large majority (82.6%, 819/991) of reported switches. Two-fifths of switching patients had lived with their disease for more than 10 years since diagnosis. Most reported switches (55.05%, 927/1684) were from injectable to oral drugs with switches from IV therapies to orals the second largest switch (15.38%, 259/1684). Switches to oral drugs accounted for more than 80% (927/1114) of the switches away from injectable therapies. Four reasons accounted for more than 90% of all switches: severe side effects, lack of efficacy, physicians' advice, and greater ease of use. Side effects were the main reason for switches to oral or to injectable therapies and search for greater efficacy was the most important factor in switches to IV therapies. Cost of medication was the reason for switching in less than 0.5% of patients. Social intelligence can be applied to outcomes research with power to analyze MS patients' personal experiences of treatments and to chart the most common reasons for switching between therapies.

Optical Multiple Access Network (OMAN) for advanced processing satellite applications

NASA Technical Reports Server (NTRS)

Mendez, Antonio J.; Gagliardi, Robert M.; Park, Eugene; Ivancic, William D.; Sherman, Bradley D.

1991-01-01

An OMAN breadboard for exploring advanced processing satellite circuit switch applications is introduced. Network architecture, hardware trade offs, and multiple user interference issues are presented. The breadboard test set up and experimental results are discussed.

Realization of multiple orbital angular momentum modes simultaneously through four-dimensional antenna arrays.

PubMed

Sun, Chao; Yang, Shiwen; Chen, Yikai; Guo, Jixin; Qu, Shiwei

2018-01-09

Electromagnetic waves carrying orbital angular momentum (OAM) in radio frequency range have drawn great attention owing to its potential applications in increasing communication capacity. In this paper, both single-pole single-throw (SPST) switches and single-pole double-throw (SPDT) switches are designed and implemented. Optimal time sequence allows four-dimensional (4-D) circular antenna array to generate multiple OAM-carrying waves as well as enhance the field intensity of each OAM-carrying wave. A novel experimental platform is developed to measure the phase distribution when the transmitting antenna and the receiving antenna operate at different frequencies. The good agreement between the measurement and simulation results demonstrate that 4-D circular antenna array is able to generate multiple OAM modes simultaneously. Furthermore, the superiority of the 4-D circular antenna array in receiving and demodulating multiple OAM-carrying signals is validated through the filter and bit error rate (BER) simulations.

Design of photonic phased array switches using nano electromechanical systems on silicon-on-insulator integration platform

NASA Astrophysics Data System (ADS)

Hussein, Ali Abdulsattar

This thesis presents an introduction to the design and simulation of a novel class of integrated photonic phased array switch elements. The main objective is to use nano-electromechanical (NEMS) based phase shifters of cascaded under-etched slot nanowires that are compact in size and require a small amount of power to operate them. The structure of the switch elements is organized such that it brings the phase shifting elements to the exterior sides of the photonic circuits. The transition slot couplers, used to interconnect the phase shifters, are designed to enable biasing one of the silicon beams of each phase shifter from an electrode located at the side of the phase shifter. The other silicon beam of each phase shifter is biased through the rest of the silicon structure of the switch element, which is taken as a ground. Phased array switch elements ranging from 2x2 up to 8x8 multiple-inputs/multiple-outputs (MIMO) are conveniently designed within reasonable footprints native to the current fabrication technologies. Chapter one presents the general layout of the various designs of the switch elements and demonstrates their novel features. This demonstration will show how waveguide disturbances in the interconnecting network from conventional switch elements can be avoided by adopting an innovative design. Some possible applications for the designed switch elements of different sizes and topologies are indicated throughout the chapter. Chapter two presents the design of the multimode interference (MMI) couplers used in the switch elements as splitters, combiners and waveguide crossovers. Simulation data and design methodologies for the multimode couplers of interest are detailed in this chapter. Chapter three presents the design and analysis of the NEMS-operated phase shifters. Both simulations and numerical analysis are utilized in the design of a 0°-180° capable NEMS-operated phase shifter. Additionally, the response of some of the designed photonic phased array switch elements is demonstrated in this chapter. An executive summary and conclusions sections are also included in the thesis.

High-Sequence Diversity and Rapid Virus Turnover Contribute to Higher Rates of Coreceptor Switching in Treatment-Experienced Subjects with HIV-1 Viremia

PubMed Central

Nedellec, Rebecca; Herbeck, Joshua T.; Hunt, Peter W.; Deeks, Steven G.; Mullins, James I.; Anton, Elizabeth D.; Reeves, Jacqueline D.

2017-01-01

Abstract Coreceptor switching from CCR5 to CXCR4 is common during chronic HIV-1 infection, but is even more common in individuals who have failed antiretroviral therapy (ART). Prior studies have suggested rapid mutation and/or recombination of HIV-1 envelope (env) genes during coreceptor switching. We compared the functional and genotypic changes in env of viruses from viremic subjects who had failed ART just before and after coreceptor switching and compared those to viruses from matched subjects without coreceptor switching. Analysis of multiple unique functional env clones from each subject revealed extensive diversity at both sample time points and rapid diversification of sequences during the 4-month interval in viruses from both 9 subjects with coreceptor switching and 15 control subjects. Only two subjects had envs with evidence of recombination. Three findings distinguished env clones from subjects with coreceptor switching from controls: (1) lower entry efficiency via CCR5; (2) longer V1/V2 regions; and (3), lower nadir CD4 T cell counts during prior years of infection. Most of these subjects harbored virus with lower replicative capacity associated with protease (PR) and/or reverse transcriptase inhibitor resistance mutations, and the extensive diversification tended to lead either to improved entry efficiency via CCR5 or the gain of entry function via CXCR4. These results suggest that R5X4 or X4 variants emerge from a diverse, low-fitness landscape shaped by chronic infection, multiple ART resistance mutations, the availability of target cells, and reduced entry efficiency via CCR5. PMID:27604829

Amplitude steered array

NASA Technical Reports Server (NTRS)

Dietrich, F. J.; Koloboff, G. J.; Martel, R. J.; Johnson, C. C. (Inventor)

1974-01-01

A spin stabilized satellite has an electronically despun antenna array comprising a multiplicity of peripheral antenna elements. A high gain energy beam is established by connecting a suitable fraction or array of the elements in phase. The beam is steered or caused to scan by switching elements in sequence into one end of the array as elements at the other end of the array are switched out. The switching transients normally associated with such steering are avoided by an amplitude control system. Instead of abruptly switching from one element to the next, a fixed value of power is gradually transferred from the element at the trailing edge of the array to the element next to the leading edge.

Context Switching with Multiple Register Windows: A RISC Performance Study

NASA Technical Reports Server (NTRS)

Konsek, Marion B.; Reed, Daniel A.; Watcharawittayakul, Wittaya

1987-01-01

Although previous studies have shown that a large file of overlapping register windows can greatly reduce procedure call/return overhead, the effects of register windows in a multiprogramming environment are poorly understood. This paper investigates the performance of multiprogrammed, reduced instruction set computers (RISCs) as a function of window management strategy. Using an analytic model that reflects context switch and procedure call overheads, we analyze the performance of simple, linearly self-recursive programs. For more complex programs, we present the results of a simulation study. These studies show that a simple strategy that saves all windows prior to a context switch, but restores only a single window following a context switch, performs near optimally.

X-linked agammaglobulinemia in northern Thailand.

PubMed

Trakultivakorn, Muthita; Ochs, Hans D

2006-03-01

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by a failure to generate immunoglobulins of all isotypes due to the absence of mature B cells and plasma cells, secondary to mutations in the Bruton's tyrosine kinase (Btk) gene. We report six patients with XLA, confirmed by mutation analysis, from northern Thailand. The mean age of onset was 2.5 years and the mean age at diagnosis was 7.3 years. All patients had a history of otitis media, pneumonia and arthritis at the time of diagnosis, five patients had developed bronchiectasis and 3 patients septicemia. Other infections reported included sinusitis (5/6), pericarditis (1/6), meningitis (1/6) and pyoderma (1/6). Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus were isolated on multiple occasions. One patient died of sepsis at the age of 16 years. These observations demonstrate that early diagnosis and treatment can improve prognosis and quality of life.

Information Switching Processor (ISP) contention analysis and control

NASA Technical Reports Server (NTRS)

Shyy, D.; Inukai, T.

1993-01-01

Future satellite communications, as a viable means of communications and an alternative to terrestrial networks, demand flexibility and low end-user cost. On-board switching/processing satellites potentially provide these features, allowing flexible interconnection among multiple spot beams, direct to the user communications services using very small aperture terminals (VSAT's), independent uplink and downlink access/transmission system designs optimized to user's traffic requirements, efficient TDM downlink transmission, and better link performance. A flexible switching system on the satellite in conjunction with low-cost user terminals will likely benefit future satellite network users.

Electrical motor/generator drive apparatus and method

DOEpatents

Su, Gui Jia

2013-02-12

The present disclosure includes electrical motor/generator drive systems and methods that significantly reduce inverter direct-current (DC) bus ripple currents and thus the volume and cost of a capacitor. The drive methodology is based on a segmented drive system that does not add switches or passive components but involves reconfiguring inverter switches and motor stator winding connections in a way that allows the formation of multiple, independent drive units and the use of simple alternated switching and optimized Pulse Width Modulation (PWM) schemes to eliminate or significantly reduce the capacitor ripple current.

Radiofrequency Ablation Using a Multiple-Electrode Switching System for Lung Tumors with 2.0-5.0-cm Maximum Diameter: Phase II Clinical Study.

PubMed

Kodama, Hiroshi; Yamakado, Koichiro; Hasegawa, Takaaki; Fujimori, Masashi; Yamanaka, Takashi; Takaki, Haruyuki; Uraki, Junji; Nakatsuka, Atsuhiro; Sakuma, Hajime

2015-12-01

To prospectively evaluate the safety and effectiveness of radiofrequency ablation (RFA) by using a multiple-electrode switching system to treat 2.0-5.0-cm lung tumors. The institutional review board approved this prospective phase II study. Written informed consent was obtained from all patients. Between September 2009 and July 2011, RFA using two or three radiofrequency (RF) electrodes and a multiple-electrode switching system was performed for malignant lung tumors with a maximum tumor diameter of 2.0-5.0 cm in nonsurgical candidates. The primary endpoint was safety, as evaluated using the Common Terminology Criteria for Adverse Events. Patients were observed for at least 1 year. Local tumor progression and overall survival were analyzed with the Kaplan-Meier method. Thirty-three patients (26 men, seven women; mean age, 70.5 years ± 10.0; age range, 46-87 years) with 35 lung tumors with a mean maximum diameter of 3.0 cm ± 0.7 (standard deviation; range, 2.0-4.4 cm) underwent treatment in 35 sessions. No procedure-related death or grade 4 adverse events (AEs) occurred. Grade 3 AEs occurred in four patients (12%), with pleural effusion requiring chest tube placement in two patients, pneumothorax requiring pleural adhesion in one patient, and pulmonary hemorrhage requiring pulmonary artery coil embolization in one patient. Grade 2 AEs were detected in 13 patients (39%). The 1-year local tumor progression and overall survival rates were 12.7% (95% confidence interval [CI]: 1.0, 25.5) and 81.2% (95% CI: 67.6, 94.8). RFA with a multiple-electrode switching system may be a safe therapeutic option with which to treat 2.0-5.0-cm lung cancer tumors.

Intelligent switches of integrated lightwave circuits with core telecommunication functions

NASA Astrophysics Data System (ADS)

Izhaky, Nahum; Duer, Reuven; Berns, Neil; Tal, Eran; Vinikman, Shirly; Schoenwald, Jeffrey S.; Shani, Yosi

2001-05-01

We present a brief overview of a promising switching technology based on Silica on Silicon thermo-optic integrated circuits. This is basically a 2D solid-state optical device capable of non-blocking switching operation. Except of its excellent performance (insertion loss<5dB, switching time<2ms...), the switch enables additional important build-in functionalities. It enables single-to- single channel switching and single-to-multiple channel multicasting/broadcasting. In addition, it has the capability of channel weighting and variable output power control (attenuation), for instance, to equalize signal levels and compensate for unbalanced different optical input powers, or to equalize unbalanced EDFA gain curve. We examine the market segments appropriate for the switch size and technology, followed by a discussion of the basic features of the technology. The discussion is focused on important requirements from the switch and the technology (e.g., insertion loss, power consumption, channel isolation, extinction ratio, switching time, and heat dissipation). The mechanical design is also considered. It must take into account integration of optical fiber, optical planar wafer, analog electronics and digital microprocessor controls, embedded software, and heating power dissipation. The Lynx Photon.8x8 switch is compared to competing technologies, in terms of typical market performance requirements.

Platform for efficient switching between multiple devices in the intensive care unit.

PubMed

De Backere, F; Vanhove, T; Dejonghe, E; Feys, M; Herinckx, T; Vankelecom, J; Decruyenaere, J; De Turck, F

2015-01-01

This article is part of the Focus Theme of METHODS of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". Handheld computers, such as tablets and smartphones, are becoming more and more accessible in the clinical care setting and in Intensive Care Units (ICUs). By making the most useful and appropriate data available on multiple devices and facilitate the switching between those devices, staff members can efficiently integrate them in their workflow, allowing for faster and more accurate decisions. This paper addresses the design of a platform for the efficient switching between multiple devices in the ICU. The key functionalities of the platform are the integration of the platform into the workflow of the medical staff and providing tailored and dynamic information at the point of care. The platform is designed based on a 3-tier architecture with a focus on extensibility, scalability and an optimal user experience. After identification to a device using Near Field Communication (NFC), the appropriate medical information will be shown on the selected device. The visualization of the data is adapted to the type of the device. A web-centric approach was used to enable extensibility and portability. A prototype of the platform was thoroughly evaluated. The scalability, performance and user experience were evaluated. Performance tests show that the response time of the system scales linearly with the amount of data. Measurements with up to 20 devices have shown no performance loss due to the concurrent use of multiple devices. The platform provides a scalable and responsive solution to enable the efficient switching between multiple devices. Due to the web-centric approach new devices can easily be integrated. The performance and scalability of the platform have been evaluated and it was shown that the response time and scalability of the platform was within an acceptable range.

The Influence of Feedback on Task-Switching Performance: A Drift Diffusion Modeling Account.

PubMed

Cohen Hoffing, Russell; Karvelis, Povilas; Rupprechter, Samuel; Seriès, Peggy; Seitz, Aaron R

2018-01-01

Task-switching is an important cognitive skill that facilitates our ability to choose appropriate behavior in a varied and changing environment. Task-switching training studies have sought to improve this ability by practicing switching between multiple tasks. However, an efficacious training paradigm has been difficult to develop in part due to findings that small differences in task parameters influence switching behavior in a non-trivial manner. Here, for the first time we employ the Drift Diffusion Model (DDM) to understand the influence of feedback on task-switching and investigate how drift diffusion parameters change over the course of task switch training. We trained 316 participants on a simple task where they alternated sorting stimuli by color or by shape. Feedback differed in six different ways between subjects groups, ranging from No Feedback (NFB) to a variety of manipulations addressing trial-wise vs. Block Feedback (BFB), rewards vs. punishments, payment bonuses and different payouts depending upon the trial type (switch/non-switch). While overall performance was found to be affected by feedback, no effect of feedback was found on task-switching learning. Drift Diffusion Modeling revealed that the reductions in reaction time (RT) switch cost over the course of training were driven by a continually decreasing decision boundary. Furthermore, feedback effects on RT switch cost were also driven by differences in decision boundary, but not in drift rate. These results reveal that participants systematically modified their task-switching performance without yielding an overall gain in performance.

Relationships between strategy switching and strategy switch costs in young and older adults: a study in arithmetic problem solving.

PubMed

Taillan, Julien; Ardiale, Eléonore; Lemaire, Patrick

2015-01-01

BACKGROUND/STUDY CONTEXT: This study investigated age-related differences in within-item strategy switching (i.e., revising initial strategy choices to select a better strategy while solving a given problem) and in strategy switch costs (i.e., longer latencies when participants switch strategies than when they do not switch strategy during strategy execution). In a computational estimation task, participants had to give approximate products to two-digit multiplication problems (e.g., 41×67) while rounding up (i.e., do 50×70 for 41×67) or rounding down (i.e., do 40×60 for 41×67) operands to their nearest decades. After executing a cued strategy during 1000 ms, participants had the possibility to switch to another strategy (or repeat the same strategy) in a selection condition. In an execution condition, participants were forced to repeat the same strategy or to switch to another strategy. It was found that (1) older adults were less able than young adults to switch strategy after starting to execute a cued strategy (36.1% vs. 45.8%); (2) older adults showed larger switch costs than young adults (422 vs. 223 ms); and (3) strategy switches and strategy switch costs correlated in older adults but not in young adults. These findings have important implications for our understanding of the mechanisms underlying within-item strategy switching and aging effects on these mechanisms as well as, more generally, of strategic variations during cognitive aging.

Nano- and micro-electromechanical switch dynamics

NASA Astrophysics Data System (ADS)

Pulskamp, Jeffrey S.; Proie, Robert M.; Polcawich, Ronald G.

2013-01-01

This paper reports theoretical analysis and experimental results on the dynamics of piezoelectric MEMS mechanical logic relays. The multiple degree of freedom analytical model, based on modal decomposition, utilizes modal parameters obtained from finite element analysis and an analytical model of piezoelectric actuation. The model accounts for exact device geometry, damping, drive waveform variables, and high electric field piezoelectric nonlinearity. The piezoelectrically excited modal force is calculated directly and provides insight into design optimization for switching speed. The model accurately predicts the propagation delay dependence on actuation voltage of mechanically distinct relay designs. The model explains the observed discrepancies in switching speed of these devices relative to single degree of freedom switching speed models and suggests the strong potential for improved switching speed performance in relays designed for mechanical logic and RF circuits through the exploitation of higher order vibrational modes.

Nanoporous frameworks exhibiting multiple stimuli responsiveness

NASA Astrophysics Data System (ADS)

Kundu, Pintu K.; Olsen, Gregory L.; Kiss, Vladimir; Klajn, Rafal

2014-04-01

Nanoporous frameworks are polymeric materials built from rigid molecules, which give rise to their nanoporous structures with applications in gas sorption and storage, catalysis and others. Conceptually new applications could emerge, should these beneficial properties be manipulated by external stimuli in a reversible manner. One approach to render nanoporous frameworks responsive to external signals would be to immobilize molecular switches within their nanopores. Although the majority of molecular switches require conformational freedom to isomerize, and switching in the solid state is prohibited, the nanopores may provide enough room for the switches to efficiently isomerize. Here we describe two families of nanoporous materials incorporating the spiropyran molecular switch. These materials exhibit a variety of interesting properties, including reversible photochromism and acidochromism under solvent-free conditions, light-controlled capture and release of metal ions, as well reversible chromism induced by solvation/desolvation.

Secretion of autoimmune antibodies in the human subcutaneous adipose tissue

PubMed Central

Diaz, Alain; Romero, Maria; Thaller, Seth; Blomberg, Bonnie B.

2018-01-01

The adipose tissue (AT) contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies. In this study we show that adipocytes in the human obese subcutaneous AT (SAT) secrete several pro-inflammatory cytokines and chemokines, which contribute to the establishment and maintenance of local and systemic inflammation, and consequent suboptimal immune responses in obese individuals, as we have previously shown. We also show that pro-inflammatory chemokines recruit immune cells expressing the corresponding receptors to the SAT, where they also contribute to local and systemic inflammation, secreting additional pro-inflammatory mediators. Moreover, we show that the SAT generates autoimmune antibodies. During the development of obesity, reduced oxygen and consequent hypoxia and cell death lead to further release of pro-inflammatory cytokines, “self” protein antigens, cell-free DNA and lipids. All these stimulate class switch and the production of autoimmune IgG antibodies which have been described to be pathogenic. In addition to hypoxia, we have measured cell cytotoxicity and DNA damage mechanisms, which may also contribute to the release of “self” antigens in the SAT. All these processes are significantly elevated in the SAT as compared to the blood. We definitively found that fat-specific IgG antibodies are secreted by B cells in the SAT and that B cells express mRNA for the transcription factor T-bet and the membrane marker CD11c, both involved in the production of autoimmune IgG antibodies. Finally, the SAT also expresses RNA for cytokines known to promote Germinal Center formation, isotype class switch, and plasma cell differentiation. Our results show novel mechanisms for the generation of autoimmune antibody responses in the human SAT and allow the identification of new pathways to possibly manipulate in order to reduce systemic inflammation and autoantibody production in obese individuals. PMID:29768501

Secretion of autoimmune antibodies in the human subcutaneous adipose tissue.

PubMed

Frasca, Daniela; Diaz, Alain; Romero, Maria; Thaller, Seth; Blomberg, Bonnie B

2018-01-01

The adipose tissue (AT) contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies. In this study we show that adipocytes in the human obese subcutaneous AT (SAT) secrete several pro-inflammatory cytokines and chemokines, which contribute to the establishment and maintenance of local and systemic inflammation, and consequent suboptimal immune responses in obese individuals, as we have previously shown. We also show that pro-inflammatory chemokines recruit immune cells expressing the corresponding receptors to the SAT, where they also contribute to local and systemic inflammation, secreting additional pro-inflammatory mediators. Moreover, we show that the SAT generates autoimmune antibodies. During the development of obesity, reduced oxygen and consequent hypoxia and cell death lead to further release of pro-inflammatory cytokines, "self" protein antigens, cell-free DNA and lipids. All these stimulate class switch and the production of autoimmune IgG antibodies which have been described to be pathogenic. In addition to hypoxia, we have measured cell cytotoxicity and DNA damage mechanisms, which may also contribute to the release of "self" antigens in the SAT. All these processes are significantly elevated in the SAT as compared to the blood. We definitively found that fat-specific IgG antibodies are secreted by B cells in the SAT and that B cells express mRNA for the transcription factor T-bet and the membrane marker CD11c, both involved in the production of autoimmune IgG antibodies. Finally, the SAT also expresses RNA for cytokines known to promote Germinal Center formation, isotype class switch, and plasma cell differentiation. Our results show novel mechanisms for the generation of autoimmune antibody responses in the human SAT and allow the identification of new pathways to possibly manipulate in order to reduce systemic inflammation and autoantibody production in obese individuals.

Phase 3 randomised study of the proposed biosimilar adalimumab GP2017 in psoriasis - impact of multiple switches.

PubMed

Blauvelt, A; Lacour, J-P; Fowler, J F; Weinberg, J M; Gospodinov, D; Schuck, E; Jauch-Lembach, J; Balfour, A; Leonardi, C L

2018-06-19

The impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) was assessed following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. This 51-week double-blinded, phase 3 study randomly assigned patients to GP2017 (N=231) or ref-ADMB (N=234) 80 mg subcutaneously at Week 0, then 40 mg biweekly from Week 1. At Week 17, patients were re-randomised to switch (n=126) or continue (n=253) treatment. Primary endpoint: patients achieving Psoriasis Area and Severity Index (PASI)75 at Week 16 (equivalence confirmed if the 95% confidence interval [CI] for the difference in PASI75 between treatments was ±18%). Key secondary endpoint: change from baseline to Week 16 in continuous PASI. Other endpoints: PASI over time, PASI 50/75/90/100, pharmacokinetics, safety, tolerability and immunogenicity for the switched and continued treatment groups. Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66.8% and 65.0%, respectively; 95% CI, -7.46, 11.15) and key secondary (-60.7% and -61.5%, respectively; 95% CI, -3.15, 4.84) endpoints. PASI improved over time and was similar between treatment groups at Week 16, and the switched/continued groups from Weeks 17-51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at Week 16, or the switched/continued groups from Weeks 17-51. No hypersensitivity to adalimumab was reported upon switching. Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Task inhibition, conflict, and the n-2 repetition cost: A combined computational and empirical approach.

PubMed

Sexton, Nicholas J; Cooper, Richard P

2017-05-01

Task inhibition (also known as backward inhibition) is an hypothesised form of cognitive inhibition evident in multi-task situations, with the role of facilitating switching between multiple, competing tasks. This article presents a novel cognitive computational model of a backward inhibition mechanism. By combining aspects of previous cognitive models in task switching and conflict monitoring, the model instantiates the theoretical proposal that backward inhibition is the direct result of conflict between multiple task representations. In a first simulation, we demonstrate that the model produces two effects widely observed in the empirical literature, specifically, reaction time costs for both (n-1) task switches and n-2 task repeats. Through a systematic search of parameter space, we demonstrate that these effects are a general property of the model's theoretical content, and not specific parameter settings. We further demonstrate that the model captures previously reported empirical effects of inter-trial interval on n-2 switch costs. A final simulation extends the paradigm of switching between tasks of asymmetric difficulty to three tasks, and generates novel predictions for n-2 repetition costs. Specifically, the model predicts that n-2 repetition costs associated with hard-easy-hard alternations are greater than for easy-hard-easy alternations. Finally, we report two behavioural experiments testing this hypothesis, with results consistent with the model predictions. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase.

PubMed

Stoyanov, B; Volinia, S; Hanck, T; Rubio, I; Loubtchenkov, M; Malek, D; Stoyanova, S; Vanhaesebroeck, B; Dhand, R; Nürnberg, B

1995-08-04

Phosphoinositide-3 kinase activity is implicated in diverse cellular responses triggered by mammalian cell surface receptors and in the regulation of protein sorting in yeast. Receptors with intrinsic and associated tyrosine kinase activity recruit heterodimeric phosphoinositide-3 kinases that consist of p110 catalytic subunits and p85 adaptor molecules containing Src homology 2 (SH2) domains. A phosphoinositide-3 kinase isotype, p110 gamma, was cloned and characterized. The p110 gamma enzyme was activated in vitro by both the alpha and beta gamma subunits of heterotrimeric guanosine triphosphate (GTP)-binding proteins (G proteins) and did not interact with p85. A potential pleckstrin homology domain is located near its amino terminus. The p110 gamma isotype may link signaling through G protein-coupled receptors to the generation of phosphoinositide second messengers phosphorylated in the D-3 position.

Monoclonal antibodies and toxins--a perspective on function and isotype.

PubMed

Chow, Siu-Kei; Casadevall, Arturo

2012-06-01

Antibody therapy remains the only effective treatment for toxin-mediated diseases. The development of hybridoma technology has allowed the isolation of monoclonal antibodies (mAbs) with high specificity and defined properties, and numerous mAbs have been purified and characterized for their protective efficacy against different toxins. This review summarizes the mAb studies for 6 toxins--Shiga toxin, pertussis toxin, anthrax toxin, ricin toxin, botulinum toxin, and Staphylococcal enterotoxin B (SEB)--and analyzes the prevalence of mAb functions and their isotypes. Here we show that most toxin-binding mAbs resulted from immunization are non-protective and that mAbs with potential therapeutic use are preferably characterized. Various common practices and caveats of protection studies are discussed, with the goal of providing insights for the design of future research on antibody-toxin interactions.

Monoclonal Antibodies and Toxins—A Perspective on Function and Isotype

PubMed Central

Chow, Siu-Kei; Casadevall, Arturo

2012-01-01

Antibody therapy remains the only effective treatment for toxin-mediated diseases. The development of hybridoma technology has allowed the isolation of monoclonal antibodies (mAbs) with high specificity and defined properties, and numerous mAbs have been purified and characterized for their protective efficacy against different toxins. This review summarizes the mAb studies for 6 toxins—Shiga toxin, pertussis toxin, anthrax toxin, ricin toxin, botulinum toxin, and Staphylococcal enterotoxin B (SEB)—and analyzes the prevalence of mAb functions and their isotypes. Here we show that most toxin-binding mAbs resulted from immunization are non-protective and that mAbs with potential therapeutic use are preferably characterized. Various common practices and caveats of protection studies are discussed, with the goal of providing insights for the design of future research on antibody-toxin interactions. PMID:22822456

Crystal structures of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) monohydrate and fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) methanol hemisolvate: rhodium structures that are isotypic with their iridium analogs.

PubMed

Merola, Joseph S; Franks, Marion A

2015-02-01

The crystal structures of two solvates of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) are reported, i.e. one with water in the crystal lattice, fac-[RhCl3(Me3P)3]·H2O, and one with methanol in the crystal lattice, fac-[RhCl3(Me3P)3]·0.5CH3OH. These rhodium compounds exhibit distorted octahedral coordination spheres at the metal and are isotypic with the analogous iridium compounds previously reported by us [Merola et al. (2013 ▶). Polyhedron, 54, 67-73]. Comparison is made between the rhodium and iridium compounds, highlighting their isostructural relationships.

Isotype InGaN/GaN heterobarrier diodes by ammonia molecular beam epitaxy

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

Fireman, Micha N.; Browne, David A.; Speck, James S.

The design of isotype InGaN/GaN heterobarrier diode structures grown by ammonia molecular beam epitaxy is presented. On the (0001) Ga-polar plane, a structure consisting of a surface n{sup +} GaN contact layer, followed by a thin InGaN layer, followed by a thick unintentionally doped (UID) GaN layer, and atop a buried n{sup +} GaN contact layer induces a large conduction band barrier via a depleted UID GaN layer. Suppression of reverse and subthreshold current in such isotype barrier devices under applied bias depends on the quality of this composite layer polarization. Sample series were grown under fixed InGaN growth conditionsmore » that varied either the UID GaN NH{sub 3} flow rate or the UID GaN thickness, and under fixed UID GaN growth conditions that varied InGaN growth conditions. Decreases in subthreshold current and reverse bias current were measured for thicker UID GaN layers and increasing InGaN growth rates. Temperature-dependent analysis indicated that although extracted barrier heights were lower than those predicted by 1D Schrödinger Poisson simulations (0.9 eV–1.4 eV for In compositions from 10% to 15%), optimized growth conditions increased the extracted barrier height from ∼11% to nearly 85% of the simulated values. Potential subthreshold mechanisms are discussed, along with those growth factors which might affect their prevalence.« less

Treatment and prevention of experimental autoimmune myocarditis with CD28 superagonists.

PubMed

Wang, Shu; Liu, Jing; Wang, Min; Zhang, Jinghui; Wang, Zhaohui

2010-01-01

Experimental autoimmune myocarditis (EAM), a rodent model of human dilated cardiomyopathy (DCM), is mediated by an autoimmune mechanism. We investigated whether a CD28 superagonistic antibody selectively targeting CD4+CD25+ regulatory T cells (T(regs)) provides effective therapy for EAM. Four groups of 5 rats were used. The normal control group was immunized with PBS. The EAM group was immunized with porcine myosin. The experimental group was immunized with myosin and superagonistic CD28 antibody JJ316. The final group was immunized with myosin and an unrelated rat IgG. Autoantibody and IL-10 production, CD4+CD25+ cell levels, Foxp3 expression and cardiac histology were analyzed. Anti-myosin autoantibody levels were higher in the EAM and isotype control groups than the normal control group (p < 0.05), and reduced in the CD28-JJ316 group (p < 0.05). The levels of CD25+CD4+ cells, IL-10 and splenocyte Foxp3 expression were significantly lower in the EAM and isotype control groups versus the CD28-JJ316 group (p < 0.05). Infiltration of inflammatory cells was observed in the EAM and isotype control groups, whereas CD28-JJ316 ameliorated myocarditis. CD28 superagonists could be effective in EAM treatment by up-regulating Foxp3 expression and contributing to CD4+CD25+ T(reg) activation and expansion. The enhancement in IL-10 by CD28 superagonists also ameliorated the disease.

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

Saad, Fawzy A.; Harvard Medical School, Boston, MA 02115; Torres, Marie

LOX, the principal enzyme involved in crosslinking of collagen, was the first of several lysyl oxidase isotypes to be characterized. Its active form was believed to be exclusively extracellular. Active LOX was later reported to be present in cell nuclei; its function there is unknown. LOX expression opposes the effect of mutationally activated Ras, which is present in about 30% of human cancers. The mechanism of LOX in countering the action of Ras is also unknown. In the present work, assessment of nuclear protein for possible effects of lysyl oxidase activity led to the discovery that proliferating cells dramatically increasemore » their nuclear protein content when exposed to BAPN ({beta}-aminopropionitrile), a highly specific lysyl oxidase inhibitor that reportedly blocks LOX inhibition of Ras-induced oocyte maturation. In three cell types (PC12 cells, A7r5 smooth muscle cells, and NIH 3T3 fibroblasts), BAPN caused a 1.8-, 1.7-, and 2.1-fold increase in total nuclear protein per cell, respectively, affecting all major components in both nuclear matrix and chromatin fractions. Since nuclear size is correlated with proliferative status, enzyme activity restricting nuclear growth may be involved in the lysyl oxidase tumor suppressive effect. Evidence is also presented for the presence of apparent lysyl oxidase isotype(s) containing a highly conserved LOX active site sequence in the nuclei of PC12 cells, which do not manufacture extracellular lysyl oxidase substrates. Results reported here support the hypothesis that nuclear lysyl oxidase regulates nuclear growth, and thereby modulates cell proliferation.« less

Factors associated with discontinuation of aripiprazole treatment after switching from other antipsychotics in patients with chronic schizophrenia: A prospective observational study.

PubMed

Takaesu, Yoshikazu; Kishimoto, Taishiro; Murakoshi, Akiko; Takahashi, Nobutada; Inoue, Yuichi

2016-02-28

The purpose of the study was to identify factors associated with discontinuation of aripiprazole after switching from other antipsychotics in patients with schizophrenia in real world clinical settings. From January 2011 to December 2012, a prospective, 48-week open-label study was undertaken. Thirty-eight subjects on antipsychotic monotherapy were switched to aripiprazole. Patients who discontinued aripiprazole were compared to those who continued with regards to demographic characteristics as well as treatment factors. Multiple regression analysis was conducted to identify predictors for aripiprazole discontinuation. Thirteen out of 38 patients (34.2%) discontinued aripiprazole during the follow up period. Nine patients (23.7%) discontinued aripiprazole due to worsening of psychotic symptoms. Multiple logistic regression analysis revealed that only the duration of previous antipsychotic treatment was associated with aripiprazole discontinuation after switching to aripiprazole. The receiver operating curve (ROC) analysis identified that the cut-off length for duration of illness to predict aripiprazole discontinuation was 10.5 years. Longer duration of illness was associated with aripiprazole discontinuation. Greater caution may be required when treating such patients with aripiprazole. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Photonic integrated circuit optical buffer for packet-switched networks.

PubMed

Burmeister, Emily F; Mack, John P; Poulsen, Henrik N; Masanović, Milan L; Stamenić, Biljana; Blumenthal, Daniel J; Bowers, John E

2009-04-13

A chip-scale optical buffer performs autonomous contention resolution for 40-byte packets with 99% packet recovery. The buffer consists of a fast, InP-based 2 x 2 optical switch and a silica-on-silicon low loss delay loop. The buffer is demonstrated in recirculating operation, but may be reconfigured in feed-forward operation for longer packet lengths. The recirculating buffer provides packet storage in integer multiples of the delay length of 12.86 ns up to 64.3 ns with 98% packet recovery. The buffer is used to resolve contention between two 40 Gb/s packet streams using multiple photonic chip optical buffers.

Phonological fluency strategy of switching differentiates relapsing-remitting and secondary progressive multiple sclerosis patients.

PubMed

Messinis, L; Kosmidis, M H; Vlahou, C; Malegiannaki, A C; Gatzounis, G; Dimisianos, N; Karra, A; Kiosseoglou, G; Gourzis, P; Papathanasopoulos, P

2013-01-01

The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls.

Mixed H∞ and passive control for linear switched systems via hybrid control approach

NASA Astrophysics Data System (ADS)

Zheng, Qunxian; Ling, Youzhu; Wei, Lisheng; Zhang, Hongbin

2018-03-01

This paper investigates the mixed H∞ and passive control problem for linear switched systems based on a hybrid control strategy. To solve this problem, first, a new performance index is proposed. This performance index can be viewed as the mixed weighted H∞ and passivity performance. Then, the hybrid controllers are used to stabilise the switched systems. The hybrid controllers consist of dynamic output-feedback controllers for every subsystem and state updating controllers at the switching instant. The design of state updating controllers not only depends on the pre-switching subsystem and the post-switching subsystem, but also depends on the measurable output signal. The hybrid controllers proposed in this paper can include some existing ones as special cases. Combine the multiple Lyapunov functions approach with the average dwell time technique, new sufficient conditions are obtained. Under the new conditions, the closed-loop linear switched systems are globally uniformly asymptotically stable with a mixed H∞ and passivity performance index. Moreover, the desired hybrid controllers can be constructed by solving a set of linear matrix inequalities. Finally, a numerical example and a practical example are given.

Multiple switch actuator

DOEpatents

Beyer, Edward T.

1976-01-06

The present invention relates to switches and switch actuating devices to be operated for purposes of arming a bomb or other missile as it is dropped or released from an aircraft. The particular bomb or missile in which this invention is applied is one in which there is a plurality of circuits which are to be armed by the closing of switches upon dropping or releasing of the bomb. The operation of the switches to closed position is normally accomplished by means of a pull-out wire; that is, a wire which is withdrawn from the bomb or missile at the time of release of the bomb, one end of the wire being attached to the aircraft. The conditions to be met are that the arming switches must be positively and surely maintained in open position until the bomb is released and the arming action is effected. The action of the pull-out wire in achieving the arming action must be sure and positive with minimum danger of malfunctioning, jamming or binding.

Can You Multitask? Evidence and Limitations of Task Switching and Multitasking in Emergency Medicine.

PubMed

Skaugset, L Melissa; Farrell, Susan; Carney, Michele; Wolff, Margaret; Santen, Sally A; Perry, Marcia; Cico, Stephen John

2016-08-01

Emergency physicians work in a fast-paced environment that is characterized by frequent interruptions and the expectation that they will perform multiple tasks efficiently and without error while maintaining oversight of the entire emergency department. However, there is a lack of definition and understanding of the behaviors that constitute effective task switching and multitasking, as well as how to improve these skills. This article reviews the literature on task switching and multitasking in a variety of disciplines-including cognitive science, human factors engineering, business, and medicine-to define and describe the successful performance of task switching and multitasking in emergency medicine. Multitasking, defined as the performance of two tasks simultaneously, is not possible except when behaviors become completely automatic; instead, physicians rapidly switch between small tasks. This task switching causes disruption in the primary task and may contribute to error. A framework is described to enhance the understanding and practice of these behaviors. Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Microwave pulse compression from a storage cavity with laser-induced switching

DOEpatents

Bolton, Paul R.

1992-01-01

A laser-induced switch and a multiple cavity configuration are disclosed for producing high power microwave pulses. The microwave pulses are well controlled in wavelength and timing, with a quick rise time and a variable shape and power of the pulse. In addition, a method of reducing pre-pulse leakage to a low level is disclosed. Microwave energy is directed coherently to one or more cavities that stores the energy in a single mode, represented as a standing wave pattern. In order to switch the stored microwave energy out of the main cavity and into the branch waveguide, a laser-actuated switch is provided for the cavity. The switch includes a laser, associated optics for delivering the beam into the main cavity, and a switching gas positioned at an antinode in the main cavity. When actuated, the switching gas ionizes, creating a plasma, which becomes reflective to the microwave energy, changing the resonance of the cavity, and as a result the stored microwave energy is abruptly switched out of the cavity. The laser may directly pre-ionize the switching gas, or it may pump an impurity in the switching gas to an energy level which switches when a pre-selected cavity field is attained. Timing of switching the cavities is controlled by varying the pathlength of the actuating laser beam. For example, the pathlengths may be adjusted to output a single pulse of high power, or a series of quick lower power pulses.

Compact high voltage solid state switch

DOEpatents

Glidden, Steven C.

2003-09-23

A compact, solid state, high voltage switch capable of high conduction current with a high rate of current risetime (high di/dt) that can be used to replace thyratrons in existing and new applications. The switch has multiple thyristors packaged in a single enclosure. Each thyristor has its own gate drive circuit that circuit obtains its energy from the energy that is being switched in the main circuit. The gate drives are triggered with a low voltage, low current pulse isolated by a small inexpensive transformer. The gate circuits can also be triggered with an optical signal, eliminating the trigger transformer altogether. This approach makes it easier to connect many thyristors in series to obtain the hold off voltages of greater than 80 kV.

Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism.

PubMed

Almeida, Julia; Polvorosa, Maria Angeles; Gonzalez-Quintela, Arturo; Madruga, Ignacio; Marcos, Miguel; Pérez-Nieto, Maria Angeles; Hernandez-Cerceño, Maria Luisa; Orfao, Alberto; Laso, Francisco Javier

2015-08-01

Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27(-) and CD27(+) memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-) /sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig-switched memory B lymphocytes and plasmablasts, particularly of IgA(+) cells. Copyright © 2015 by the Research Society on Alcoholism.

Impact of CD40 expression by flowcytometry on outcome of patients with non-Hodgkin's lymphoma.

PubMed

Soliman, Mohamed A; Fathy, Amr Ahmed; Alkilani, Amira; Abd El-Bary, Naser; El-Bassal, Fathai

2009-01-01

Lymphoid malignancies represent a wide variety of disease entities characterized by malignant proliferation of lymphoid cells which have distinct clinical features, cellular morphology, immunophenotype, cytogenetic changes and histologic features. CD40 is a member of the tumor necrosis factor receptor super-family. It was first identified and characterized in B cell, signaling through the CD40 receptor was found to play an important role in multiple events in T-cell dependent antibody response including B-cell survival and proliferation, memory B-cell formation and immunoglobulin isotype switching. The aim of this study is to detect the expression of CD40 on B lymphocytes in patients suffering from Non-Hodgkin's Lymphoma and correlate the results with the patients' response to treatment protocols. This study was carried out on 114 patients, of them only 100 patients completed 4 cycles of chemotherapy and were valuable. Their age was ranged from 17 to 63 years old. Fifteen age and gender matched individuals were, also, selected as a control group. CD40 expression was measured on peripheral blood samples by flowcytometry at patient's presentation as well as after 4 cycles of chemotherapy. This study showed that there's significant decrease in the mean values of % of CD40 on B-cell in patients with NHL in all stages when compared with normal control group. Also the study showed that there's statistical significant correlation between percent of CD40 on B-lymphocytes and stage of lymphoma, i.e., the more advanced stage, the lower the % of CD40 on B-cell. After receiving a corresponding treatment, the CD40 expression is increased in significant correlation with the response to treatment. (This is a preliminary result after 4 cycles of CHOP treatment). We concluded that CD40 Lymphocyte development occurs in discrete functional steps that are defined by the onset of expression is highly expressed in healthy subjects and its expression on B-lymphocyte is decreased with advanced stage of NHL. Percent of CD40 on B-lymphocyte can be considered as an evaluation marker for outcome of treatment in NHL patients as its expression is increased in responding patients.

Observer-based H∞ resilient control for a class of switched LPV systems and its application

NASA Astrophysics Data System (ADS)

Yang, Dong; Zhao, Jun

2016-11-01

This paper deals with the issue of observer-based H∞ resilient control for a class of switched linear parameter-varying (LPV) systems by utilising a multiple parameter-dependent Lyapunov functions method. First, attention is focused upon the design of a resilient observer, an observer-based resilient controller and a parameter and estimate state-dependent switching signal, which can stabilise and achieve the disturbance attenuation for the given systems. Then, a solvability condition of the H∞ resilient control problem is given in terms of matrix inequality for the switched LPV systems. This condition allows the H∞ resilient control problem for each individual subsystem to be unsolvable. The observer, controller, and switching signal are explicitly computed by solving linear matrix inequalities (LMIs). Finally, the effectiveness of the proposed control scheme is illustrated by its application to a turbofan engine, which can hardly be handled by the existing approaches.

Principles of dynamical modularity in biological regulatory networks

PubMed Central

Deritei, Dávid; Aird, William C.; Ercsey-Ravasz, Mária; Regan, Erzsébet Ravasz

2016-01-01

Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory. We posit that distinct phenotype-combinations are generated by interactions among robust regulatory switches, each in control of a discrete set of phenotypic outcomes. First, we demonstrate the advantage of characterizing multi-switch regulatory systems in terms of their constituent switches by building a multiswitch cell cycle model which points to novel, testable interactions critical for early G2/M commitment to division. Second, we define quantitative measures of dynamical modularity, namely that global cell states are discrete combinations of switch-level phenotypes. Finally, we formulate three general principles that govern the way coupled switches coordinate their function. PMID:26979940

Multi-function all optical packet switch by periodic wavelength arrangement in an arrayed waveguide grating and wideband optical filters.

PubMed

Feng, Kai-Ming; Wu, Chung-Yu; Wen, Yu-Hsiang

2012-01-16

By utilizing the cyclic filtering function of an NxN arrayed waveguide grating (AWG), we propose and experimentally demonstrate a novel multi-function all optical packet switching (OPS) architecture by applying a periodical wavelength arrangement between the AWG in the optical routing/buffering unit and a set of wideband optical filters in the switched output ports to achieve the desired routing and buffering functions. The proposed OPS employs only one tunable wavelength converter at the input port to convert the input wavelength to a designated wavelength which reduces the number of active optical components and thus the complexity of the traffic control is simplified in the OPS. With the proposed OPS architecture, multiple optical packet switching functions, including arbitrary packet switching and buffering, first-in-first-out (FIFO) packet multiplexing, packet demultiplexing and packet add/drop multiplexing, have been successfully demonstrated.

The impact on health outcomes and healthcare utilisation of switching to generic medicines consequent to reference pricing: the case of lamotrigine in New Zealand.

PubMed

Lessing, Charon; Ashton, Toni; Davis, Peter

2014-10-01

Many countries have implemented generic reference pricing and substitution as methods of containing pharmaceutical expenditure. However, resistance to switching between medicines is apparent, especially in the case of anti-epileptic medicines. This study sought to exploit a nation-wide policy intervention on generic reference pricing in New Zealand to evaluate the health outcomes of patients switching from originator to generic lamotrigine, an anti-epileptic medicine. A retrospective study using the national health collections and prescription records was conducted comparing patients who switched from originator brand to generic lamotrigine with patients who remained on the originator brand. Primary outcome measures included switch behaviour, changes in utilisation of healthcare services at emergency departments, hospitalisations and use of specialist services, and mortality. Approximately one-quarter of all patients using the originator brand of lamotrigine switched to generic lamotrigine, half of whom made the switch within 60 days of the policy implementation. Multiple switches (three or more) between generic and brand products were evident for around 10% of switchers. Switch-back rates of 3% were apparent within 30 days post-switch. No difference in heath outcome measures was associated with switching from originator lamotrigine to a generic equivalent and hence no increased costs could be found for switchers. Switching from brand to generic lamotrigine is largely devoid of adverse health outcomes; however, creating an incentive to ensure a greater proportion of patients switch to generic lamotrigine is required to achieve maximal financial savings from a policy of generic reference pricing.

Operations manual for the patient assist device. [to handle electrical appliances

NASA Technical Reports Server (NTRS)

Schrader, M. A.

1973-01-01

Quadriplegic patients and multiple amputee patients are almost totally dependent on nursing personnel for any activities or interests in which they participate. A patient assist device is reported which provides patient control over electrical devices in his environment. The patient operates three switches to acquire control over a desired electrical appliance. The type switches employed are chosen to conform to patient capabilities, even when such capabilities are as limited as eye or head movements. The switch operations are sensed and converted into command signals by the patient assist device to control ten electrical appliances simulataneously and independently.

Improved multi-level capability in Si3N4-based resistive switching memory using continuous gradual reset switching

NASA Astrophysics Data System (ADS)

Kim, Sungjun; Park, Byung-Gook

2017-01-01

In this letter, we compare three different types of reset switching behavior in a bipolar resistive random-access memory (RRAM) system that is housed in a Ni/Si3N4/Si structure. The abrupt, step-like gradual and continuous gradual reset transitions are largely determined by the low-resistance state (LRS). For abrupt reset switching, the large conducting path shows ohmic behavior or has a weak nonlinear current-voltage (I-V) characteristics in the LRS. For gradual switching, including both the step-like and continuous reset types, trap-assisted direct tunneling is dominant in the low-voltage regime, while trap-assisted Fowler-Nordheim tunneling is dominant in the high-voltage regime, thus causing nonlinear I-V characteristics. More importantly, we evaluate the multi-level capabilities of the two different gradual switching types, including both step-like and continuous reset behavior, using identical and incremental voltage conditions. Finer control of the conductance level with good uniformity is achieved in continuous gradual reset switching when compared to that in step-like gradual reset switching. For continuous reset switching, a single conducting path, which initially has a tunneling gap, gradually responds to pulses with even and identical amplitudes, while for step-like reset switching, the multiple conducting paths only respond to incremental pulses to obtain effective multi-level states.

Using multiple-accumulator CMACs to improve efficiency of the X part of an input-buffered FX correlator

NASA Astrophysics Data System (ADS)

Lapshev, Stepan; Hasan, S. M. Rezaul

2017-04-01

This paper presents the approach of using complex multiplier-accumulators (CMACs) with multiple accumulators to reduce the total number of memory operations in an input-buffered architecture for the X part of an FX correlator. A processing unit of this architecture uses an array of CMACs that are reused for different groups of baselines. The disadvantage of processing correlations in this way is that each input data sample has to be read multiple times from the memory because each input signal is used in many of these baseline groups. While a one-accumulator CMAC cannot switch to a different baseline until it is finished integrating the current one, a multiple-accumulator CMAC can. Thus, the array of multiple-accumulator CMACs can switch between processing different baselines that share some input signals at any moment to reuse the current data in the processing buffers. In this way significant reductions in the number of memory read operations are achieved with only a few accumulators per CMAC. For example, for a large number of input signals three-accumulator CMACs reduce the total number of memory operations by more than a third. Simulated energy measurements of four VLSI designs in a high-performance 28 nm CMOS technology are presented in this paper to demonstrate that using multiple accumulators can also lead to reduced power dissipation of the processing array. Using three accumulators as opposed to one has been found to reduce the overall energy of 8-bit CMACs by 1.4% through the reduction of the switching activity within their circuits, which is in addition to a more than 30% reduction in the memory.

Antibody-defective, genetically susceptible CBA/N mice have an altered Salmonella typhimurium-specific B cell repertoire.

PubMed

Duran, L W; Metcalf, E S

1987-01-01

CBA/N mice, which express the X-linked immunodeficiency gene xid, are susceptible to Salmonella typhimurium. The basis for this susceptibility is currently unknown. However, previous studies (10) from this laboratory have provided evidence that susceptibility may be due to a defective anti-S. typhimurium antibody response. In that report we hypothesized that the defective antibody response may be a reflection of an altered S. typhimurium-specific B cell repertoire. In the studies described here, we have investigated this hypothesis using a modification of the in vitro splenic focus system. The frequency and characteristics of salmonella-specific B cells in normal, innately resistant, CBA/Ca mice have been compared with those of salmonella-susceptible, anti-S. typhimurium antibody-defective CBA/N mice. The results show that CBA/N mice express no primary or secondary S. typhimurium-specific B cell precursors after stimulation with an acetone-killed and dried (AKD) preparation of S. typhimurium strain TML. However, after three immunizations, the CBA/N tertiary frequency of 15.4 per 10(6) splenic B cells was similar to the primary precursor frequency in immunologically normal CBA/Ca mice, but 23-fold lower than the tertiary precursor frequency in CBA/Ca control mice. Moreover, CBA/N mice had an altered isotype distribution pattern after stimulation with AKD-TML. Greater than 70% of the tertiary CBA/N TML-specific B cells secreted IgG2, in contrast to either nonimmune or primed control mice. In addition, 80% of the CBA/N TML-specific B cells secreted only a single isotype, whereas the majority of B cells from primed normal mice secreted multiple isotypes. Fine specificity analysis of the TML-specific B cells indicated that the array of antigenic determinants to which CBA/N B cells could respond was restricted. Although the majority of primed CBA/Ca and primed CBA/N B cells were specific for LPS, the fine specificity pattern exhibited by CBA/N B cells was similar to that observed in unprimed normal mice, i.e., the vast majority were specific for the O antigen region of the LPS molecule. In contrast, a major portion of the LPS-specific B cells in primed CBA/Ca mice were directed against the KDO/lipid A region of the LPS molecule. Therefore, it appears that CBA/N mice lack or are unable to stimulate the B cell subset that predominates in primed, normal mice. Taken together, these studies indicate that the basis for susceptibility of CBA/N mice to S. typhimurium is multifactorial and suggests that the inability of some animals to respond to some infectious agents may be related to holes in their B cell repertoire.

Multiple-electrode radiofrequency ablation: simultaneous production of separate zones of coagulation in an in vivo porcine liver model.

PubMed

Laeseke, Paul F; Sampson, Lisa A; Haemmerich, Dieter; Brace, Chris L; Fine, Jason P; Frey, Tina M; Winter, Thomas C; Lee, Fred T

2005-12-01

A multiple-electrode radiofrequency (RF) system was developed based on switching between electrodes that allows for the simultaneous use of as many as three electrically independent electrodes. The purpose of this study was to determine if each multiple-electrode ablation zone is identical to an ablation zone created with conventional single-electrode mode. Nine female domestic pigs (mean weight, 90 kg) were used for this study. A prototype monopolar multiple-electrode RF ablation system was created with use of an RF generator and an electronic switching algorithm. A maximum of three electrodes can be used simultaneously by switching between electrodes at each impedance spike (30 omega greater than baseline levels). A total of 39 zones of ablation were created at open laparotomy in pig livers with use of a conventional single electrode (n = 9), two single electrodes simultaneously (n = 6 ablations; 12 ablation zones), or three single electrodes simultaneously (n = 6 ablations; 18 ablation zones). RF electrodes were spaced in separate lobes of the liver when multiple zones of coagulation were created simultaneously. Animals were euthanized after RF ablation, livers were removed, and ablation zones were sectioned and measured. Zones of coagulation created simultaneously with two or three electrodes were equivalent to ablation zones created with use of conventional single-electrode ablation. No significant differences were observed among control animals treated with a single electrode, those with two separate zones of ablation created simultaneously, and those with three simultaneously created ablation zones in terms of mean (+/-SD) minimum diameter (1.6 cm +/- 0.6, 1.6 cm +/- 0.5, and 1.7 cm +/- 0.4, respectively), maximum diameter (2.0 cm +/- 0.5, 2.3 cm +/- 0.5, 2.2 cm +/- 0.5, respectively), and volume (6.7 cm3 +/- 3.7, 7.4 cm3 +/- 3.8, and 7.8 cm3 +/- 3.9; P > .30, analysis of variance, pairwise t-test comparisons). A rapid-switching multiple-electrode RF system was able to simultaneously create as many as three separate ablation zones of equivalent size compared with single-electrode controls. This system would allow physicians to simultaneously treat multiple tumors, substantially reducing procedure time and anesthesia risk.

Circuit-switch architecture for a 30/20-GHz FDMA/TDM geostationary satellite communications network

NASA Technical Reports Server (NTRS)

Ivancic, William D.

1992-01-01

A circuit switching architecture is described for a 30/20 GHz frequency division, multiple access uplink/time division multiplexed downlink (FDMA/TDM) geostationary satellite communications network. Critical subsystems and problem areas are identified and addressed. Work was concentrated primarily on the space segment; however, the ground segment was considered concurrently to ensure cost efficiency and realistic operational constraints.

Destination-directed, packet-switching architecture for 30/20-GHz FDMA/TDM geostationary communications satellite network

NASA Technical Reports Server (NTRS)

Ivancic, William D.; Shalkhauser, Mary JO

1992-01-01

A destination-directed packet switching architecture for a 30/20-GHz frequency division multiple access/time division multiplexed (FDMA/TDM) geostationary satellite communications network is discussed. Critical subsystems and problem areas are identified and addressed. Efforts have concentrated heavily on the space segment; however, the ground segment has been considered concurrently to ensure cost efficiency and realistic operational constraints.

Three Temperature Regimes in Superconducting Photon Detectors: Quantum, Thermal and Multiple Phase-Slips as Generators of Dark Counts

PubMed Central

Murphy, Andrew; Semenov, Alexander; Korneev, Alexander; Korneeva, Yulia; Gol’tsman, Gregory; Bezryadin, Alexey

2015-01-01

We perform measurements of the switching current distributions of three w ≈ 120 nm wide, 4 nm thick NbN superconducting strips which are used for single-photon detectors. These strips are much wider than the diameter of the vortex cores, so they are classified as quasi-two-dimensional (quasi-2D). We discover evidence of macroscopic quantum tunneling by observing the saturation of the standard deviation of the switching distributions at temperatures around 2 K. We analyze our results using the Kurkijärvi-Garg model and find that the escape temperature also saturates at low temperatures, confirming that at sufficiently low temperatures, macroscopic quantum tunneling is possible in quasi-2D strips and can contribute to dark counts observed in single photon detectors. At the highest temperatures the system enters a multiple phase-slip regime. In this range single phase-slips are unable to produce dark counts and the fluctuations in the switching current are reduced. PMID:25988591

Electron transport and light-harvesting switches in cyanobacteria

PubMed Central

Mullineaux, Conrad W.

2014-01-01

Cyanobacteria possess multiple mechanisms for regulating the pathways of photosynthetic and respiratory electron transport. Electron transport may be regulated indirectly by controlling the transfer of excitation energy from the light-harvesting complexes, or it may be more directly regulated by controlling the stoichiometry, localization, and interactions of photosynthetic and respiratory electron transport complexes. Regulation of the extent of linear vs. cyclic electron transport is particularly important for controlling the redox balance of the cell. This review discusses what is known of the regulatory mechanisms and the timescales on which they occur, with particular regard to the structural reorganization needed and the constraints imposed by the limited mobility of membrane-integral proteins in the crowded thylakoid membrane. Switching mechanisms requiring substantial movement of integral thylakoid membrane proteins occur on slower timescales than those that require the movement only of cytoplasmic or extrinsic membrane proteins. This difference is probably due to the restricted diffusion of membrane-integral proteins. Multiple switching mechanisms may be needed to regulate electron transport on different timescales. PMID:24478787

Three temperature regimes in superconducting photon detectors: quantum, thermal and multiple phase-slips as generators of dark counts.

PubMed

Murphy, Andrew; Semenov, Alexander; Korneev, Alexander; Korneeva, Yulia; Gol'tsman, Gregory; Bezryadin, Alexey

2015-05-19

We perform measurements of the switching current distributions of three w ≈ 120 nm wide, 4 nm thick NbN superconducting strips which are used for single-photon detectors. These strips are much wider than the diameter of the vortex cores, so they are classified as quasi-two-dimensional (quasi-2D). We discover evidence of macroscopic quantum tunneling by observing the saturation of the standard deviation of the switching distributions at temperatures around 2 K. We analyze our results using the Kurkijärvi-Garg model and find that the escape temperature also saturates at low temperatures, confirming that at sufficiently low temperatures, macroscopic quantum tunneling is possible in quasi-2D strips and can contribute to dark counts observed in single photon detectors. At the highest temperatures the system enters a multiple phase-slip regime. In this range single phase-slips are unable to produce dark counts and the fluctuations in the switching current are reduced.

A novel all-optical label processing based on multiple optical orthogonal codes sequences for optical packet switching networks

NASA Astrophysics Data System (ADS)

Zhang, Chongfu; Qiu, Kun; Xu, Bo; Ling, Yun

2008-05-01

This paper proposes an all-optical label processing scheme that uses the multiple optical orthogonal codes sequences (MOOCS)-based optical label for optical packet switching (OPS) (MOOCS-OPS) networks. In this scheme, each MOOCS is a permutation or combination of the multiple optical orthogonal codes (MOOC) selected from the multiple-groups optical orthogonal codes (MGOOC). Following a comparison of different optical label processing (OLP) schemes, the principles of MOOCS-OPS network are given and analyzed. Firstly, theoretical analyses are used to prove that MOOCS is able to greatly enlarge the number of available optical labels when compared to the previous single optical orthogonal code (SOOC) for OPS (SOOC-OPS) network. Then, the key units of the MOOCS-based optical label packets, including optical packet generation, optical label erasing, optical label extraction and optical label rewriting etc., are given and studied. These results are used to verify that the proposed MOOCS-OPS scheme is feasible.

Multiple-object permanence tracking: limitation in maintenance and transformation of perceptual objects.

PubMed

Saiki, Jun

2002-01-01

Research on change blindness and transsaccadic memory revealed that a limited amount of information is retained across visual disruptions in visual working memory. It has been proposed that visual working memory can hold four to five coherent object representations. To investigate their maintenance and transformation in dynamic situations, I devised an experimental paradigm called multiple-object permanence tracking (MOPT) that measures memory for multiple feature-location bindings in dynamic situations. Observers were asked to detect any color switch in the middle of a regular rotation of a pattern with multiple colored disks behind an occluder. The color-switch detection performance dramatically declined as the pattern rotation velocity increased, and this effect of object motion was independent of the number of targets. The MOPT task with various shapes and colors showed that color-shape conjunctions are not available in the MOPT task. These results suggest that even completely predictable motion severely reduces our capacity of object representations, from four to only one or two.

Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigen-selected memory B cells

PubMed Central

Souza, Tatyana A.; Stollar, B. David; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

2005-01-01

Epstein–Barr virus (EBV) establishes a lifelong persistent infection within peripheral blood B cells with the surface phenotype of memory cells. To date there is no proof that these cells have the genotype of true germinal-center-derived memory B cells. It is critical to understand the relative contribution of viral mimicry versus antigen signaling to the production of these cells because EBV encodes proteins that can affect the surface phenotype of infected cells and provide both T cell help and B cell receptor signals in the absence of cognate antigen. To address these questions we have developed a technique to identify single EBV-infected cells in the peripheral blood and examine their expressed Ig genes. The genes were all isotype-switched and somatically mutated. Furthermore, the mutations do not cause stop codons and display the pattern expected for antigen-selected memory cells based on their frequency, type, and location within the Ig gene. We conclude that latently infected peripheral blood B cells display the molecular hallmarks of classical antigen-selected memory B cells. Therefore, EBV does not disrupt the normal processing of latently infected cells into memory, and deviations from normal B cell biology are not tolerated in the infected cells. This article provides definitive evidence that EBV in the peripheral blood persists in true memory B cells. PMID:16330748

Intestinal colonization with Candida albicans and mucosal immunity

PubMed Central

Bai, Xiao-Dong; Liu, Xian-Hua; Tong, Qing-Ying

2004-01-01

AIM: To observe the relationship between intestinal lumen colonization with Candida albicans and mucosal secretory IgA (sIgA). METHODS: A total of 82 specific-pathogen-free mice were divided randomly into control and colonization groups. After Candida albicans were inoculated into specific-pathogen-free mice, the number of Candida albicans adhering to cecum and mucosal membrane was counted. The lymphocyte proliferation in Peyer’s patch and in lamina propria was shown by BrdU incorporation, while mucosal sIgA (surface membrane) isotype switch in Peyer’s patch was investigated. IgA plasma cells in lamina propria were observed by immunohistochemical staining. Specific IgA antibodies to Candida albicans were measured with ELISA. RESULTS: From d 3 to d 14 after Candida albicans gavaging to mice, the number of Candida albicans colonizing in lumen and adhering to mucosal membrane was sharply reduced. Candida albicans translocation to mesenteric lymph nodes occurred at early time points following gavage administration and disappeared at later time points. Meanwhile, the content of specific IgA was increased obviously. Proliferation and differentiation of lymphocytes in lamina propria were also increased. CONCLUSION: Lymphocytes in lamina propria play an important role in intestinal mucosal immunity of specific-pathogen-free mice when they are first inoculated with Candida albicans. The decreasing number of Candida albicans in intestine is related to the increased level of specific IgA antibodies in the intestinal mucus. PMID:15237449

Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies.

PubMed

Berrón-Ruíz, L; López-Herrera, G; Ávalos-Martínez, C E; Valenzuela-Ponce, C; Ramírez-SanJuan, E; Santoyo-Sánchez, G; Mújica Guzmán, F; Espinosa-Rosales, F J; Santos-Argumedo, L

Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination

PubMed Central

Wang, Lilin; Smith, Dan; Bot, Simona; Dellamary, Luis; Bloom, Amy; Bot, Adrian

2002-01-01

The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by “danger” motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity. PMID:12393853

Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma.

PubMed

Mansoor, Jim K; Decile, Kendra C; Giri, Shri N; Pinkerton, Kent E; Walby, William F; Bratt, Jennifer M; Grewal, Harinder; Margolin, Solomon B; Schelegle, Edward S

2007-01-01

Pirfenidone was administered to sensitized Brown Norway rats prior to a series of ovalbumin challenges. Airway hyperresponsiveness, inflammatory cell infiltration, mucin and collagen content, and the degree of epithelium and smooth muscle staining for TGF-beta were examined in control, sensitized, and sensitized/challenged rats fed a normal diet or pirfenidone diet. Pirfenidone had no effect on airway hyperresponsiveness, but reduced distal bronchiolar cell infiltration and proximal and distal mucin content. Statistical analysis showed that the control group and sensitized/challenged pirfenidone diet group TGF-beta staining intensity scores were not significantly different from isotype controls, but that the staining intensity scores for the sensitized/challenged normal diet group was significantly different from isotype controls. These results suggest that pirfenidone treatment is effective in reducing some of the components of acute inflammation induced by allergen challenge.

Mathematical modeling and design of a novel 2-DOF micro attraction actuator for a micro optical switch

NASA Astrophysics Data System (ADS)

Kamiya, Daiki; Bagheri, Saeed; Horie, Mikio

2004-08-01

Many studies on optical switches have been performed in an attempt to develop optical information networks to speed information technology. In reality, however, mirror manipulators cannot be applied to multiple input and output systems due to both insufficient output displacements by the mirror parts inside the manipulator, and the difficulty of designing structures and mechanisms suitable for multi-dimensional manipulation. The principal reasons for insufficient displacement are the high rigidity of the elastic parts compared to the available driving forces and the pull-in effect. Therefore, in order to develop optical switches capable of multiple input and output switching, we suggest a novel 2-DOF(degree of freedom) electrostatic microactuator. The actuator is composed of one mirror with four beams laid about it in a corkscrew pattern, with four corkscrew electrodes on the substrate below and one mirror support pyramid situated under the mirror. Using electrostatic force, one or more of the beams are attracted from their outer ends toward the substrate. The mirror is then tilted by an angle proportional to the attracted length along the beam. The inclination and direction of the mirror are determined by the combined attracted length of the four beams. In this work we derive the mathematical model for the corkscrew beam microactuator for optical switches and show that this mathematical model accurately simulates the device by comparison with finite element analysis results. We use this mathematical model for design of the microactuator. Further we show that the designed optical switch microactuator is capable of rotating the mirror from +32 to -32 degrees about two axes with a maximum operating voltage of 163 volts. Finally, stress analysis of the actuator shows that the generated stress in the structure is at most 369 MPa.

Simulation and analysis of main steam control system based on heat transfer calculation

NASA Astrophysics Data System (ADS)

Huang, Zhenqun; Li, Ruyan; Feng, Zhongbao; Wang, Songhan; Li, Wenbo; Cheng, Jiwei; Jin, Yingai

2018-05-01

In this paper, after thermal power plant 300MW boiler was studied, mat lab was used to write calculation program about heat transfer process between the main steam and boiler flue gas and amount of water was calculated to ensure the main steam temperature keeping in target temperature. Then heat transfer calculation program was introduced into Simulink simulation platform based on control system multiple models switching and heat transfer calculation. The results show that multiple models switching control system based on heat transfer calculation not only overcome the large inertia of main stream temperature, a large hysteresis characteristic of main stream temperature, but also adapted to the boiler load changing.

Charging system with galvanic isolation and multiple operating modes

DOEpatents

Kajouke, Lateef A.; Perisic, Milun; Ransom, Ray M.

2013-01-08

Systems and methods are provided for operating a charging system with galvanic isolation adapted for multiple operating modes. A vehicle charging system comprises a DC interface, an AC interface, a first conversion module coupled to the DC interface, and a second conversion module coupled to the AC interface. An isolation module is coupled between the first conversion module and the second conversion module. The isolation module comprises a transformer and a switching element coupled between the transformer and the second conversion module. The transformer and the switching element are cooperatively configured for a plurality of operating modes, wherein each operating mode of the plurality of operating modes corresponds to a respective turns ratio of the transformer.

Electrically-controlled nonlinear switching and multi-level storage characteristics in WOx film-based memory cells

NASA Astrophysics Data System (ADS)

Duan, W. J.; Wang, J. B.; Zhong, X. L.

2018-05-01

Resistive switching random access memory (RRAM) is considered as a promising candidate for the next generation memory due to its scalability, high integration density and non-volatile storage characteristics. Here, the multiple electrical characteristics in Pt/WOx/Pt cells are investigated. Both of the nonlinear switching and multi-level storage can be achieved by setting different compliance current in the same cell. The correlations among the current, time and temperature are analyzed by using contours and 3D surfaces. The switching mechanism is explained in terms of the formation and rupture of conductive filament which is related to oxygen vacancies. The experimental results show that the non-stoichiometric WOx film-based device offers a feasible way for the applications of oxide-based RRAMs.

Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study.

PubMed

Cohen, Jeffrey A; Khatri, Bhupendra; Barkhof, Frederik; Comi, Giancarlo; Hartung, Hans-Peter; Montalban, Xavier; Pelletier, Jean; Stites, Tracy; Ritter, Shannon; von Rosenstiel, Philipp; Tomic, Davorka; Kappos, Ludwig

2016-05-01

The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to fingolimod. NCT00340834. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Identification of immunodominant Leishmania major antigenic markers of the early C57BL/6 and BALB/c mice infection stages.

PubMed

Sassi, Atfa; Kaak, Olfa; Elgaaied, Amel Benammar

2015-08-24

The C57BL/6 mouse strain is resistant to Leishmania (L.) major infection and, unlike susceptible BALB/c, develops small self healing cutaneous lesions. The specific antibody responses of C57BL/6 and BALB/c mice were previously characterized by the predominance of IgG2a ("resistant" isotype associated with Th1) and IgG1 ("pathogenic" isotype associated with Th2) antibodies, respectively. In this study, we looked for the presence of antigens able to elicit an exclusive or predominant IgG1 production during the early stages of C57BL/6 lesion development and checked whether they are recognized or not by BALB/c mice. We demonstrate first that IgG2a predominance in C57BL/6 sera occurs only late after infection whereas in BALB/c, IgG1 antibodies dominate mostly in the early stages. Interestingly, soon after inoculation of live amastigotes, C57BL/6 displayed an exclusive IgG1 reactivity against particular L. major antigens but with MWs different from those identified in BALB/c. Furthermore, mice immunized with killed amastigotes displayed striking differences in their immunodetection profiles, particularly for the IgG1 isotype. Taken together, the observed differences in the specific antibody repertoires between infected mice resulted, at least in part, from immunological events independent from those triggered by the replicating parasite, and bring new insights into the selection of future vaccine candidates. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas.

PubMed

Ordonez, Alvaro A; Pokkali, Supriya; Kim, Sunhwa; Carr, Brian; Klunk, Mariah H; Tong, Leah; Saini, Vikram; Chang, Yong S; McKevitt, Matthew; Smith, Victoria; Gossage, David L; Jain, Sanjay K

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas

PubMed Central

Kim, Sunhwa; Carr, Brian; Klunk, Mariah H.; Tong, Leah; Saini, Vikram; Chang, Yong S.; McKevitt, Matthew; Smith, Victoria; Gossage, David L.; Jain, Sanjay K.

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments. PMID:29758082

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

PubMed Central

Bard, Frédérique; Barbour, Robin; Cannon, Catherine; Carretto, Robert; Fox, Michael; Games, Dora; Guido, Teresa; Hoenow, Kathleen; Hu, Kang; Johnson-Wood, Kelly; Khan, Karen; Kholodenko, Dora; Lee, Celeste; Lee, Mike; Motter, Ruth; Nguyen, Minh; Reed, Amanda; Schenk, Dale; Tang, Pearl; Vasquez, Nicki; Seubert, Peter; Yednock, Ted

2003-01-01

Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing β-amyloid peptide (Aβ) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Aβ peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Aβ. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Aβ epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Aβ were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Aβ was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for Aβ itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease. PMID:12566568

Determining antibody-binding site of streptococcal pyrogenic exotoxin B to protect mice from group a streptococcus infection.

PubMed

Tsao, Nina; Cheng, Miao-Hui; Yang, Hsiu-Chen; Wang, Yu-Chieh; Liu, Yi-Ling; Kuo, Chih-Feng

2013-01-01

Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcal (GAS) infection. SPE B binds and cleaves antibody isotypes and further impairs the immune system by inhibiting complement activation. In this study, we examined the antibody-binding site of SPE B and used it to block SPE B actions during GAS infection. We constructed different segments of the spe B gene and induced them to express different recombinant fragments of SPE B. Using an enzyme-linked immunosorbent assay (ELISA), we found that residues 345-398 of the C-terminal domain of SPE B (rSPE B(345-398)), but not the N-terminal domain, was the major binding site for antibody isotypes. Using a competitive ELISA, we also found that rSPE B(345-398) bound to the Fc portion of IgG. The in vitro functional assays indicate that rSPE B(345-398) not only interfered with cleavage of antibody isotypes but also interfered with SPE B-induced inhibition of complement activation. Immunization of BALB/c mice using rSPE B(345-398) was able to induce production of a high titer of anti-rSPE B(345-398) antibodies and efficiently protected mice from GAS-induced death. These findings suggest that SPE B uses its C-terminal domain to bind the Fc portion of IgG and that immunization of mice with this binding domain (rSPE B(345-398)) could protect mice from GAS infection.

Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review.

PubMed

McKinnon, Ross A; Cook, Matthew; Liauw, Winston; Marabani, Mona; Marschner, Ian C; Packer, Nicolle H; Prins, Johannes B

2018-02-01

The efficacy, safety and immunogenicity risk of switching between an originator biologic and a biosimilar or from one biosimilar to another are of potential concern. The aim was to conduct a systematic literature review of the outcomes of switching between biologics and their biosimilars and identify any evidence gaps. A systematic literature search was conducted in PubMed, EMBASE and Cochrane Library from inception to June 2017. Relevant societal meetings were also checked. Peer-reviewed studies reporting efficacy and/or safety data on switching between originator and biosimilar products or from one biosimilar to another were selected. Studies with fewer than 20 switched patients were excluded. Data were extracted on interventions, study population, reason for treatment switching, efficacy outcomes, safety and anti-drug antibodies. The systematic literature search identified 63 primary publications covering 57 switching studies. The reason for switching was reported as non-medical in 50 studies (23 clinical, 27 observational). Seven studies (all observational) did not report whether the reasons for switching were medical or non-medical. In 38 of the 57 studies, fewer than 100 patients were switched. Follow-up after switching went beyond 1 year in eight of the 57 studies. Of the 57 studies, 33 included statistical analysis of disease activity or patient outcomes; the majority of these studies found no statistically significant differences between groups for main efficacy parameters (based on P < 0.05 or predefined acceptance ranges), although some studies observed changes for some parameters. Most studies reported similar safety profiles between groups. There are important evidence gaps around the safety of switching between biologics and their biosimilars. Sufficiently powered and appropriately statistically analysed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switches, are needed to support decision-making around biosimilar switching.

Decentralized Adaptive Neural Output-Feedback DSC for Switched Large-Scale Nonlinear Systems.

PubMed

Lijun Long; Jun Zhao

2017-04-01

In this paper, for a class of switched large-scale uncertain nonlinear systems with unknown control coefficients and unmeasurable states, a switched-dynamic-surface-based decentralized adaptive neural output-feedback control approach is developed. The approach proposed extends the classical dynamic surface control (DSC) technique for nonswitched version to switched version by designing switched first-order filters, which overcomes the problem of multiple "explosion of complexity." Also, a dual common coordinates transformation of all subsystems is exploited to avoid individual coordinate transformations for subsystems that are required when applying the backstepping recursive design scheme. Nussbaum-type functions are utilized to handle the unknown control coefficients, and a switched neural network observer is constructed to estimate the unmeasurable states. Combining with the average dwell time method and backstepping and the DSC technique, decentralized adaptive neural controllers of subsystems are explicitly designed. It is proved that the approach provided can guarantee the semiglobal uniformly ultimately boundedness for all the signals in the closed-loop system under a class of switching signals with average dwell time, and the tracking errors to a small neighborhood of the origin. A two inverted pendulums system is provided to demonstrate the effectiveness of the method proposed.

Characterizing switching and congruency effects in the Implicit Association Test as reactive and proactive cognitive control.

PubMed

Hilgard, Joseph; Bartholow, Bruce D; Dickter, Cheryl L; Blanton, Hart

2015-03-01

Recent research has identified an important role for task switching, a cognitive control process often associated with executive functioning, in the Implicit Association Test (IAT). However, switching does not fully account for IAT effects, particularly when performance is scored using more recent d-score formulations. The current study sought to characterize multiple control processes involved in IAT performance through the use of event-related brain potentials (ERPs). Participants performed a race-evaluative IAT while ERPs were recorded. Behaviorally, participants experienced superadditive reaction time costs of incongruency and task switching, consistent with previous studies. The ERP showed a marked medial frontal negativity (MFN) 250-450 ms post-stimulus at midline fronto-central locations that were more negative for incongruent than congruent trials but more positive for switch than for no-switch trials, suggesting separable control processes are engaged by these two factors. Greater behavioral IAT bias was associated with both greater switch-related and congruency-related ERP activity. Findings are discussed in terms of the Dual Mechanisms of Control model of reactive and proactive cognitive control. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

PubMed

Warrender-Sparkes, Matthew; Spelman, Tim; Izquierdo, Guillermo; Trojano, Maria; Lugaresi, Alessandra; Grand'Maison, François; Havrdova, Eva; Horakova, Dana; Boz, Cavit; Oreja-Guevara, Celia; Alroughani, Raed; Iuliano, Gerardo; Duquette, Pierre; Girard, Marc; Terzi, Murat; Hupperts, Raymond; Grammond, Pierre; Petersen, Thor; Fernandez-Bolaños, Ricardo; Fiol, Marcela; Pucci, Eugenio; Lechner-Scott, Jeannette; Verheul, Freek; Cristiano, Edgardo; Van Pesch, Vincent; Petkovska-Boskova, Tatjana; Moore, Fraser; Kister, Ilya; Bergamaschi, Roberto; Saladino, Maria Laura; Slee, Mark; Barnett, Michael; Amato, Maria Pia; Shaw, Cameron; Shuey, Neil; Young, Carolyn; Gray, Orla; Kappos, Ludwig; Butzkueven, Helmut; Kalincik, Tomas; Jokubaitis, Vilija

2016-04-01

We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications. © The Author(s), 2015.

Impact of oxygen stoichiometry on electroforming and multiple switching modes in TiN/TaOx/Pt based ReRAM

NASA Astrophysics Data System (ADS)

Sharath, S. U.; Joseph, M. J.; Vogel, S.; Hildebrandt, E.; Komissinskiy, P.; Kurian, J.; Schroeder, T.; Alff, L.

2016-10-01

We have investigated the material and electrical properties of tantalum oxide thin films (TaOx) with engineered oxygen contents grown by RF-plasma assisted molecular beam epitaxy. The optical bandgap and the density of the TaOx films change consistently with oxygen contents in the range of 3.63 to 4.66 eV and 12.4 to 9.0 g/cm3, respectively. When exposed to atmosphere, an oxidized Ta2O5-y surface layer forms with a maximal thickness of 1.2 nm depending on the initial oxygen deficiency of the film. X-ray photoelectron spectroscopy studies show that multiple sub-stoichiometric compositions occur in oxygen deficient TaOx thin films, where all valence states of Ta including metallic Ta are possible. Devices of the form Pt/Ta2O5-y/TaOx/TiN exhibit highly tunable forming voltages of 10.5 V to 1.5 V with decreasing oxygen contents in TaOx. While a stable bipolar resistive switching (BRS) occurs in all devices irrespective of oxygen content, unipolar switching was found to coexist with BRS only at higher oxygen contents, which transforms to a threshold switching behaviour in the devices grown under highest oxidation.

Positive Emotion Facilitates Cognitive Flexibility: An fMRI Study

PubMed Central

Wang, Yanmei; Chen, Jie; Yue, Zhenzhu

2017-01-01

Cognitive flexibility is the ability to switch rapidly between multiple goals. By using a task-switching paradigm, the present study investigated how positive emotion affected cognitive flexibility and the underlying neural mechanisms. After viewing pictures of different emotional valence (positive, negative, or neutral), participants discriminated whether a target digit in a specific color was odd or even. After a series of trials, the color of target stimuli was changed, i.e., the switch condition. Switch costs were measured by the increase of reaction times (RTs) in the switch trials compared to those in the repeat trials. Behavior results indicated that switch costs significantly decreased in the positive emotional condition, and increased in the negative emotional condition, compared with those in the neutral condition. Imaging data revealed enhanced activation in the dorsal anterior cingulate cortex (dACC) in switch trials than those in repeat trials. Moreover, the interaction between emotion (positive, negative, neutral) and trial type (repeat vs. switch) was significant. For switch trials, the activation of dACC decreased significantly in the positive condition, while increased significantly in the negative condition compared to neutral condition. By contrast, for repeat trials, no significant difference was observed for the activation of dACC among three emotional conditions. Our results showed that positive emotions could increase the cognitive flexibility and reduce the conflict by decreasing the activation of dACC. PMID:29163255

Potential damage to DC superconducting magnets due to the high frequency electromagnetic waves

NASA Technical Reports Server (NTRS)

Gabriel, G. J.

1977-01-01

Experimental data are presented in support of the hypothesis that a dc superconducting magnet coil does not behave strictly as an inductor, but as a complicated electrodynamic device capable of supporting electromagnetic waves. Travel times of nanosecond pulses and evidence of sinusoidal standing waves were observed on a prototype four-layer solenoidal coil at room temperature. Ringing observed during switching transients appears as a sequence of multiple reflected square pulses whose durations are related to the layer lengths. With sinusoidal excitation of the coil, the voltage amplitude between a pair of points on the coil exhibits maxima at those frequencies such that the distance between these points is an odd multiple of half wavelength in free space. Evidence indicates that any disturbance, such as that resulting from switching or sudden fault, initiates multiple reflections between layers, thus raising the possibility for sufficiently high voltages to cause breakdown.

Predictive Multiple Model Switching Control with the Self-Organizing Map

NASA Technical Reports Server (NTRS)

Motter, Mark A.

2000-01-01

A predictive, multiple model control strategy is developed by extension of self-organizing map (SOM) local dynamic modeling of nonlinear autonomous systems to a control framework. Multiple SOMs collectively model the global response of a nonautonomous system to a finite set of representative prototype controls. Each SOM provides a codebook representation of the dynamics corresponding to a prototype control. Different dynamic regimes are organized into topological neighborhoods where the adjacent entries in the codebook represent the global minimization of a similarity metric. The SOM is additionally employed to identify the local dynamical regime, and consequently implements a switching scheme that selects the best available model for the applied control. SOM based linear models are used to predict the response to a larger family of control sequences which are clustered on the representative prototypes. The control sequence which corresponds to the prediction that best satisfies the requirements on the system output is applied as the external driving signal.

Fast polar decomposition of an arbitrary matrix

NASA Technical Reports Server (NTRS)

Higham, Nicholas J.; Schreiber, Robert S.

1988-01-01

The polar decomposition of an m x n matrix A of full rank, where m is greater than or equal to n, can be computed using a quadratically convergent algorithm. The algorithm is based on a Newton iteration involving a matrix inverse. With the use of a preliminary complete orthogonal decomposition the algorithm can be extended to arbitrary A. How to use the algorithm to compute the positive semi-definite square root of a Hermitian positive semi-definite matrix is described. A hybrid algorithm which adaptively switches from the matrix inversion based iteration to a matrix multiplication based iteration due to Kovarik, and to Bjorck and Bowie is formulated. The decision when to switch is made using a condition estimator. This matrix multiplication rich algorithm is shown to be more efficient on machines for which matrix multiplication can be executed 1.5 times faster than matrix inversion.

Comparative analysis of novel autoantibody isotypes against citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)(542-556) peptide in serum from Taiwanese females with rheumatoid arthritis, primary Sjögren's syndrome and secondary Sjögren's syndrome in rheumatoid arthritis.

PubMed

Liao, Chen-Chung; Chou, Pei-Lun; Cheng, Chao-Wen; Chang, Yu-Sheng; Chi, Wei-Ming; Tsai, Kai-Leun; Chen, Wei-Jung; Kung, Ting-Shuan; Tai, Chih-Chun; Lee, Kuan-Wei; Chen, You-Chia; Lin, Ching-Yu

2016-06-01

The purpose of this study was to discover and validate inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) as novel biomarkers, and evaluate autoantibody isotypes against an unmodified and citrullinated ITIH3(542-556) peptide among Taiwanese female patients with rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), secondary Sjögren's syndrome in rheumatoid arthritis (RA-sSS), and healthy controls (HCs). We used concanavalin A (Con A) affinity chromatography, 1-D SDS-PAGE, and label-free nano-LC-MS/MS to screen biomarker candidates (serum-derived Con A-captured proteins) and then identify PTMs of validated biomarkers (serum proteins) using pooled serum from 7 RA-sSS female patients and 7 age-matched HCs (the discovery set). Furthermore, the protein level and autoantibody isotype analyses were further validated against individual serum from 18 HCs, 18 RA, 18 pSS, and 18 RA-sSS patients (the validation set). Con A-bound ITIH3 was identified and validated as the only differentially expressed protein, which was elevated. Additionally, 2 novel PTMs in ITIH3 were identified and included citrullination at arginine-(546) and arginine-(556), and hexosamine at tryptophan-(558). Further, concentrations of anti-citrullinatd-ITIH3(542-556) peptide autoantibodies significantly increased in patients with RA, pSS, and RA-sSS compared to HCs. Especially, autoantibody IgM against the citrullinated-ITIH3(542-556) peptide showed better diagnostic performance in discriminating both RA versus pSS and pSS versus RA-sSS. By using comparative proteomic analysis of serum samples, the current study discovered and validates differentially expressed Con A-bound ITIH3 as a potential biomarker for secondary Sjögren's syndrome (SS) in rheumatoid arthritis (RA) patients and healthy controls (HCs). Besides, hexosamine and citrullination on ITIH3 were further identified. Through analyzing autoantibody isotypes against the citrullinated ITIH3 peptide, patients with RA, primary SS, and RA-secondary SS, and HCs can be further discriminated. The current strategy can be applied for identifying potential diagnostic and pathologic markers for autoimmune diseases. Copyright © 2016. Published by Elsevier B.V.

Use of multiple modes of flight subsidy by a soaring terrestrial bird, the golden eagle Aquila chrysaetos, when on migration

PubMed Central

Katzner, Todd E.; Turk, Philip J.; Duerr, Adam E.; Miller, Tricia A.; Lanzone, Michael J.; Cooper, Jeff L.; Brandes, David; Tremblay, Junior A.; Lemaître, Jérôme

2015-01-01

Large birds regularly use updrafts to subsidize flight. Although most research on soaring bird flight has focused on use of thermal updrafts, there is evidence suggesting that many species are likely to use multiple modes of subsidy. We tested the degree to which a large soaring species uses multiple modes of subsidy to provide insights into the decision-making that underlies flight behaviour. We statistically classified more than 22 000 global positioning satellite–global system for mobile communications telemetry points collected at 30-s intervals to identify the type of subsidized flight used by 32 migrating golden eagles during spring in eastern North America. Eagles used subsidized flight on 87% of their journey. They spent 41.9% ± 1.5 (, range: 18–56%) of their subsidized northbound migration using thermal soaring, 45.2% ± 2.1 (12–65%) of time gliding between thermals, and 12.9% ± 2.2 (1–55%) of time using orographic updrafts. Golden eagles responded to the variable local-scale meteorological events they encountered by switching flight behaviour to take advantage of multiple modes of subsidy. Orographic soaring occurred more frequently in morning and evening, earlier in the migration season, and when crosswinds and tail winds were greatest. Switching between flight modes allowed migration for relatively longer periods each day and frequent switching behaviour has implications for a better understanding of avian flight behaviour and of the evolution of use of subsidy in flight. PMID:26538556

Switching auditory attention using spatial and non-spatial features recruits different cortical networks.

PubMed

Larson, Eric; Lee, Adrian K C

2014-01-01

Switching attention between different stimuli of interest based on particular task demands is important in many everyday settings. In audition in particular, switching attention between different speakers of interest that are talking concurrently is often necessary for effective communication. Recently, it has been shown by multiple studies that auditory selective attention suppresses the representation of unwanted streams in auditory cortical areas in favor of the target stream of interest. However, the neural processing that guides this selective attention process is not well understood. Here we investigated the cortical mechanisms involved in switching attention based on two different types of auditory features. By combining magneto- and electro-encephalography (M-EEG) with an anatomical MRI constraint, we examined the cortical dynamics involved in switching auditory attention based on either spatial or pitch features. We designed a paradigm where listeners were cued in the beginning of each trial to switch or maintain attention halfway through the presentation of concurrent target and masker streams. By allowing listeners time to switch during a gap in the continuous target and masker stimuli, we were able to isolate the mechanisms involved in endogenous, top-down attention switching. Our results show a double dissociation between the involvement of right temporoparietal junction (RTPJ) and the left inferior parietal supramarginal part (LIPSP) in tasks requiring listeners to switch attention based on space and pitch features, respectively, suggesting that switching attention based on these features involves at least partially separate processes or behavioral strategies. © 2013 Elsevier Inc. All rights reserved.

The effect of pain on task switching: pain reduces accuracy and increases reaction times across multiple switching paradigms.

PubMed

Attridge, Nina; Keogh, Edmund; Eccleston, Christopher

2016-10-01

Pain disrupts attention, which may have negative consequences for daily life for people with acute or chronic pain. It has been suggested that switching between tasks may leave us particularly susceptible to pain-related attentional disruption, because we need to disengage our attention from one task before shifting it onto another. Switching tasks typically elicit lower accuracies and/or longer reaction times when participants switch to a new task compared with repeating the same task, and pain may exacerbate this effect. We present 3 studies to test this hypothesis. In study 1, participants completed 2 versions of an alternating runs switching task under pain-free and thermal pain-induction conditions. Pain did not affect performance on either task. In studies 2 and 3, we examined 7 versions of the switching task using large general population samples, experiencing a variety of naturally occurring pain conditions, recruited and tested on the internet. On all tasks, participants with pain had longer reaction times on both switch and repeat trials compared with participants without pain, but pain did not increase switch costs. In studies 2 and 3, we also investigated the effects of type of pain, duration of pain, and analgesics on task performance. We conclude that pain has a small dampening effect on performance overall on switching tasks. This suggests that pain interrupts attention even when participants are engaged in a trial, not only when attention has been disengaged for shifting to a new task set.

Note: All solid-state high repetitive sub-nanosecond risetime pulse generator based on bulk gallium arsenide avalanche semiconductor switches.

PubMed

Hu, Long; Su, Jiancang; Ding, Zhenjie; Hao, Qingsong; Fan, Yajun; Liu, Chunliang

2016-08-01

An all solid-state high repetitive sub-nanosecond risetime pulse generator featuring low-energy-triggered bulk gallium arsenide (GaAs) avalanche semiconductor switches and a step-type transmission line is presented. The step-type transmission line with two stages is charged to a potential of 5.0 kV also biasing at the switches. The bulk GaAs avalanche semiconductor switch closes within sub-nanosecond range when illuminated with approximately 87 nJ of laser energy at 905 nm in a single pulse. An asymmetric dipolar pulse with peak-to-peak amplitude of 9.6 kV and risetime of 0.65 ns is produced on a resistive load of 50 Ω. A technique that allows for repetition-rate multiplication of pulse trains experimentally demonstrated that the parallel-connected bulk GaAs avalanche semiconductor switches are triggered in sequence. The highest repetition rate is decided by recovery time of the bulk GaAs avalanche semiconductor switch, and the operating result of 100 kHz of the generator is discussed.

Reconfigurable radio-over-fiber system based on optical switch and tunable filter

NASA Astrophysics Data System (ADS)

Li, Xiao; Yin, Rui; Ji, Wei; Sun, Kai; Zhang, Shicheng

2017-09-01

As the best candidate for wireless-access networks, radio-over-fiber (RoF) technology can carry a variety of business. It is necessary to provide differentiated services for different users, so the network needs to produce signals with different modulation formats and different frequencies. A reconfigurable RoF system based on a switch and tunable optical filter that can realize modulation format conversion and multiple frequency signal switching functions is designed. It has a good performance in terms of bit error rate and an eye diagram. The design can help to use radio frequency resources efficiently and make dynamic bandwidth resources controllable.

Modeling the Potential Effects of New Tobacco Products and Policies. A Dynamic Population Model for Multiple Product Use and Harm

DOE PAGES

Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; ...

2015-03-27

Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use formore » the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.« less

Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm

PubMed Central

Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; Brodsky, Nancy S.; Brown, Theresa J.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.

2015-01-01

Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability. PMID:25815840

Modeling the potential effects of new tobacco products and policies: a dynamic population model for multiple product use and harm.

PubMed

Vugrin, Eric D; Rostron, Brian L; Verzi, Stephen J; Brodsky, Nancy S; Brown, Theresa J; Choiniere, Conrad J; Coleman, Blair N; Paredes, Antonio; Apelberg, Benjamin J

2015-01-01

Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.

Modeling the Potential Effects of New Tobacco Products and Policies. A Dynamic Population Model for Multiple Product Use and Harm

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

Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.

Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use formore » the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.« less

Discovering Indices of Contingency Awareness in Adults with Multiple Profound Disabilities

ERIC Educational Resources Information Center

Saunders, Richard R.; Saunders, Muriel D.; Struve, Brittany; Munce, Abbie L.; Olswang, Lesley B.; Dowden, Patricia A.; Klasner, Estelle R.

2007-01-01

Two studies were conducted to examine parameters of social attention in contingency awareness training using switch activation with individuals who had multiple profound disabilities. Study 1 compared leisure devices and social attention as reinforcing stimuli with 5 individuals. Results indicated the reinforcing qualities of social attention over…

Contraceptive method switching in the United States.

PubMed

Grady, William R; Billy, John O G; Klepinger, Daniel H

2002-01-01

Switching among contraceptive method types is the primary determinant of the prevalence of use of specific contraceptive methods, and it has direct implications for women's ability to avoid unintended pregnancies. Yet, method switching among U.S. women has received little attention from researchers. Data from the 1995 National Survey of Family Growth were used to construct multiple-decrement life tables to explore the gross switching rates of married and unmarried women. Within each group, discrete-time hazard models were estimated to determine how women's characteristics affect their switching behavior. Overall rates of method switching are high among both married and unmarried women (40% and 61%, respectively). Married women's two-year switching rates vary from 30% among women who use the implant, injectable, IUD or other reversible methods to 43% among nonusers, while unmarried women's rates vary from 33% among women who use the implant, injectable or IUD to 70% among nonusers. Multivariate analyses of method switching according to women's characteristics indicate that among married women, women without children are less likely than other women to adopt sterilization or a long-term reversible contraceptive (the implant, injectable or IUD). Older married women have a higher rate than their younger counterparts of switching to sterilization, but are also more likely to continue using no method. Among unmarried women, younger and more highly educated women have high rates of switching to the condom and to dual methods. Women's method switching decisions may be driven primarily by concerns related to level and duration of contraceptive effectiveness, health risks associated with contraceptive use and, among single women, sexually transmitted disease prevention.

Consequences of non-medical switch among patients with type 2 diabetes.

PubMed

Flores, Natalia M; Patel, Charmi A; Bookhart, Brahim K; Bacchus, Shaffeeulah

2018-04-27

This study aimed to describe real-world experiences following a non-medical switch among adults with type 2 diabetes mellitus (T2DM) in the United States. For this cross-sectional study, patients with T2DM (N = 451) provided data on demographics, and how a non-medical switch of their anti-hyperglycemic agent (AHA) affected their general health, HbA1c levels and medication management, via an Internet-based survey. Patients self-reported their level of satisfaction with the original medication and emotional reactions to the non-medical switch. Patients who recently experienced a non-medical switch of their AHA(s) (n = 379) were asked about the consequences of switching and their satisfaction with the switch (vs. the original) medication. Patients most frequently reported feeling very/extremely frustrated, surprised, upset and angry in reaction to a non-medical switch. Patients were somewhat satisfied with their original medication. Between 20% and 30% of patients reported the non-medical switch had a moderate/major effect on their general health, diabetes, mental well-being and control over their health. The blood glucose levels of recent switchers were somewhat/much worse (20.7%) and medication management was somewhat/much worse (12.9%) on the switch (vs. the original) medication. Some recent switchers reported old symptoms returning (7.7%) and experiencing new side-effects (14.2%). Approximately one in five patients reported a moderate/major negative impact on their blood glucose level, diabetes, mental well-being, general health and control over their health following a non-medical switch. Findings suggest that a non-medical switch may have unintended negative health consequences and results in considerable burden across multiple domains for a sizeable minority of patients with T2DM.

Dynamic-load-enabled ultra-low power multiple-state RRAM devices.

PubMed

Yang, Xiang; Chen, I-Wei

2012-01-01

Bipolar resistance-switching materials allowing intermediate states of wide-varying resistance values hold the potential of drastically reduced power for non-volatile memory. To exploit this potential, we have introduced into a nanometallic resistance-random-access-memory (RRAM) device an asymmetric dynamic load, which can reliably lower switching power by orders of magnitude. The dynamic load is highly resistive during on-switching allowing access to the highly resistive intermediate states; during off-switching the load vanishes to enable switching at low voltage. This approach is entirely scalable and applicable to other bipolar RRAM with intermediate states. The projected power is 12 nW for a 100 × 100 nm(2) device and 500 pW for a 10 × 10 nm(2) device. The dynamic range of the load can be increased to allow power to be further decreased by taking advantage of the exponential decay of wave-function in a newly discovered nanometallic random material, reaching possibly 1 pW for a 10×10 nm(2) nanometallic RRAM device.

Low-frequency switching in a transistor amplifier.

PubMed

Carroll, T L

2003-04-01

It is known from extensive work with the diode resonator that the nonlinear properties of a P-N junction can lead to period doubling, chaos, and other complicated behaviors in a driven circuit. There has been very little work on what happens when more than one P-N junction is present. In this work, the first step towards multiple P-N junction circuits is taken by doing both experiments and simulations with a single-transistor amplifier using a bipolar transistor. Period doubling and chaos are seen when the amplifier is driven with signals between 100 kHz and 1 MHz, and they coincide with a very low frequency switching between different period doubled (or chaotic) wave forms. The switching frequencies are between 5 and 10 Hz. The switching behavior was confirmed in a simplified model of the transistor amplifier.

GLOBECOM '88 - IEEE Global Telecommunications Conference and Exhibition, Hollywood, FL, Nov. 28-Dec. 1, 1988, Conference Record. Volumes 1, 2, & 3

NASA Astrophysics Data System (ADS)

Various papers on communications for the information age are presented. Among the general topics considered are: telematic services and terminals, satellite communications, telecommunications mangaement network, control of integrated broadband networks, advances in digital radio systems, the intelligent network, broadband networks and services deployment, future switch architectures, performance analysis of computer networks, advances in spread spectrum, optical high-speed LANs, and broadband switching and networks. Also addressed are: multiple access protocols, video coding techniques, modulation and coding, photonic switching, SONET terminals and applications, standards for video coding, digital switching, progress in MANs, mobile and portable radio, software design for improved maintainability, multipath propagation and advanced countermeasure, data communication, network control and management, fiber in the loop, network algorithm and protocols, and advances in computer communications.

Light controlled prebreakdown characteristics of a semi-insulating GaAs photoconductive switch

NASA Astrophysics Data System (ADS)

Xiangrong, Ma; Wei, Shi; Weili, Ji; Hong, Xue

2011-12-01

A 4 mm gap semi-insulating (SI) GaAs photoconductive switch (PCSS) was triggered by a pulse laser with a wavelength of 1064 nm and a pulse energy of 0.5 mJ. In the experiment, when the bias field was 4 kV, the switch did not induce self-maintained discharge but worked in nonlinear (lock-on) mode. The phenomenon is analyzed as follows: an exciton effect contributes to photoconduction in the generation and dissociation of excitons. Collision ionization, avalanche multiplication and the exciton effect can supply carrier concentration and energy when an outside light source was removed. Under the combined influence of these factors, the SI-GaAs PCSS develops into self-maintained discharge rather than just in the light-controlled prebreakdown status. The characteristics of the filament affect the degree of damage to the switch.

Advanced architectures and the required technologies for next-generation communications satellite systems

NASA Technical Reports Server (NTRS)

Arnold, Ray; Naderi, F. Michael

1988-01-01

The hardware requirements for multibeam operation and onboard data processing and switching on future communication satellites are reviewed. Topics addressed include multiple-beam antennas, frequency-addressable beams, baseband vs IF switching, FDM/TDMA systems, and bulk demodulators. The proposed use of these technologies in the NASA ACTS, Italsat, and the Japanese ETS-VI is discussed in detail and illustrated with extensive diagrams, maps, drawings, and tables of projected performance data.

Steering of quantum waves: Demonstration of Y-junction transistors using InAs quantum wires

NASA Astrophysics Data System (ADS)

Jones, Gregory M.; Qin, Jie; Yang, Chia-Hung; Yang, Ming-Jey

2005-06-01

In this paper we demonstrate using an InAs quantum wire Y-branch switch that the electron wave can be switched to exit from the two drains by a lateral gate bias. The gating modifies the electron wave functions as well as their interference pattern, causing the anti-correlated, oscillatory transconductances. Our result suggests a new transistor function in a multiple-lead ballistic quantum wire system.

Integrated packaging of multiple double sided cooling planar bond power modules

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

Liang, Zhenxian

An integrated double sided cooled power module has one or multiple phase legs configuration including one or more planar power packages, each planar power package having an upper power switch unit and a lower power switch unit directly bonded and interconnected between two insulated power substrates, and further sandwiched between two heat exchangers via direct bonds. A segmented coolant manifold is interposed with the one or more planar power packages and creates a sealed enclosure that defines a coolant inlet, a coolant outlet and a coolant flow path between the inlet and the outlet. A coolant circulates along the flowmore » path to remove heat and increase the power density of the power module.« less

Multistability and switching in oppositely-directed saturated coupler

NASA Astrophysics Data System (ADS)

Nithyanandan, K.; Shafeeque Ali, A. K.; Porsezian, K.; Nishad, M. P. M.; Tchofo Dinda, P.; Grelu, Ph.

2018-06-01

We investigate theoretically the optical multistability that takes place in a two-core oppositely-directed saturated coupler (ODSC) having negative index material (NIM) channel. The dynamics are studied using the Lagrangian variational method, and analytical solutions are constructed with Jacobi elliptic functions. The ODSC exhibits a bandgap as a consequence of the effective feedback mechanism due to the opposite directionality of the phase velocity and the Poynting vector in the NIM channel. Depending on the strength of the nonlinear saturation, the system admits multiple stable states. Considering the additional degrees of design freedom with respect to conventional nonlinear couplers, the ODSC could become an attractive choice for all-optical switching. The existence of multiple transmission resonance windows could also facilitate the realization of gap solitons.

Study of repeater technology for advanced multifunctional communications satellites

NASA Technical Reports Server (NTRS)

1972-01-01

Investigations are presented concerning design concepts and implementation approaches for the satellite communication repeater subsystems of advanced multifunctional satellites. In such systems the important concepts are the use of multiple antenna beams, repeater switching (routing), and efficient spectrum utilization through frequency reuse. An information base on these techniques was developed and tradeoff analyses were made of repeater design concepts, with the work design taken in a broad sense to include modulation beam coverage patterns. There were five major areas of study: requirements analysis and processing; study of interbeam interference in multibeam systems; characterization of multiple-beam switching repeaters; estimation of repeater weight and power for a number of alternatives; and tradeoff analyses based on these weight and power data.

High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice.

PubMed

Okai, Shinsaku; Usui, Fumihito; Yokota, Shuhei; Hori-I, Yusaku; Hasegawa, Makoto; Nakamura, Toshinobu; Kurosawa, Manabu; Okada, Seiji; Yamamoto, Kazuya; Nishiyama, Eri; Mori, Hiroshi; Yamada, Takuji; Kurokawa, Ken; Matsumoto, Satoshi; Nanno, Masanobu; Naito, Tomoaki; Watanabe, Yohei; Kato, Tamotsu; Miyauchi, Eiji; Ohno, Hiroshi; Shinkura, Reiko

2016-07-04

Immunoglobulin A (IgA) is the main antibody isotype secreted into the intestinal lumen. IgA plays a critical role in the defence against pathogens and in the maintenance of intestinal homeostasis. However, how secreted IgA regulates gut microbiota is not completely understood. In this study, we isolated monoclonal IgA antibodies from the small intestine of healthy mouse. As a candidate for an efficient gut microbiota modulator, we selected a W27 IgA, which binds to multiple bacteria, but not beneficial ones such as Lactobacillus casei. W27 could suppress the cell growth of Escherichia coli but not L. casei in vitro, indicating an ability to improve the intestinal environment. Indeed W27 oral treatment could modulate gut microbiota composition and have a therapeutic effect on both lymphoproliferative disease and colitis models in mice. Thus, W27 IgA oral treatment is a potential remedy for inflammatory bowel disease, acting through restoration of host-microbial symbiosis.

Flexible, fast and accurate sequence alignment profiling on GPGPU with PaSWAS.

PubMed

Warris, Sven; Yalcin, Feyruz; Jackson, Katherine J L; Nap, Jan Peter

2015-01-01

To obtain large-scale sequence alignments in a fast and flexible way is an important step in the analyses of next generation sequencing data. Applications based on the Smith-Waterman (SW) algorithm are often either not fast enough, limited to dedicated tasks or not sufficiently accurate due to statistical issues. Current SW implementations that run on graphics hardware do not report the alignment details necessary for further analysis. With the Parallel SW Alignment Software (PaSWAS) it is possible (a) to have easy access to the computational power of NVIDIA-based general purpose graphics processing units (GPGPUs) to perform high-speed sequence alignments, and (b) retrieve relevant information such as score, number of gaps and mismatches. The software reports multiple hits per alignment. The added value of the new SW implementation is demonstrated with two test cases: (1) tag recovery in next generation sequence data and (2) isotype assignment within an immunoglobulin 454 sequence data set. Both cases show the usability and versatility of the new parallel Smith-Waterman implementation.

Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI.

PubMed

Arribas, Jose R; DeJesus, Edwin; van Lunzen, Jan; Zurawski, Christine; Doroana, Manuela; Towner, William; Lazzarin, Adriano; Nelson, Mark; McColl, Damian; Andreatta, Kristen; Swamy, Raji; Szwarcberg, Javier; Nguyen, Thai

2017-05-01

Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills. We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens. STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min. At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7-26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating). E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.

Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience.

PubMed

D'Amico, E; Patti, F; Zanghì, A; Lo Fermo, S; Chisari, C G; Zappia, M

2018-05-01

The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months.

Enhancement of macroscopic quantum tunneling in the higher-order phase switches of Bi2212 intrinsic Josephson junctions

NASA Astrophysics Data System (ADS)

Kitano, Haruhisa; Yamaguchi, Ayami; Takahashi, Yusaku; Umegai, Shunpei; Watabe, Yuji; Ohnuma, Haruka; Hosaka, Kazutaka; Kakehi, Daiki

2018-03-01

The macroscopic quantum tunneling (MQT) in the current-biased intrinsic Josephson junctions (IJJs) of high-T c cuprates has attracted much attention for decades. Although the MQT for the phase switches from the zero to the first voltage state (1st SW) in the multiple-branched I-V curves is well explained by the conventional theory, the occurrence of MQT for the higher order switches such as the switch from the 1st to 2nd voltage state (2nd SW) has been still debated. Here, we present an experimental study on the phase switches of small IJJs fabricated from underdoped Bi2Sr2(Ca,Y)Cu2Oy. We observed the single photon transition between quantized energy levels in the 3rd phase switches at 59.15 GHz and 2 K. The comparison with the previous studies on the nearly optimal-doped Bi2Sr2CaCu2Oy clearly suggests a possibility that the MQT rate for the higher-order phase switches is commonly enhanced by the effective suppression of the energy barrier for the higher-order phase escape due to the phase-running state after the 1st SW, in spite of the large difference in a critical current density and T c.

Treatment with a neutralising anti-rat interleukin-17 antibody after multiple-trauma reduces lung inflammation.

PubMed

Dai, Heling; Xu, Li; Tang, Yu; Liu, Zhi; Sun, Tiansheng

2015-08-01

It has been well recognised that a deficit of numbers and function of CD4(+)CD25(+)Foxp3(+) cells (Treg) is attributed to the development of autoimmune diseases and inflammatory diseases; additionally, IL-17-producing cells (Th17) have a pro-inflammatory role. The balance between Th17 and Treg may be essential for maintaining immune homeostasis and has long been thought as one of the important factors in the development/prevention of autoimmune diseases and inflammatory diseases. In our previous research, we explored that cytokines (IL-17) and the balance of Treg/Th17 had a significant relevance with tissue (lung) inflammation and injury in acute-phase after multiple-trauma. To more verify whether an imbalance of Treg/Th17 is characteristic of rats suffering from multiple trauma. Using IL-17 monoclonal antibody (IL-17mAb)-treated multiple-trauma rat, we tested the pathogenic role of IL-17 in the development of multiple-trauma. Rat models were treated respectively with IL-17mAb or rat IgG 2A isotype control or phosphate-buffered solution after model was established. Normal rats only received anaesthesia and cannulation were taken as sham. Rats in each group were killed respectively at the end of 1h, 4h, 8h after injection. Collected serum and lung samples for assessment dynamically of MPO, IL-17, IL-6, and TGF-β-mRNA, and cytokine (IL-17, IL-6, TGF-β) and lung tissue for pulmonary histological analysis. Neutralisation of IL-17 with anti-IL-17 can decrease serum IL-17 level and the IL-17-mRNA transcript level in lung, and ameliorate tissue inflammatory, defer disease course. Our data suggest that IL-17 is crucially involved in the pathogenesis of multiple-trauma in rat, IL-17 inhibition might ameliorate the lung inflammation in acute-phase after multiple-trauma. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.

PubMed

Ramer, Robert; Bublitz, Katharina; Freimuth, Nadine; Merkord, Jutta; Rohde, Helga; Haustein, Maria; Borchert, Philipp; Schmuhl, Ellen; Linnebacher, Michael; Hinz, Burkhard

2012-04-01

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.

DNA β-Amyloid1–42 Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model

PubMed Central

Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Eagar, Todd N.; Stüve, Olaf; Rosenberg, Roger N.

2010-01-01

Context DNA β-amyloid1–42 (Aβ42) trimer immunization was developed to produce specific T helper 2 cell (TH2)–type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Aβ42 peptide that occur in the brain of patients with AD. Objective To compare the immune response in wild-type mice after immunization with DNA Aβ42 trimer and Aβ42 peptide. Design and Intervention Wild-type mice received either 4 µg of DNA Aβ42 trimer immunization administered with gene gun (n=8) or intraperitoneal injection of 100 µg of human Aβ42 peptide with the adjuvant Quil A (n=8). Titers, epitope mapping, and isotypes of the Aβ42-specific antibodies were analyzed. Main Outcome Measures Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Aβ42-specific antibodies, and T-cell activation. Results DNA Aβ42 trimer immunization resulted in antibody titers with a mean of 15 µg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a TH2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed TH1/TH2 immune response (IgG1/IgG2a ratio of 1) (P<.001). No increased T-cell proliferation was observed in the DNA-immunized mice (P=.03). Conclusion In this preliminary study in a wild-type mouse model, DNA Aβ42 trimer immunization protocol produced a TH2 immune response and appeared to have low potential to cause an inflammatory T-cell response. PMID:19861672

Rabbit haemorrhagic disease: advantages of cELISA in assessing immunity in wild rabbits (Oryctolagus cuniculus).

PubMed

Zheng, Tao; Parkes, John P

2011-12-15

Rabbit haemorrhagic disease (RHD) is an acute fatal disease of domestic and wild European rabbits (Oryctolagus cuniculus) caused by RHD virus (RHDV). Accurate assessment of immunity is of great importance for the conservation and control of wild rabbits. We evaluated a competitive ELISA (cELISA) against isotype ELISAs for assessing the protective immunity against the disease by challenging 50 wild-caught rabbits with a lethal dose of RHDV. Death or survival to the challenge was used as a criterion to determine the performance characteristics of the assay for the assessment of immunity in rabbits. At 1:10 dilution, a serum exhibiting ≥ 25% inhibition (1:10(25)) was regarded as the presence of RHDV-specific antibodies. Eleven of 16 (68.8%) rabbits with antibodies at 1:10(25) (<1:40) died of RHD. When the cut-off was moved from 25% to 50% inhibition (1:10(50)) at 1:10 serum dilution, the assay sensitivity, specificity and accuracy for the protective immunity were improved from 84%, 54.2% and 69.4% to 84%, 100% and 91.8%, respectively. We also demonstrated at the epitope amino acid sequence level why the presence of the RHDV-cross reactive benign rabbit calicivirus, which interfered with isotype ELISAs, had little impact on the specificity of the cELISA for the diagnosis of RHDV infection. The presence of RHDV-specific antibody at 1:10(50) by the cELISA is a reliable indicator for the protective immunity. In contrast to isotype ELISAs, the cELISA is a valuable specific tool for monitoring the herd immunity to RHD for the conservation and management of wild rabbits in the field. Copyright © 2011 Elsevier B.V. All rights reserved.

Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV Rhesus macaque model

PubMed Central

Demberg, Thorsten; Mohanram, Venkatramanan; Venzon, David; Robert-Guroff, Marjorie

2014-01-01

As vaccine-elicited antibodies have now been associated with HIV protective efficacy, a thorough understanding of mucosal and systemic B-cell development and maturation is needed. We phenotyped mucosal memory B-cells, investigated isotype expression and homing patterns, and defined plasmablasts and plasma cells at three mucosal sites (duodenum, jejunum and rectum) in rhesus macaques, the commonly used animal model for pre-clinical vaccine studies. Unlike humans, macaque mucosal memory B-cells lacked CD27 expression; only two sub-populations were present: naïve (CD21+CD27−) and tissue-like (CD21−CD27−) memory. Similar to humans, IgA was the dominant isotype expressed. The homing markers CXCR4, CCR6, CCR9 and α4β7 were differentially expressed between naïve and tissue-like memory B-cells. Mucosal plasmablasts were identified as CD19+CD20+/−HLA-DR+Ki-67+IRF4+CD138+/− and mucosal plasma cells as CD19+CD20−HLA-DR−Ki-67−IRF4+CD138+. Both populations were CD39+/−CD27−. Plasma cell phenotype was confirmed by spontaneous IgA secretion by ELISpot of positively-selected cells and J-chain expression by real-time PCR. Duodenal, jejunal and rectal samples were similar in B-cell memory phenotype, isotype expression, homing receptors and plasmablast/plasma cell distribution among the three tissues. Thus rectal biopsies adequately monitor B-cell dynamics in the gut mucosa, and provide a critical view of mucosal B-cell events associated with development of vaccine-elicited protective immune responses and SIV/SHIV pathogenesis and disease control. PMID:24814239

The antibody response to Dracunculus medinensis in an endemic human population of northern Ghana.

PubMed

Bloch, P; Simonsen, P E; Vennervald, B J

1993-03-01

The serum antibody response (total, and isotypes IgG1, IgG4, IgM, IgA and IgE) to Guinea worm infection was examined in humans from a highly endemic area of northern Ghana by ELISA and SDS-PAGE/Western blot techniques using an adult D. medinensis antigen. Sera were obtained early and late in the peak transmission period, from persons with patent and postpatent infections, as well as from persons from the same endemic area who claimed never to have had Guinea worm infection. To observe for potential cross-reactions in the tests, sera were also obtained from areas with no transmission of Guinea worm from patients with hookworm, O. volvulus and W. bancrofti infections, and from non-infected controls. Sera from persons living in the Guinea worm endemic area reacted extensively with Guinea worm antigen in both tests, and large numbers of bands were produced in the Western blots (up to 35 identified for some sera). For most antibody isotypes, the ELISA absorbance values obtained with sera from the same individuals varied between the two transmission seasons, with the highest titres present towards the end of the peak transmission period. The mean antibody titres for persons in the patent and postpatent infection categories were not significantly different when sera were obtained at the same season of the year. Persons from the endemic area, who claimed never to experience patent infections, also had antibodies to Guinea worm, although at significantly lower mean levels than for the patent and postpatent categories. The highest specificity in the ELISA and the most homogenous Western blots were obtained when detecting for antibodies of the IgG4 isotype.

Electrostatic differences: A possible source for the functional differences between MCF7 and brain microtubules.

PubMed

Feizabadi, Mitra Shojania; Rosario, Brandon; Hernandez, Marcos A V

2017-11-04

Recent studies suggested a link between diversity of beta tubulin isotypes in microtubule structures and the regulatory roles that they play not only on microtubules' intrinsic dynamic, but also on the translocation characteristics of some of the molecular motors along microtubules. Remarkably, unlike porcine brain microtubules, MCF7 microtubules are structured from a different beta tubulin distribution. These types of cancer microtubules show a relatively stable and slow dynamic. In addition, the translocation parameters of some molecular motors are distinctly different along MCF7 as compared to those parameters on brain microtubules. It is known that the diversity of beta tubulin isotypes differ predominantly in the specifications and the electric charge of their carboxy-terminal tails. A key question is to identify whether the negative electrostatic charge of tubulin isotypes and, consequently, microtubules, can potentially be considered as one of the sources of functional differences in MCF7 vs. brain microtubules. We tested this possibility experimentally by monitoring the electro-orientation of these two types of microtubules inside a uniform electric field. Through this evaluation, we quantified and compared the average normalized polarization coefficient of MCF7 vs. Porcine brain microtubules. The higher value obtained for the polarization of MCF7 microtubules, which is associated to the higher negative charge of these types of microtubules, is significant as it can further explain the slow intrinsic dynamic that has been recently reported for single MCF7 microtubules in vitro. Furthermore, it can be potentially considered as a factor that can directly impact the translocation parameters of some molecular motors along MCF7 microtubules, by altering the mutual electrostatic interactions between microtubules and molecular motors. Copyright © 2017 Elsevier Inc. All rights reserved.

Review: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis.

PubMed

Pucheu-Haston, Cherie M; Bizikova, Petra; Eisenschenk, Melissa N C; Santoro, Domenico; Nuttall, Tim; Marsella, Rosanna

2015-04-01

Canine atopic dermatitis (AD) is considered to be an immunoglobulin E (IgE)-mediated hypersensitivity response to environmental allergens. The role of other antibody isotypes and nonenvironmental allergens in disease pathogenesis remains unclear. The objective of this review is to provide an update on advances in the understanding of the relevance of specific antibody isotypes, autoallergens and nonenvironmental allergens in the pathogenesis of canine AD. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed. Where necessary, older articles were included for background information. Neither total nor allergen-specific IgE necessarily correlates with clinical disease in canine AD. Some dogs exhibit clinical signs that are indistinguishable from AD but have no demonstrable allergen-specific IgE (atopic-like dermatitis). Allergen-specific immunoglobulin G may be demonstrated in canine AD, but there is no evidence that this isotype plays a role in disease development. Although humans with AD may develop serum IgE against autoallergens, this finding has not been substantiated in the dog. In contrast, adverse food reactions are frequently co-associated with AD in the dog. Ingestion of food and environmental allergens may trigger exacerbations of AD. Determination of the role of IgE in the pathogenesis of canine AD still requires clarification. Clinical trials and research studies must distinguish atopic dogs with allergen-specific IgE or skin test reactivity from those without. There is no convincing evidence demonstrating a pathogenic role for either allergen-specific immunoglobulin G or autoallergens in canine AD, but food items may be triggers for disease flares in certain individuals. © 2015 ESVD and ACVD.

DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model.

PubMed

Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Eagar, Todd N; Stüve, Olaf; Rosenberg, Roger N

2009-10-28

DNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD. To compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide. Wild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed. Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation. DNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03). In this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.

Serum anti-phenolic glycolipid-1 IgA correlates to IgM isotype in leprosy patients: a possible candidate for seroepidemiological surveys?

PubMed

de Macedo, Alexandre C; Guimarães, Juliana A; Rodrigues, Raphael O; Araújo, Thiago D V; Tavares, Clodis M; Cabral, Paula B; de Moraes-Pinto, Maria Isabel; Nagao-Dias, Aparecida T

2018-03-01

The aim of this study was to compare serum anti-phenolic glycolipid-1 IgA, IgG, and IgM levels in leprosy patients and controls. Analysis of anti-PGL-1 IgA, IgG, or IgM in serum samples from multibacillary (MB, n=32) and paucibacillary (PB, n=22) leprosy patients, and in non-endemic controls (n=17), using an indirect enzyme-linked immunosorbent assay. A strong correlation between serum IgM and IgA isotypes was found (r=.745, P<.0001) in MB patients. A moderate correlation was found in all analyses in PB patients. A moderate agreement was found between anti-PGL1 IgA and IgM tests. Based on the ROC curves, the cut-off values were selected and the parameters of validation were calculated. Considering the clinical forms altogether, the diagnostic sensitivities were 50.0% for IgA, 22.2% for IgG, and 74.1% for IgM. The positive (VPP) and negative (VPN) predictive values were estimated for each isotype. For IgA, the VPP and VPN were, respectively, 100.0% (87.0%-100.0%; 95% confidence interval) and 38.7% (24.4%-54.5%); for IgG, 100% (87.0%-100.0%) and 28.8% (17.8%-42.1%), respectively; and for IgM, 95.2% (83.8%-99.4%) and 51.7% (32.5%-70.6%), respectively. Despite the limiting factors, anti-PGL1 IgA correlates to IgM levels and it could be considered as a possible laboratorial tool to be also used, for instance, in serological follow-up studies. © 2017 Wiley Periodicals, Inc.

Development of monoclonal antibodies against axenic amastigotes of Leishmania infantum strain in Iran: implication for diagnosis of Kala-azar

PubMed Central

Nourizadeh, Ezzat; Zargar, Seyed Jalal; Alimohammadian, Mohammad Hossein; Ajdary, Soheila; Mahdavi, Mahdi

2018-01-01

Objective(s): Leishmaniasis is endemic in 88 countries. Amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection. Monoclonal antibodies are key reagents used in the diagnosis of infectious and non-infectious diseases. The aim of this study was to produce monoclonal antibodies against axenic amastigotes of the Leishmania infantum strain in Iran. Materials and Methods: First, standard strains were cultured and axenic amastigote antigens of L. infantum were obtained. Since then, BALB/c smice were immunized and antibody titers were determined. For hybridoma cell formation, lymphocytes isolated from spleen of immunized mice and myeloma cells were fused at a ratio of 10 to 1 in the presence of polyethylene glycol, followed by limiting dilution for the isolation of monoclones. Subsequently, antibody isotypes were determined by using the isotyping kit. The best clone was injected intraperitoneally to pristane-primed mice for large scale production of monoclonal antibodies. The specificity of antibody was determined with Western blotting. Results: Approximately 25 positive monoclones were obtained, of which four hybrids producing anti-amastigotes L. infantum monoclonal antibodies with high optical density (OD), selected and designated as 8D2 FVI6, 8D2 FVI3, 6G2 FV4 and 6G2 FV3. Results from isotype determination showed the IgG2b sub-class in 6G2FV2 and 8D2FVI6 monoclones. Conclusion: This study produced monoclonal antibody against amastigotes of Iranian strain of L. infantum for the first time. These antibodies have reactivity against Iranian strain of L. infantum and can be used in the diagnosis of Kala-azar.

Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic basal forebrain neurons.

PubMed

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E

2012-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls.Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage.

Genome-wide identification, phylogenetic classification, and exon-intron structure characterisation of the tubulin and actin genes in flax (Linum usitatissimum).

PubMed

Pydiura, Nikolay; Pirko, Yaroslav; Galinousky, Dmitry; Postovoitova, Anastasiia; Yemets, Alla; Kilchevsky, Aleksandr; Blume, Yaroslav

2018-06-08

Flax (Linum usitatissimum L.) is a valuable food and fiber crop cultivated for its quality fiber and seed oil. α-, β-, γ-tubulins and actins are the main structural proteins of the cytoskeleton. α- and γ-tubulin and actin genes have not been characterized yet in the flax genome. In this study, we have identified 6 α-tubulin genes, 13 β-tubulin genes, 2 γ-tubulin genes, and 15 actin genes in the flax genome and analysed the phylogenetic relationships between flax and A. thaliana tubulin and actin genes. Six α-tubulin genes are represented by 3 paralogous pairs, among 13 β-tubulin genes 7 different isotypes can be distinguished, 6 of which are encoded by two paralogous genes each. γ-tubulin is represented by a paralogous pair of genes one of which may be not functional. Fifteen actin genes represent 7 paralogous pairs - 7 actin isotypes and a sequentially duplicated copy of one of the genes of one of the isotypes. Exon-intron structure analysis has shown intron length polymorphism within the β-tubulin genes and intron number variation among the α-tubulin gene: 3 or 4 introns are found in two or four genes, respectively. Intron positioning occurs at conservative sites, as observed in numerous other plant species. Flax actin genes show both intron length polymorphisms and variation in the number of intron that may be 2 or 3. These data will be useful to support further studies on the specificity, functioning, regulation and evolution of the flax cytoskeleton proteins. This article is protected by copyright. All rights reserved.

Out-of-plane three-stable-state ferroelectric switching: Finding the missing middle states

NASA Astrophysics Data System (ADS)

Lee, Jin Hong; Chu, Kanghyun; Kim, Kwang-Eun; Seidel, Jan; Yang, Chan-Ho

2016-03-01

By realizing a nonvolatile third intermediate ferroelectric state through anisotropic misfit strain, we demonstrate electrical switching among three stable out-of-plane polarizations in bismuth ferrite thin films grown on (110) pc-oriented gadolinium scandate substrates (where pc stands for pseudocubic) by the use of an asymmetric external electric field at the step edge of a bottom electrode. We employ phenomenological Landau theory, in conjunction with electrical poling experiments using piezoresponse force microscopy, to understand the role of anisotropic misfit strain and an in-plane electric field in stabilization of multiple ferroelectric states and their competition. Our finding provides a useful insight into multistep ferroelectric switching in rhombohedral ferroelectrics.

Model for multishot all-thermal all-optical switching in ferromagnets

NASA Astrophysics Data System (ADS)

Gorchon, J.; Yang, Y.; Bokor, J.

2016-07-01

All-optical magnetic switching (AOS) is a recently observed rich and puzzling phenomenon that offers promising technological applications. However, a fundamental understanding of the underlying mechanisms remains elusive. Here we present a model for multishot helicity-dependent AOS in ferromagnetic materials based on a purely heat-driven mechanism in the presence of magnetic circular dichroism (MCD). We predict that AOS should be possible with as little as 0.5% of MCD, after a minimum number of laser shots heat the sample close to the Curie temperature. Finally, we qualitatively reproduce the all-optically switched domain patterns observed experimentally by numerically simulating the result of multiple laser shots on an FePtC granular ferromagnetic film.

Design and Implementation of nine level multilevel Inverter

NASA Astrophysics Data System (ADS)

Dhineshkumar, K.; Subramani, C.

2018-04-01

In this paper the solar based boost converter integrated Nine level multilevel inverter presented. It uses 7 switches to produce nine level output stepped waveform. The aim of the work to produce 9 level wave form using solar and boost converter. The conventional inverter has multiple sources and has 16 switches are required and also more number of voltage sources required. The proposed inverter required single solar panel and reduced number of switches and integrated boost converter which increase the input voltage of the inverter. The proposed inverter simulated and compared with R load using Mat lab and prototype model experimentally verified. The proposed inverter can be used in n number of solar applications.

Multiple-Ring Digital Communication Network

NASA Technical Reports Server (NTRS)

Kirkham, Harold

1992-01-01

Optical-fiber digital communication network to support data-acquisition and control functions of electric-power-distribution networks. Optical-fiber links of communication network follow power-distribution routes. Since fiber crosses open power switches, communication network includes multiple interconnected loops with occasional spurs. At each intersection node is needed. Nodes of communication network include power-distribution substations and power-controlling units. In addition to serving data acquisition and control functions, each node acts as repeater, passing on messages to next node(s). Multiple-ring communication network operates on new AbNET protocol and features fiber-optic communication.

Performance of real time associative memory using a photorefractive crystal and liquid crystal electrooptic switches

NASA Astrophysics Data System (ADS)

Xu, Haiying; Yuan, Yang; Yu, Youlong; Xu, Kebin; Xu, Yuhuan

1990-08-01

This paper presents a real time holographic associative memory implemented with photorefractive KNSBN:Co crystal as the memory element and a liquid crystal electrooptic switch array as the reflective thresholding device. The experiment stores and recalls two images and shows that the system has real-time multiple-image storage and recall functions. An associative memory with a dynamic threshold level to decide the closest match of an incomplete input is proposed.

Moving Beyond 3D Hetero-Integration and Towards Monolithic Integration of Phase-Change RF Switches with SiGe BiCMOS

DTIC Science & Technology

2016-03-31

Corporation, Linthicum, Maryland *Corresponding author: Pavel.Borodulin@ngc.com Abstract: A chip -scale, highly-reconfigurable transmitter and...the technology has been used in a chip -scale, reconfigurable receiver demonstration and ongoing efforts to increase the level of performance and...circuit (RF-FPGA). It consists of a heterogeneous assembly of a SiGe BiCMOS chip with multiple 3D-integrated, low-loss, phase-change switch chiplets

Immune responses of B. malayi thioredoxin (TRX) and venom allergen homologue (VAH) chimeric multiple antigen for lymphatic filariasis.

PubMed

Anugraha, Gandhirajan; Jeyaprita, Parasurama Jawaharlal; Madhumathi, Jayaprakasam; Sheeba, Tamilvanan; Kaliraj, Perumal

2013-12-01

Although multiple vaccine strategy for lymphatic filariasis has provided tremendous hope, the choice of antigens used in combination has determined its success in the previous studies. Multiple antigens comprising key vaccine candidates from different life cycle stages would provide a promising strategy if the antigenic combination is chosen by careful screening. In order to analyze one such combination, we have used a chimeric construct carrying the well studied B. malayi antigens thioredoxin (BmTRX) and venom allergen homologue (BmVAH) as a fusion protein (TV) and evaluated its immune responses in mice model. The efficacy of fusion protein vaccine was explored in comparison with the single antigen vaccines and their cocktail. In mice, TV induced significantly high antibody titer of 1,28,000 compared to cocktail vaccine TRX+VAH (50,000) and single antigen vaccine TRX (16,000) or VAH (50,000). Furthermore, TV elicited higher level of cellular proliferative response together with elevated levels of IFN-γ, IL-4 and IL-5 indicating a Th1/Th2 balanced response. The isotype antibody profile showed significantly high level of IgG1 and IgG2b confirming the balanced response elicited by TV. Immunization with TV antigen induced high levels of both humoral and cellular immune responses compared to either cocktail or antigen given alone. The result suggests that TV is highly immunogenic in mice and hence the combination needs to be evaluated for its prophylactic potential.

Extension and applications of switching model: Range theory, multiple scattering model of Goudsmit-Saunderson, and lateral spread treatment of Marwick-Sigmund

NASA Astrophysics Data System (ADS)

Ikegami, Seiji

2017-09-01

The switching model (PSM) developed in the previous paper is extended to obtain an ;extended switching model (ESM). In the ESM, the mixt electronic-and-nuclear energy-loss region, in addition to the electronic and nuclear energy-loss regions in PSM, is taken into account analytically and appropriately. This model is combined with a small-angle multiple scattering range theory considering both nuclear and electronic stopping effects developed by Marwick-Sigmund and Valdes-Arista to formulate a improved range theory. The ESM is also combined with the multiple scattering theory with non-small angle approximation by Goudsmit-Saunderson. Furthermore, we applied ESM to lateral spread model of Marwick-Sigmund. Numerical calculations of the entire distribution functions including one of the mixt region are roughly and approximately possible. However, exact numerical calculation may be impossible. Consequently, several preliminary numerical calculations of the electronic, mixt, and nuclear regions are performed to examine their underlying behavior with respect to the incident energy, the scattering angle, the outgoing projectile intensity, and the target thickness. We show the numerical results not only of PSM and but also of ESM. Both numerical results are shown in the present paper for the first time. Since the theoretical relations are constructed using reduced variables, the calculations are made only on the case of C colliding on C.

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.

PubMed

Lenz, Georg; Nagel, Inga; Siebert, Reiner; Roschke, Anna V; Sanger, Warren; Wright, George W; Dave, Sandeep S; Tan, Bruce; Zhao, Hong; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Campo, Elias; Jaffe, Elaine S; Smeland, Erlend B; Fisher, Richard I; Kuehl, W Michael; Chan, Wing C; Staudt, Louis M

2007-03-19

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.

Switched-Observer-Based Adaptive Neural Control of MIMO Switched Nonlinear Systems With Unknown Control Gains.

PubMed

Long, Lijun; Zhao, Jun

2017-07-01

In this paper, the problem of adaptive neural output-feedback control is addressed for a class of multi-input multioutput (MIMO) switched uncertain nonlinear systems with unknown control gains. Neural networks (NNs) are used to approximate unknown nonlinear functions. In order to avoid the conservativeness caused by adoption of a common observer for all subsystems, an MIMO NN switched observer is designed to estimate unmeasurable states. A new switched observer-based adaptive neural control technique for the problem studied is then provided by exploiting the classical average dwell time (ADT) method and the backstepping method and the Nussbaum gain technique. It effectively handles the obstacle about the coexistence of multiple Nussbaum-type function terms, and improves the classical ADT method, since the exponential decline property of Lyapunov functions for individual subsystems is no longer satisfied. It is shown that the technique proposed is able to guarantee semiglobal uniformly ultimately boundedness of all the signals in the closed-loop system under a class of switching signals with ADT, and the tracking errors converge to a small neighborhood of the origin. The effectiveness of the approach proposed is illustrated by its application to a two inverted pendulum system.

Conceptual design of a high-speed electromagnetic switch for a modified flux-coupling-type SFCL and its application in renewable energy system.

PubMed

Chen, Lei; Chen, Hongkun; Yang, Jun; Shu, Zhengyu; He, Huiwen; Shu, Xin

2016-01-01

The modified flux-coupling-type superconducting fault current (SFCL) is a high-efficient electrical auxiliary device, whose basic function is to suppress the short-circuit current by controlling the magnetic path through a high-speed switch. In this paper, the high-speed switch is based on electromagnetic repulsion mechanism, and its conceptual design is carried out to promote the application of the modified SFCL. Regarding that the switch which is consisting of a mobile copper disc, two fixed opening and closing coils, the computational method for the electromagnetic force is discussed, and also the dynamic mathematical model including circuit equation, magnetic field equation as well as mechanical motion equation is theoretically deduced. According to the mathematical modeling and calculation of characteristic parameters, a feasible design scheme is presented, and the high-speed switch's response time can be less than 0.5 ms. For that the modified SFCL is equipped with this high-speed switch, the SFCL's application in a 10 kV micro-grid system with multiple renewable energy sources are assessed in the MATLAB software. The simulations are well able to affirm the SFCL's performance behaviors.

High frequency modulation circuits based on photoconductive wide bandgap switches

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

Sampayan, Stephen

Methods, systems, and devices for high voltage and/or high frequency modulation. In one aspect, an optoelectronic modulation system includes an array of two or more photoconductive switch units each including a wide bandgap photoconductive material coupled between a first electrode and a second electrode, a light source optically coupled to the WBGP material of each photoconductive switch unit via a light path, in which the light path splits into multiple light paths to optically interface with each WBGP material, such that a time delay of emitted light exists along each subsequent split light path, and in which the WBGP materialmore » conducts an electrical signal when a light signal is transmitted to the WBGP material, and an output to transmit the electrical signal conducted by each photoconductive switch unit. The time delay of the photons emitted through the light path is substantially equivalent to the time delay of the electrical signal.« less

Antibody-Mediated Small Molecule Detection Using Programmable DNA-Switches.

PubMed

Rossetti, Marianna; Ippodrino, Rudy; Marini, Bruna; Palleschi, Giuseppe; Porchetta, Alessandro

2018-06-13

The development of rapid, cost-effective, and single-step methods for the detection of small molecules is crucial for improving the quality and efficiency of many applications ranging from life science to environmental analysis. Unfortunately, current methodologies still require multiple complex, time-consuming washing and incubation steps, which limit their applicability. In this work we present a competitive DNA-based platform that makes use of both programmable DNA-switches and antibodies to detect small target molecules. The strategy exploits both the advantages of proximity-based methods and structure-switching DNA-probes. The platform is modular and versatile and it can potentially be applied for the detection of any small target molecule that can be conjugated to a nucleic acid sequence. Here the rational design of programmable DNA-switches is discussed, and the sensitive, rapid, and single-step detection of different environmentally relevant small target molecules is demonstrated.

Intermittent metabolic switching, neuroplasticity and brain health

PubMed Central

Mattson, Mark P.; Moehl, Keelin; Ghena, Nathaniel; Schmaedick, Maggie; Cheng, Aiwu

2018-01-01

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease. PMID:29321682

Evaluation of Right Ventricular Myocardial Mechanics Using Velocity Vector Imaging of Cardiac MRI Cine Images in Transposition of the Great Arteries Following Atrial and Arterial Switch Operations.

PubMed

Thattaliyath, Bijoy D; Forsha, Daniel E; Stewart, Chad; Barker, Piers C A; Campbell, Michael J

2015-01-01

The aim of the study was to determine right and left ventricle deformation parameters in patients with transposition of the great arteries who had undergone atrial or arterial switch procedures. Patients with transposition are born with a systemic right ventricle. Historically, the atrial switch operation, in which the right ventricle remains the systemic ventricle, was performed. These patients have increased rates of morbidity and mortality. We used cardiac MRI with Velocity Vector Imaging analysis to characterize and compare ventricular myocardial deformation in patients who had an atrial switch or arterial switch operation. Patients with a history of these procedures, who had a clinically ordered cardiac MRI were included in the study. Consecutive 20 patients (75% male, 28.7 ± 1.8 years) who underwent atrial switch operation and 20 patients (60% male, 17.7 ± 1.9 years) who underwent arterial switch operation were included in the study. Four chamber and short-axis cine images were used to determine longitudinal and circumferential strain and strain rate using Vector Velocity Imaging software. Compared with the arterial switch group, the atrial switch group had decreased right ventricular ejection fraction and increased end-diastolic and end-systolic volumes, and no difference in left ventricular ejection fraction and volumes. The atrial switch group had decreased longitudinal and circumferential strain and strain rate. When compared with normal controls multiple strain parameters in the atrial switch group were reduced. Myocardial deformation analysis of transposition patients reveals a reduction of right ventricular function and decreased longitudinal and circumferential strain parameters in patients with an atrial switch operation compared with those with arterial switch operation. A better understanding of the mechanisms of right ventricle failure in transposition of great arteries may lead to improved therapies and adaptation. © 2015 Wiley Periodicals, Inc.

Isotype Diversification of IgG Antibodies to HIV Gag Proteins as a Therapeutic Vaccination Strategy for HIV Infection.

PubMed

French, Martyn A; Abudulai, Laila N; Fernandez, Sonia

2013-08-09

The development of vaccines to treat and prevent human immunodeficiency virus (HIV) infection has been hampered by an incomplete understanding of "protective" immune responses against HIV. Natural control of HIV-1 infection is associated with T-cell responses against HIV-1 Gag proteins, particularly CD8⁺ T-cell responses restricted by "protective" HLA-B alleles, but other immune responses also contribute to immune control. These immune responses appear to include IgG antibodies to HIV-1 Gag proteins, interferon-a-dependant natural killer (NK) cell responses and plasmacytoid dendritic cell (pDC) responses. Here, it is proposed that isotype diversification of IgG antibodies against HIV-1 Gag proteins, to include IgG2, as well as IgG3 and IgG1 antibodies, will broaden the function of the antibody response and facilitate accessory cell responses against HIV-1 by NK cells and pDCs. We suggest that this should be investigated as a vaccination strategy for HIV-1 infection.

Role of antibody in recovery from experimental rabies. I. Effect of depletion of B and T cells

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

Miller, A.; Morse, H.C. III; Winkelstein, J.

1978-07-01

The avirulent high egg passage (HEP) strain of rabies virus produces an inapparent infection limited to the central nervous system (CNS) in intracerebrally inoculated adult mice. Heavy chain isotype (anti-..mu.. antiserum) immunosuppression potentiates the infection, with a mortality of about 60% and with elevated virus titers in the brain. Anti-..mu..-treated mice fail to raise antibody responses to rabies virus although their T cell function is normal when measured by the concanavalin A response of splenic lymphocytes. This indicates that the B cell response plays an important role in clearance of rabies virus from the neuroparenchyma. Treatment with cyclophosphamide or bymore » adult thymectomy, x-irradiation, and bone marrow reconstitution potentiates HEP infection to a greater extent than does isotype supression. Since these suppressive techniques impair both T and B lymphocyte responses, the data suggest that cellular immune mechanisms may also contribute to host defenses against this central nervous system (CNS) virus infection.« less

Digitally switchable multi-focal lens using freeform optics.

PubMed

Wang, Xuan; Qin, Yi; Hua, Hong; Lee, Yun-Han; Wu, Shin-Tson

2018-04-16

Optical technologies offering electrically tunable optical power have found a broad range of applications, from head-mounted displays for virtual and augmented reality applications to microscopy. In this paper, we present a novel design and prototype of a digitally switchable multi-focal lens (MFL) that offers the capability of rapidly switching the optical power of the system among multiple foci. It consists of a freeform singlet and a customized programmable optical shutter array (POSA). Time-multiplexed multiple foci can be obtained by electrically controlling the POSA to switch the light path through different segments of the freeform singlet rapidly. While this method can be applied to a broad range of imaging and display systems, we experimentally demonstrate a proof-of-concept prototype for a multi-foci imaging system.

Multipulsed dynamic moire interferometer

DOEpatents

Deason, Vance A.

1991-01-01

An improved dynamic moire interferometer comprised of a lasing medium providing a plurality of beams of coherent light, a multiple q-switch producing multiple trains of 100,000 or more pulses per second, a combining means collimating multiple trains of pulses into substantially a single train and directing beams to specimen gratings affixed to a test material, and a controller, triggering and sequencing the emission of the pulses with the occurrence and recording of a dynamic loading event.

A Multiple-range Self-balancing Thermocouple Potentiometer

NASA Technical Reports Server (NTRS)

Warshawsky, I; Estrin, M

1951-01-01

A multiple-range potentiometer circuit is described that provides automatic measurement of temperatures or temperature differences with any one of several thermocouple-material pairs. Techniques of automatic reference junction compensation, span adjustment, and zero suppression are described that permit rapid selection of range and wire material, without the necessity for restandardization, by setting of two external tap switches.

Double-Pulsed 2-micron Laser Transmitter for Multiple Lidar Applications

NASA Technical Reports Server (NTRS)

Singh, Upendra N.; Yu, Jirong

2002-01-01

A high energy double-pulsed Ho:Tm:YLF 2-micron laser amplifier has been demonstrated. 600 mJ per pulse pair under Q-switch operation is achieved with the gain of 4.4. This solid-state laser source can be used as lidar transmitter for multiple lidar applications such as coherent wind and carbon dioxide measurements.

Understanding Human-Plasmodium falciparum Immune Interactions Uncovers the Immunological Role of Worms

PubMed Central

Roussilhon, Christian; Brasseur, Philippe; Agnamey, Patrice; Pérignon, Jean-Louis; Druilhe, Pierre

2010-01-01

Background Former studies have pointed to a monocyte-dependant effect of antibodies in protection against malaria and thereby to cytophilic antibodies IgG1 and IgG3, which trigger monocyte receptors. Field investigations have further documented that a switch from non-cytophilic to cytophilic classes of antimalarial antibodies was associated with protection. The hypothesis that the non-cytophilic isotype imbalance could be related to concomittant helminthic infections was supported by several interventions and case-control studies. Methods and Findings We investigated here the hypothesis that the delayed acquisition of immunity to malaria could be related to a worm-induced Th2 drive on antimalarial immune responses. IgG1 to IgG4 responses against 6 different parasite-derived antigens were analyzed in sera from 203 Senegalese children, half carrying intestinal worms, presenting 421 clinical malaria attacks over 51 months. Results show a significant correlation between the occurrence of malaria attacks, worm carriage (particularly that of hookworms) and a decrease in cytophilic IgG1 and IgG3 responses and an increase in non-cytophilic IgG4 response to the merozoite stage protein 3 (MSP3) vaccine candidate. Conclusion The results confirm the association with protection of anti-MSP3 cytophilic responses, confirm in one additional setting that worms increase malaria morbidity and show a Th2 worm-driven pattern of anti-malarial immune responses. They document why large anthelminthic mass treatments may be worth being assessed as malaria control policies. PMID:20174576

Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing

PubMed Central

Tsioris, Konstantinos; Gupta, Namita T.; Ogunniyi, Adebola O.; Zimnisky, Ross M.; Qian, Feng; Yao, Yi; Wang, Xiaomei; Stern, Joel N. H.; Chari, Raj; Briggs, Adrian W.; Clouser, Christopher R.; Vigneault, Francois; Church, George M.; Garcia, Melissa N.; Murray, Kristy O.; Montgomery, Ruth R.; Kleinstein, Steven H.; Love, J. Christopher

2015-01-01

West Nile virus infection (WNV) is an emerging mosquito-borne disease that can lead to severe neurological illness and currently has no available treatment or vaccine. Using microengraving, an integrated single-cell analysis method, we analyzed a cohort of subjects infected with WNV - recently infected and post-convalescent subjects - and efficiently identified four novel WNV neutralizing antibodies. We also assessed the humoral response to WNV on a single-cell and repertoire level by integrating next generation sequencing (NGS) into our analysis. The results from single-cell analysis indicate persistence of WNV-specific memory B cells and antibody-secreting cells in post-convalescent subjects. These cells exhibited class-switched antibody isotypes. Furthermore, the results suggest that the antibody response itself does not predict the clinical severity of the disease (asymptomatic or symptomatic). Using the nucleotide coding sequences for WNV-specific antibodies derived from single cells, we revealed the ontogeny of expanded WNV-specific clones in the repertoires of recently infected subjects through NGS and bioinformatic analysis. This analysis also indicated that the humoral response to WNV did not depend on an anamnestic response, due to an unlikely previous exposure to the virus. The innovative and integrative approach presented here to analyze the evolution of neutralizing antibodies from natural infection on a single-cell and repertoire level can also be applied to vaccine studies, and could potentially aid the development of therapeutic antibodies and our basic understanding of other infectious diseases. PMID:26481611

Conjugate-like immunogens produced as protein capsular matrix vaccines.

PubMed

Thanawastien, Ann; Cartee, Robert T; Griffin, Thomas J; Killeen, Kevin P; Mekalanos, John J

2015-03-10

Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell-independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a "carrier protein" antigen. Such "conjugate vaccines" efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines.

Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing.

PubMed

Tsioris, Konstantinos; Gupta, Namita T; Ogunniyi, Adebola O; Zimnisky, Ross M; Qian, Feng; Yao, Yi; Wang, Xiaomei; Stern, Joel N H; Chari, Raj; Briggs, Adrian W; Clouser, Christopher R; Vigneault, Francois; Church, George M; Garcia, Melissa N; Murray, Kristy O; Montgomery, Ruth R; Kleinstein, Steven H; Love, J Christopher

2015-12-01

West Nile virus (WNV) infection is an emerging mosquito-borne disease that can lead to severe neurological illness and currently has no available treatment or vaccine. Using microengraving, an integrated single-cell analysis method, we analyzed a cohort of subjects infected with WNV - recently infected and post-convalescent subjects - and efficiently identified four novel WNV neutralizing antibodies. We also assessed the humoral response to WNV on a single-cell and repertoire level by integrating next generation sequencing (NGS) into our analysis. The results from single-cell analysis indicate persistence of WNV-specific memory B cells and antibody-secreting cells in post-convalescent subjects. These cells exhibited class-switched antibody isotypes. Furthermore, the results suggest that the antibody response itself does not predict the clinical severity of the disease (asymptomatic or symptomatic). Using the nucleotide coding sequences for WNV-specific antibodies derived from single cells, we revealed the ontogeny of expanded WNV-specific clones in the repertoires of recently infected subjects through NGS and bioinformatic analysis. This analysis also indicated that the humoral response to WNV did not depend on an anamnestic response, due to an unlikely previous exposure to the virus. The innovative and integrative approach presented here to analyze the evolution of neutralizing antibodies from natural infection on a single-cell and repertoire level can also be applied to vaccine studies, and could potentially aid the development of therapeutic antibodies and our basic understanding of other infectious diseases.

Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

PubMed Central

Pérez-Mazliah, Damián; Ng, Dorothy Hui Lin; Freitas do Rosário, Ana Paula; McLaughlin, Sarah; Mastelic-Gavillet, Béatris; Sodenkamp, Jan; Kushinga, Garikai; Langhorne, Jean

2015-01-01

Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of Plasmodium chabaudi in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of P. chabaudi infection and P. yoelii infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated P. chabaudi-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the Il21 gene, or B cells with a targeted disruption of the Il21r gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic P. chabaudi infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, Il21, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses. PMID:25763578

Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen

PubMed Central

1987-01-01

Viruses have been postulated to be involved in the induction of autoantibodies by: autoimmunization with tissue proteins released by virally induced tissue damage; immunization with virally encoded antigens bearing molecular similarities to normal tissue proteins; or nonspecific (polyclonal) B cell stimulation by the infection. Infectious mononucleosis (IM) is an experiment of nature that provides the opportunity for examining these possibilities. We show here that IgM antibodies produced in this disease react with at least nine normal tissue proteins, in addition to the virally encoded Epstein-Barr nuclear antigen (EBNA-1). The antibodies are generated to configurations in the glycine-alanine repeat region of EBNA-1 and are crossreactive with the normal tissue proteins through similar configurations, as demonstrated by the effectiveness of a synthetic glycine-alanine peptide in inhibiting the reactions. The antibodies are absent in preillness sera and gradually disappear over a period of months after illness, being replaced by IgG anti-EBNA-1 antibodies that do not crossreact with the normal tissue proteins but that are still inhibited by the glycine-alanine peptide. These findings are most easily explained by either a molecular mimicry model of IgM autoantibody production or by the polyclonal activation of a germline gene for a crossreactive antibody. It also indicates a selection of highly specific, non-crossreactive anti-EBNA-1 antibodies during IgM to IgG isotype switching. PMID:2435830

Stable individual characteristics in the perception of multiple embedded patterns in multistable auditory stimuli

PubMed Central

Denham, Susan; Bõhm, Tamás M.; Bendixen, Alexandra; Szalárdy, Orsolya; Kocsis, Zsuzsanna; Mill, Robert; Winkler, István

2014-01-01

The ability of the auditory system to parse complex scenes into component objects in order to extract information from the environment is very robust, yet the processing principles underlying this ability are still not well understood. This study was designed to investigate the proposal that the auditory system constructs multiple interpretations of the acoustic scene in parallel, based on the finding that when listening to a long repetitive sequence listeners report switching between different perceptual organizations. Using the “ABA-” auditory streaming paradigm we trained listeners until they could reliably recognize all possible embedded patterns of length four which could in principle be extracted from the sequence, and in a series of test sessions investigated their spontaneous reports of those patterns. With the training allowing them to identify and mark a wider variety of possible patterns, participants spontaneously reported many more patterns than the ones traditionally assumed (Integrated vs. Segregated). Despite receiving consistent training and despite the apparent randomness of perceptual switching, we found individual switching patterns were idiosyncratic; i.e., the perceptual switching patterns of each participant were more similar to their own switching patterns in different sessions than to those of other participants. These individual differences were found to be preserved even between test sessions held a year after the initial experiment. Our results support the idea that the auditory system attempts to extract an exhaustive set of embedded patterns which can be used to generate expectations of future events and which by competing for dominance give rise to (changing) perceptual awareness, with the characteristics of pattern discovery and perceptual competition having a strong idiosyncratic component. Perceptual multistability thus provides a means for characterizing both general mechanisms and individual differences in human perception. PMID:24616656

Stable individual characteristics in the perception of multiple embedded patterns in multistable auditory stimuli.

PubMed

Denham, Susan; Bõhm, Tamás M; Bendixen, Alexandra; Szalárdy, Orsolya; Kocsis, Zsuzsanna; Mill, Robert; Winkler, István

2014-01-01

The ability of the auditory system to parse complex scenes into component objects in order to extract information from the environment is very robust, yet the processing principles underlying this ability are still not well understood. This study was designed to investigate the proposal that the auditory system constructs multiple interpretations of the acoustic scene in parallel, based on the finding that when listening to a long repetitive sequence listeners report switching between different perceptual organizations. Using the "ABA-" auditory streaming paradigm we trained listeners until they could reliably recognize all possible embedded patterns of length four which could in principle be extracted from the sequence, and in a series of test sessions investigated their spontaneous reports of those patterns. With the training allowing them to identify and mark a wider variety of possible patterns, participants spontaneously reported many more patterns than the ones traditionally assumed (Integrated vs. Segregated). Despite receiving consistent training and despite the apparent randomness of perceptual switching, we found individual switching patterns were idiosyncratic; i.e., the perceptual switching patterns of each participant were more similar to their own switching patterns in different sessions than to those of other participants. These individual differences were found to be preserved even between test sessions held a year after the initial experiment. Our results support the idea that the auditory system attempts to extract an exhaustive set of embedded patterns which can be used to generate expectations of future events and which by competing for dominance give rise to (changing) perceptual awareness, with the characteristics of pattern discovery and perceptual competition having a strong idiosyncratic component. Perceptual multistability thus provides a means for characterizing both general mechanisms and individual differences in human perception.

Event and Cost Offsets of Switching 20% of the Type 1 Diabetes Population in Germany From Multiple Daily Injections to Continuous Subcutaneous Insulin Infusion: A 4-Year Simulation Model.

PubMed

Zöllner, York Francis; Ziegler, Ralph; Stüve, Magnus; Krumreich, Julia; Schauf, Marion

2016-09-01

Most patients with type 1 diabetes (T1D) administer insulin by multiple daily injections (MDI). However, continuous subcutaneous insulin infusion (CSII) therapy has been shown to improve glycemic control compared with MDI. The objective was to determine the key medical event and cost offsets generated over a 4-year period by introducing CSII to T1D patients who have inadequately controlled glucose metabolism on MDI in Germany. A decision-analytic budget impact model, simulating a treatment switch scenario, was developed. In the base case, all T1D patients received MDI, while in the switch scenario, 20% of the eligible T1D population, randomly selected, moved to CSII. The model focused on 2 medical endpoints and their corresponding cost offsets: severe hypoglycemic events requiring hospitalization (SHEH) and complication-borne diabetic events (CDEs) avoided. Event rates and costs were taken from the literature and official sources, adopting a health insurance perspective. Compared with the base case, treating 20% of patients with CSII in the switch scenario resulted in 47 864 fewer SHEH and 5543 fewer CDEs. This led to total cost offsets of €183 085 281 within the 4-year time horizon. Of these, 92% were driven by avoided SHEH. Compared to an expected budget impact (cost increase) of 83%, only treatment costs considered, the total impact of the switch scenario amounted merely to a 24.5% increase in costs (reduction by 58.5% points; a factor of 3.4). The use of CSII resulted in fewer SHEH and CDEs compared to MDI. The incurred CSII implementation costs are hence offset to a substantial degree by cost savings in complication treatment. © 2016 Diabetes Technology Society.

Electrical Circuit Tester

DOEpatents

Love, Frank

2006-04-18

An electrical circuit testing device is provided, comprising a case, a digital voltage level testing circuit with a display means, a switch to initiate measurement using the device, a non-shorting switching means for selecting pre-determined electrical wiring configurations to be tested in an outlet, a terminal block, a five-pole electrical plug mounted on the case surface and a set of adapters that can be used for various multiple-pronged electrical outlet configurations for voltages from 100 600 VAC from 50 100 Hz.

Tm:germanate Fiber Laser: Tuning And Q-switching

NASA Technical Reports Server (NTRS)

Barnes, Norman P.; Walsh, Brian M.; Reichle, Donald J.; DeYoung, R. J.; Jiang, Shibin

2007-01-01

A Tm:germanate fiber laser produced >0.25 mJ/pulse in a 45 ns pulse. It is capable of producing multiple Q-switched pulses from a single p ump pulse. With the addition of a diffraction grating, Tm:germanate f iber lasers produced a wide, but length dependent, tuning range. By s electing the fiber length, the tuning range extends from 1.88 to 2.04 ?m. These traits make Tm:germanate lasers suitable for remote sensin g of water vapor.

Comparative efficacy of switching to natalizumab in active multiple sclerosis

PubMed Central

Spelman, Timothy; Kalincik, Tomas; Zhang, Annie; Pellegrini, Fabio; Wiendl, Heinz; Kappos, Ludwig; Tsvetkova, Larisa; Belachew, Shibeshih; Hyde, Robert; Verheul, Freek; Grand-Maison, Francois; Izquierdo, Guillermo; Grammond, Pierre; Duquette, Pierre; Lugaresi, Alessandra; Lechner-Scott, Jeannette; Oreja-Guevara, Celia; Hupperts, Raymond; Petersen, Thor; Barnett, Michael; Trojano, Maria; Butzkueven, Helmut

2015-01-01

Objective To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets. Methods Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]). Results Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65–75%, the risk of first relapse by 53–82% (mean follow-up 1.7–2.2 years) and treatment discontinuation events by 48–65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch. Interpretation Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity. PMID:25909083

Association between switching antiepileptic drug products and healthcare utilization: A systematic review.

PubMed

Kwan, Patrick; Palmini, André

2017-08-01

There is ongoing concern whether switching between different antiepileptic drug (AED) products may compromise patient care. We systematically reviewed changes in healthcare utilization following AED switch. We searched MEDLINE and EMBASE databases (1980-October 2016) for studies that assessed the effect of AED switching in patients with epilepsy on outpatient visits, emergency room visits, hospitalization and hospital stay duration. A total of 14 articles met the inclusion criteria. All were retrospective studies. Four provided findings for specific AEDs only (lamotrigine, topiramate, phenytoin and divalproex), 9 presented pooled findings from multiple AEDs, and 1 study provided both specific (lamotrigine, topiramate, oxcarbazepine, and levetiracetam) and pooled findings. Three studies found an association between a switch of topiramate and an increase in healthcare utilization. Another three studies found that a brand-to-generic lamotrigine switch was not associated with an increased risk of emergently treated events (ambulance use, ER visits or hospitalization). The outcomes of the pooled AED switch studies were inconsistent; 5 studies reported an increased healthcare utilization while 5 studies did not. Studies that have examined the association between an AED switch and a change in healthcare utilization report conflicting findings. Factors that may explain these inconsistent outcomes include inter-study differences in the type of analysis undertaken (pooled vs individual AED data), the covariates used for data adjustment, and the type of switch examined. Future medical claim database studies employing a prospective design are encouraged to address these and other factors in order to enhance inter-study comparability and extrapolation of findings. Copyright © 2017 Elsevier Inc. All rights reserved.

Oral contraceptive discontinuation and its aftermath in 19 developing countries.

PubMed

Ali, Mohamed M; Cleland, John

2010-01-01

The purpose of the article was to document oral contraceptive (OC) discontinuation and switching in a large number of low- and middle-income countries, and to assess the effects of women's education and reason for use (spacing vs. limitation). An attempt was made to explain intercountry variations. Calendar data from 19 Demographic and Health Surveys conducted between 1999 and 2005 were used. Data were analyzed by single- and multiple-decrement life tables and by Cox proportional hazard model. The probability of stopping OC use within 12 months for reasons that implied dissatisfaction with the method ranged from 15% in Indonesia to over 40% in Bolivia and Peru with a median value of 28%. On average, 35% switched to a modern method within 3 months and 16% to a less effective 'traditional' method. Both education and reason for use were strongly related to the probability of switching to a modern method. Discontinuation was lower and switching higher in countries judged to have strong family planning programs. Both discontinuation of use and inadequate switching to alternative methods are major but neglected problems in the family planning services of many developing countries.

Avalanche atomic switching in strain engineered Sb2Te3-GeTe interfacial phase-change memory cells

NASA Astrophysics Data System (ADS)

Zhou, Xilin; Behera, Jitendra K.; Lv, Shilong; Wu, Liangcai; Song, Zhitang; Simpson, Robert E.

2017-09-01

By confining phase transitions to the nanoscale interface between two different crystals, interfacial phase change memory heterostructures represent the state of the art for energy efficient data storage. We present the effect of strain engineering on the electrical switching performance of the {{Sb}}2{{Te}}3-GeTe superlattice van der Waals devices. Multiple Ge atoms switching through a two-dimensional Te layer reduces the activation barrier for further atoms to switch; an effect that can be enhanced by biaxial strain. The out-of-plane phonon mode of the GeTe crystal remains active in the superlattice heterostructures. The large in-plane biaxial strain imposed by the {{Sb}}2{{Te}}3 layers on the GeTe layers substantially improves the switching speed, reset energy, and cyclability of the superlattice memory devices. Moreover, carefully controlling residual stress in the layers of {{Sb}}2{{Te}}3-GeTe interfacial phase change memories provides a new degree of freedom to design the properties of functional superlattice structures for memory and photonics applications.

Phase-Change Thermoplastic Elastomer Blends for Tunable Shape Memory by Physical Design

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

Mineart, Kenneth P.; Tallury, Syamal S.; Li, Tao

Shape-memory polymers (SMPs) change shape upon exposure to an environmental stimulus.1-3 They are of considerable importance in the ongoing development of stimuli-responsive biomedical4,5 and deployable6 devices, and their function depends on the presence of two components.7 The first provides mechanical rigidity to ensure retention of one or more temporary strain states and also serves as a switch capable of releasing a temporary strain state. The second, a network-forming component, is required to restore the polymer to a prior strain state upon stimulation. In thermally-activated SMPs, the switching element typically relies on a melting or glass transition temperature,1-3,7 and broad ormore » multiple switches permit several temporary strain states.8-10 Chemical integration of network-forming and switching species endows SMPs with specific properties.8,10,11 Here, we demonstrate that phase-change materials incorporated into network-forming macromolecules yield shape-memory polymer blends (SMPBs) with physically tunable switching temperatures and recovery kinetics for use in multi-responsive laminates and shape-change electronics.« less

Risk for switch from unipolar to bipolar disorder in youth with ADHD: a long term prospective controlled study.

PubMed

Biederman, Joseph; Petty, Carter R; Byrne, Deirdre; Wong, Patricia; Wozniak, Janet; Faraone, Stephen V

2009-12-01

To investigate whether ADHD is a risk factor for switches from unipolar to bipolar disorder over time. Data from two large controlled longitudinal family studies of boys and girls with and without ADHD and their siblings were used. Subjects (n=168) were followed prospectively and blindly over an average follow-up period of 7 years. Comparisons were made between youth with unipolar major depression who did and did not switch to full or subthreshold BP-I disorder at the follow-up assessment. Subjects were assessed at baseline and follow-up on multiple domains of functioning. Positive family history of parental psychiatric disorders was also compared between groups. ADHD was associated with a significantly higher risk for switches from unipolar to bipolar disorder (28% versus 6%; z=2.80, p=0.005). In subjects with ADHD, switches from unipolar to bipolar disorder were predicted by baseline comorbid conduct disorder, school behavior problems, and a positive family history of parental mood disorder. Psychosis was an exclusionary criterion in the original ascertainment of the studies of ADHD probands, so we were unable to test this as a predictor of switching to BPD. ADHD is a risk factor for switches from unipolar to bipolar disorder, and switches could be predicted by the presence of baseline conduct disorder, school behavior problems, and a positive family history of a mood disorder in a parent. These characteristics can aid clinicians in their treatment of youth with MDD.

An Evaluation of Health Service Impacts Consequent to Switching from Brand to Generic Venlafaxine in New Zealand under Conditions of Price Neutrality.

PubMed

Lessing, Charon; Ashton, Toni; Davis, Peter

2015-07-01

To study the health impact on adult New Zealand patients who switch from originator brand to generic venlafaxine. The national pharmacy database was used to select patients using venlafaxine for at least 6 months. Switchers and nonswitchers were identified, and switch behavior was compared for a 12-month follow-up period. Change in health service use following switching was also compared between switchers and nonswitchers including use of the emergency department, hospital, and specialist outpatient services over the same period. Approximately 12% of all originator brand users switched to generic venlafaxine, at least half of whom continued to use the generic throughout the follow-up period to August 1, 2012. Almost 60% of new users of the generic venlafaxine, however, switched to using the originator brand. Aside from a slight reduction in the use of outpatient services among switchers, there were no significant differences in health services use between switchers and nonswitchers for either existing or new venlafaxine users. Although both products remain fully subsidized and available, there is little incentive for prescribers, pharmacists, or patients to switch to the less expensive generic brand. If savings to the national New Zealand budget are to be realized, additional policy measures should be implemented to minimize incentives for multiple and reverse switching, and prescribers, as key opinion leaders, could take the lead in promoting generics to their patients. Copyright © 2015. Published by Elsevier Inc.

Optical MEMS platform for low-cost on-chip integration of planar light circuits and optical switching

NASA Astrophysics Data System (ADS)

German, Kristine A.; Kubby, Joel; Chen, Jingkuang; Diehl, James; Feinberg, Kathleen; Gulvin, Peter; Herko, Larry; Jia, Nancy; Lin, Pinyen; Liu, Xueyuan; Ma, Jun; Meyers, John; Nystrom, Peter; Wang, Yao Rong

2004-07-01

Xerox Corporation has developed a technology platform for on-chip integration of latching MEMS optical waveguide switches and Planar Light Circuit (PLC) components using a Silicon On Insulator (SOI) based process. To illustrate the current state of this new technology platform, working prototypes of a Reconfigurable Optical Add/Drop Multiplexer (ROADM) and a l-router will be presented along with details of the integrated latching MEMS optical switches. On-chip integration of optical switches and PLCs can greatly reduce the size, manufacturing cost and operating cost of multi-component optical equipment. It is anticipated that low-cost, low-overhead optical network products will accelerate the migration of functions and services from high-cost long-haul markets to price sensitive markets, including networks for metropolitan areas and fiber to the home. Compared to the more common silica-on-silicon PLC technology, the high index of refraction of silicon waveguides created in the SOI device layer enables miniaturization of optical components, thereby increasing yield and decreasing cost projections. The latching SOI MEMS switches feature moving waveguides, and are advantaged across multiple attributes relative to alternative switching technologies, such as thermal optical switches and polymer switches. The SOI process employed was jointly developed under the auspice of the NIST APT program in partnership with Coventor, Corning IntelliSense Corp., and MicroScan Systems to enable fabrication of a broad range of free space and guided wave MicroOptoElectroMechanical Systems (MOEMS).

A 10Gbps optical burst switching network incorporating ultra-fast (5ns) wavelength switched tunable laser sources

NASA Astrophysics Data System (ADS)

Ryan, Neil; Todd, Michael; Farrell, Tom; Lavin, Adrian; Rigole, Pierre-Jean; Corbett, Brian; Roycroft, Brendan; Engelstaedter, Jan-Peter

2017-11-01

This paper outlines the development of a prototype optical burst mode switching network based upon a star topology, the ultimate application of which could be as a transparent payload processor onboard satellite repeaters. The network architecture incorporates multiple tunable laser sources, burst mode receivers and a passive optical router (Arrayed Waveguide Grating). Each tunable optical signal should carry >=10Gbps and be capable of wavelength switching in c. 5ns timescales. Two monolithic tunable laser types, based upon different technologies, will be utilised: a Slotted Fabry Perot laser (a Fabry Perot laser with slots added in order to introduce controlled cavity perturbations); and a Modulated Grating Y-Branch Laser (MGY: a widely tunable, multi-section device similar to the DBR laser). While the Slotted Fabry Perot laser is expected to achieve the required switching times, it is an immature technology not yet capable of achieving tunability over 80 ITU channels from a single chip. The MGY device is a more mature technology and has full C-band ITU channel coverage, but is not capable of the required short switching times. Hence, in order to facilitate the integration of this more mature technology into the prototype breadboard with the requisite switching time capabilities, a system of `dual laser' transmitters is being developed to enable data transmission from one MGY laser while the other switches and vice-versa. This work is being performed under ESA contract AO 1-5025/06/NL/PM, Optical Technologies for Ultra - fast Processing.

Healthcare resource utilization following switch or discontinuation in multiple sclerosis patients on disease modifying drugs.

PubMed

Reynolds, Matthew W; Stephen, Reejis; Seaman, Chris; Rajagopalan, Kitty

2010-03-01

The objective of this study was to explore the cost and utilization in the period following discontinuations or switches of disease modifying drugs (DMDs) for patients with multiple sclerosis (MS). Secondary objectives included an assessment of the time to switch or discontinuation from index DMD treatment. Cases were defined as a billed MS diagnosis in continuously enrolled patients initiated with interferon-beta1a IM, interferon-beta1b SC, glatiramer acetate, and interferon-beta1a SC found in the PharMetrics Patient-Centric Database. Information on patient demographics, diagnoses, procedures, pharmacy-dispensed drugs, and costs was extracted; reasons for discontinuation and expenses outside of the healthcare system were not available. Treatment discontinuations and switches between study drugs were defined using pharmacy prescription patterns and analyzed by descriptive and regression methods. The non-pharmacy medical costs in the 18 months following switching or discontinuation were compared to the costs in a randomly selected similar period for those patients who did not switch or discontinue these agents. A total of 5,772 MS patients were continuously enrolled and were treated with one or more of the four drugs of interest, and about half of these patients switched drugs or discontinued treatment for at least 90 days. Patients initiated with interferon-beta1b SC were more likely to discontinue treatment compared to interferon-beta1a IM users. Non-pharmaceutical medical costs were highest for those switching treatments followed by those discontinuing DMDs in the 18 months following a switch or discontinuation, compared to persistent users of these drugs. Interferon beta1b SC initiators had higher costs following changes or discontinuations, while glatiramer acetate and interferon-beta1a SC users had lower subsequent costs compared to interferon-beta1a IM users. Unfortunately, the reasons for stopping the initial treatment cannot be determined from analysis of an administrative claims database. Also, the MS cases followed in this analysis are billing diagnostic events unconfirmed through a review of medical records or other data sources. The results are unstratified in terms of severity and thus while treatment patterns may vary for patients with different types of MS (e.g., progressive vs. relapsing-remitting), this cannot be examined in this analysis. Changing or discontinuing DMDs is common among MS patients and is associated with higher non-pharmaceutical medical costs that vary based on the initiating drug and other demographics characteristics.

Design and construction of a double inversion recombination switch for heritable sequential genetic memory.

PubMed

Ham, Timothy S; Lee, Sung K; Keasling, Jay D; Arkin, Adam P

2008-07-30

Inversion recombination elements present unique opportunities for computing and information encoding in biological systems. They provide distinct binary states that are encoded into the DNA sequence itself, allowing us to overcome limitations posed by other biological memory or logic gate systems. Further, it is in theory possible to create complex sequential logics by careful positioning of recombinase recognition sites in the sequence. In this work, we describe the design and synthesis of an inversion switch using the fim and hin inversion recombination systems to create a heritable sequential memory switch. We have integrated the two inversion systems in an overlapping manner, creating a switch that can have multiple states. The switch is capable of transitioning from state to state in a manner analogous to a finite state machine, while encoding the state information into DNA. This switch does not require protein expression to maintain its state, and "remembers" its state even upon cell death. We were able to demonstrate transition into three out of the five possible states showing the feasibility of such a switch. We demonstrate that a heritable memory system that encodes its state into DNA is possible, and that inversion recombination system could be a starting point for more complex memory circuits. Although the circuit did not fully behave as expected, we showed that a multi-state, temporal memory is achievable.

Design and Construction of a Double Inversion Recombination Switch for Heritable Sequential Genetic Memory

PubMed Central

Ham, Timothy S.; Lee, Sung K.; Keasling, Jay D.; Arkin, Adam P.

2008-01-01

Background Inversion recombination elements present unique opportunities for computing and information encoding in biological systems. They provide distinct binary states that are encoded into the DNA sequence itself, allowing us to overcome limitations posed by other biological memory or logic gate systems. Further, it is in theory possible to create complex sequential logics by careful positioning of recombinase recognition sites in the sequence. Methodology/Principal Findings In this work, we describe the design and synthesis of an inversion switch using the fim and hin inversion recombination systems to create a heritable sequential memory switch. We have integrated the two inversion systems in an overlapping manner, creating a switch that can have multiple states. The switch is capable of transitioning from state to state in a manner analogous to a finite state machine, while encoding the state information into DNA. This switch does not require protein expression to maintain its state, and “remembers” its state even upon cell death. We were able to demonstrate transition into three out of the five possible states showing the feasibility of such a switch. Conclusions/Significance We demonstrate that a heritable memory system that encodes its state into DNA is possible, and that inversion recombination system could be a starting point for more complex memory circuits. Although the circuit did not fully behave as expected, we showed that a multi-state, temporal memory is achievable. PMID:18665232

Power- and Low-Resistance-State-Dependent, Bipolar Reset-Switching Transitions in SiN-Based Resistive Random-Access Memory

NASA Astrophysics Data System (ADS)

Kim, Sungjun; Park, Byung-Gook

2016-08-01

A study on the bipolar-resistive switching of an Ni/SiN/Si-based resistive random-access memory (RRAM) device shows that the influences of the reset power and the resistance value of the low-resistance state (LRS) on the reset-switching transitions are strong. For a low LRS with a large conducting path, the sharp reset switching, which requires a high reset power (>7 mW), was observed, whereas for a high LRS with small multiple-conducting paths, the step-by-step reset switching with a low reset power (<7 mW) was observed. The attainment of higher nonlinear current-voltage ( I-V) characteristics in terms of the step-by-step reset switching is due to the steep current-increased region of the trap-controlled space charge-limited current (SCLC) model. A multilevel cell (MLC) operation, for which the reset stop voltage ( V STOP) is used in the DC sweep mode and an incremental amplitude is used in the pulse mode for the step-by-step reset switching, is demonstrated here. The results of the present study suggest that well-controlled conducting paths in a SiN-based RRAM device, which are not too strong and not too weak, offer considerable potential for the realization of low-power and high-density crossbar-array applications.

Review of the expression of Peroxisome Proliferator Activated Receptors alpha (PPARα), beta (PPAR β), and gamma (PPAR() in rodent and human development.

EPA Science Inventory

The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily and there are three primary isotypes, PPARα, β, and (. These receptors regulate important physiological processes that impact lipid homeostasis, inflammation, adipogenesis, r...

Demonstration of optically controlled data routing with the use of multiple-quantum-well bistable and electro-optical devices.

PubMed

Koppa, P; Chavel, P; Oudar, J L; Kuszelewicz, R; Schnell, J P; Pocholle, J P

1997-08-10

We present experimental results on a 1-to-64-channel free-space photonic switching demonstration system based on GaAs/GaAlAs multiple-quantum-well active device arrays. Two control schemes are demonstrated: data transparent optical self-routing usable in a packet-switching environment and direct optical control with potential signal amplification for circuit switching. The self-routing operation relies on the optical recognition of the binary destination address coded in each packet header. Address decoding is implemented with elementary optical bistable devices and modulator pixels as all-optical latches and electro-optical and gates, respectively. All 60 defect-free channels of the system could be operated one by one, but the simultaneous operation of only three channels could be achieved mainly because of the spatial nonhomogeneities of the devices. Direct-control operation is based on directly setting the bistable device reflectivity with a variable-control beam power. This working mode turned out to be much more tolerant of spatial noises: 37 channels of the system could be operated simultaneously. Further development of the system to a crossbar of N inputs and M outputs and system miniaturization are also considered.

Joint Interference Alignment and Power Allocation for K-User Multicell MIMO Channel through Staggered Antenna Switching.

PubMed

Selvaprabhu, Poongundran; Chinnadurai, Sunil; Sarker, Md Abdul Latif; Lee, Moon Ho

2018-01-28

In this paper, we characterise the joint interference alignment (IA) and power allocation strategies for a K -user multicell multiple-input multiple-output (MIMO) Gaussian interference channel. We consider a MIMO interference channel with blind-IA through staggered antenna switching on the receiver. We explore the power allocation and feasibility condition for cooperative cell-edge (CE) mobile users (MUs) by assuming that the channel state information is unknown. The new insight behind the transmission strategy of the proposed scheme is premeditated (randomly generated transmission strategy) and partial cooperative CE MUs, where the transmitter is equipped with a conventional antenna, the receiver is equipped with a reconfigurable multimode antenna (staggered antenna switching pattern), and the receiver switches between preset T modes. Our proposed scheme assists and aligns the desired signals and interference signals to cancel the common interference signals because the received signal must have a corresponding independent signal subspace. The capacity for a K -user multicell MIMO Gaussian interference channel with reconfigurable multimode antennas is completely characterised. Furthermore, we show that the proposed K -user multicell MIMO scheduling and K -user L -cell CEUs partial cooperation algorithms elaborate the generalisation of K -user IA and power allocation strategies. The numerical results demonstrate that the proposed intercell interference scheme with partial-cooperative CE MUs achieves better capacity and signal-to-interference plus noise ratio (SINR) performance compared to noncooperative CE MUs and without intercell interference schemes.

Joint Interference Alignment and Power Allocation for K-User Multicell MIMO Channel through Staggered Antenna Switching

PubMed Central

2018-01-01

In this paper, we characterise the joint interference alignment (IA) and power allocation strategies for a K-user multicell multiple-input multiple-output (MIMO) Gaussian interference channel. We consider a MIMO interference channel with blind-IA through staggered antenna switching on the receiver. We explore the power allocation and feasibility condition for cooperative cell-edge (CE) mobile users (MUs) by assuming that the channel state information is unknown. The new insight behind the transmission strategy of the proposed scheme is premeditated (randomly generated transmission strategy) and partial cooperative CE MUs, where the transmitter is equipped with a conventional antenna, the receiver is equipped with a reconfigurable multimode antenna (staggered antenna switching pattern), and the receiver switches between preset T modes. Our proposed scheme assists and aligns the desired signals and interference signals to cancel the common interference signals because the received signal must have a corresponding independent signal subspace. The capacity for a K-user multicell MIMO Gaussian interference channel with reconfigurable multimode antennas is completely characterised. Furthermore, we show that the proposed K-user multicell MIMO scheduling and K-user L-cell CEUs partial cooperation algorithms elaborate the generalisation of K-user IA and power allocation strategies. The numerical results demonstrate that the proposed intercell interference scheme with partial-cooperative CE MUs achieves better capacity and signal-to-interference plus noise ratio (SINR) performance compared to noncooperative CE MUs and without intercell interference schemes. PMID:29382100

Progress with infliximab biosimilars for inflammatory bowel disease.

PubMed

Kurti, Zsuzsanna; Gonczi, Lorant; Lakatos, Peter L

2018-04-29

Biological therapies have revolutionized the treatment of inflammatory bowel diseases (IBD) in the last two decades. Though biological drugs are effective, their use is associated with high costs and access to biological agents varies among countries. As the patent for the reference products expired, the advent of biosimilar monoclonal antibodies has been expected. Biosimilars represent less expensive alternatives compared to the reference product. Areas covered: In this review, authors will review the literature on the clinical efficacy, safety and immunogenicity of current and future biosimilar infliximabs. Short- and medium-term data from real-life cohorts and from randomized-clinical trials in IBD demonstrated similar outcomes in terms of efficacy, safety and immunogenicity as the reference product for CT-P13. Switch data from the reference to the biosimilar product are also accumulating (including the NOR-SWITCH and the CT-P13 3.4 study). Expert opinion: The use of biosimilar infliximab in IBD is increasing worldwide. Its use may be associated with budget savings leading to better access to biological therapies and consequently improved health outcomes. Switching from the originator to a biosimilar in patients with IBD is acceptable, although scientific and clinical evidence is lacking regarding reverse switching, multiple switching, and cross-switching among biosimilars in IBD patients.

Theory and calculus of cubical complexes

NASA Technical Reports Server (NTRS)

Perlman, M.

1973-01-01

Combination switching networks with multiple outputs may be represented by Boolean functions. Report has been prepared which describes derivation and use of extraction algorithm that may be adapted to simplification of such simultaneous Boolean functions.

Can the Focus of Attention Accommodate Multiple, Separate Items?

PubMed Central

Gilchrist, Amanda L.; Cowan, Nelson

2011-01-01

Researchers of working memory currently debate capacity limits of the focus of attention, the proposed mental faculty in which items are most easily accessed. Cowan (1999) suggested that its capacity is about 4 chunks, whereas others have suggested that its capacity is only 1 chunk. Recently, Oberauer and Bialkova (2009) found evidence that 2 items could reside in the focus of attention, but only because they were combined into a single chunk. We modified their experimental procedure, which depends on a pattern of switch costs, to obtain a situation in which chunking was not likely to occur (i.e., each item remained a separate chunk), and still obtained results consistent with a capacity of at least 2 items. Therefore, either the focus of attention can hold multiple chunks, or the switch cost logic must be reconsidered. PMID:21767065

Multiple mechanisms switch an electrically coupled, synaptically inhibited neuron between competing rhythmic oscillators.

PubMed

Gutierrez, Gabrielle J; O'Leary, Timothy; Marder, Eve

2013-03-06

Rhythmic oscillations are common features of nervous systems. One of the fundamental questions posed by these rhythms is how individual neurons or groups of neurons are recruited into different network oscillations. We modeled competing fast and slow oscillators connected to a hub neuron with electrical and inhibitory synapses. We explore the patterns of coordination shown in the network as a function of the electrical coupling and inhibitory synapse strengths with the help of a novel visualization method that we call the "parameterscape." The hub neuron can be switched between the fast and slow oscillators by multiple network mechanisms, indicating that a given change in network state can be achieved by degenerate cellular mechanisms. These results have importance for interpreting experiments employing optogenetic, genetic, and pharmacological manipulations to understand circuit dynamics. Copyright © 2013 Elsevier Inc. All rights reserved.

Damping-tunable energy-harvesting vehicle damper with multiple controlled generators: Design, modeling and experiments

NASA Astrophysics Data System (ADS)

Xie, Longhan; Li, Jiehong; Li, Xiaodong; Huang, Ledeng; Cai, Siqi

2018-01-01

Hydraulic dampers are used to decrease the vibration of a vehicle, where vibration energy is dissipated as heat. In addition to resulting in energy waste, the damping coefficient in hydraulic dampers cannot be changed during operation. In this paper, an energy-harvesting vehicle damper was proposed to replace traditional hydraulic dampers. The goal is not only to recover kinetic energy from suspension vibration but also to change the damping coefficient during operation according to road conditions. The energy-harvesting damper consists of multiple generators that are independently controlled by switches. One of these generators connects to a tunable resistor for fine tuning the damping coefficient, while the other generators are connected to a control and rectifying circuit, each of which both regenerates electricity and provides a constant damping coefficient. A mathematical model was built to investigate the performance of the energy-harvesting damper. By controlling the number of switched-on generators and adjusting the value of the external tunable resistor, the damping can be fine tuned according to the requirement. In addition to the capability of damping tuning, the multiple controlled generators can output a significant amount of electricity. A prototype was built to test the energy-harvesting damper design. Experiments on an MTS testing system were conducted, with results that validated the theoretical analysis. Experiments show that changing the number of switched-on generators can obviously tune the damping coefficient of the damper and simultaneously produce considerable electricity.

Continuous Subcutaneous Insulin Infusion as an Effective Method of Desensitization Therapy for Diabetic Patients with Insulin Allergy: A 4-year Single-center Experience.

PubMed

Yuan, Tao; Zhao, Weigang; Wang, Lianglu; Dong, Yingyue; Li, Naishi

2016-11-01

This article summarizes our experiences in the application of continuous subcutaneous insulin infusion (CSII) as a method of rapid desensitization therapy for diabetic patients with insulin allergy that was subsequently switched to a regimen of multiple-dose injections for long-term insulin therapy. The clinical data of 11 diabetic patients with insulin allergy in Peking Union Medical College Hospital from April 1, 2008, through December 31, 2011, were retrospectively analyzed. All 11 conditions were diagnosed by case history, skin testing, determination of serum specific anti-insulin IgE, and reaction to withdrawal of insulin. Seven patients accepted the traditional injection method of desensitization, and 5 patients accepted CSII with the protocol designed for this study (1 patient accepted CSII after failure by the formal method). Six of the 7 patients who accepted the traditional method and all 5 patients who accepted CSII had successful results. All 5 patients in the CSII group switched to a regimen of multiple dosage injections. In a survey of 28 nurses, both experienced nurses and practical nurses preferred to use CSII as the method of desensitization. It is feasible and effective for diabetic patients with insulin allergy to use CSII as a method of rapid desensitization with subsequent switching to a regimen of multiple-dose injections for long-term insulin therapy. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

A coherent through-wall MIMO phased array imaging radar based on time-duplexed switching

NASA Astrophysics Data System (ADS)

Chen, Qingchao; Chetty, Kevin; Brennan, Paul; Lok, Lai Bun; Ritchie, Matthiew; Woodbridge, Karl

2017-05-01

Through-the-Wall (TW) radar sensors are gaining increasing interest for security, surveillance and search and rescue applications. Additionally, the integration of Multiple-Input, Multiple-Output (MIMO) techniques with phased array radar is allowing higher performance at lower cost. In this paper we present a 4-by-4 TW MIMO phased array imaging radar operating at 2.4 GHz with 200 MHz bandwidth. To achieve high imaging resolution in a cost-effective manner, the 4 Tx and 4 Rx elements are used to synthesize a uniform linear array (ULA) of 16 virtual elements. Furthermore, the transmitter is based on a single-channel 4-element time-multiplexed switched array. In transmission, the radar utilizes frequency modulated continuous wave (FMCW) waveforms that undergo de-ramping on receive to allow digitization at relatively low sampling rates, which then simplifies the imaging process. This architecture has been designed for the short-range TW scenarios envisaged, and permits sufficient time to switch between antenna elements. The paper first outlines the system characteristics before describing the key signal processing and imaging algorithms which are based on traditional Fast Fourier Transform (FFT) processing. These techniques are implemented in LabVIEW software. Finally, we report results from an experimental campaign that investigated the imaging capabilities of the system and demonstrated the detection of personnel targets. Moreover, we show that multiple targets within a room with greater than approximately 1 meter separation can be distinguished from one another.

Performance Benefits Associated with Context-Dependent Arm Pointing Adaptation

NASA Technical Reports Server (NTRS)

Seidler, R. D.; Bloomberg, J. J.; Stelmach, George E.

2000-01-01

Our previous work has demonstrated that head orientation can be used as a contextual cue to switch between mUltiple adaptive states. Subjects were assigned to one of three groups: the head orientation group tilted the head towards the right shoulder when drawing under a 0.5 gain of display and towards the left shoulder when drawing under a 1.5 gain of display; the target orientation group had the home & target positions rotated counterclockwise when drawing under the 0.5 gain and clockwise for the l.5 gain; the arm posture group changed the elbow angle of the arm they were not drawing with from full flexion to full extension with 0.5 and l.5 gain display changes. The head orientation cue was effectively associated with the multiple gains, in comparison to the control conditions. The purpose of the current investigation was to determine whether this context-dependent adaptation results in any savings in terms of performance measures such as movement duration and movement smoothness when subjects switch between multiple adaptive states. Subjects in the head adaptation group demonstrated reduced movement duration and increased movement smoothness (measured via normalized j erk scores) in comparison to the two control groups when switching between the 0.5 and 1.5 gain. of display. This work has demonstrated not only that subjects can acquire context-dependent adaptation, but also that it results in a significant savings of performance upon transfer between adaptive states

Switching between global and local levels: the level repetition effect and its hemispheric asymmetry

PubMed Central

Kéïta, Luc; Bedoin, Nathalie; Burack, Jacob A.; Lepore, Franco

2014-01-01

The global level of hierarchical stimuli (Navon’s stimuli) is typically processed quicker and better than the local level; further differential hemispheric dominance is described for local (left hemisphere, LH) and global (right hemisphere, RH) processing. However, neuroimaging and behavioral data indicate that stimulus category (letter or object) could modulate the hemispheric asymmetry for the local level processing. Besides, when the targets are unpredictably displayed at the global or local level, the participant has to switch between levels, and the magnitude of the switch cost increases with the number of repeated-level trials preceding the switch. The hemispheric asymmetries associated with level switching is an unresolved issue. LH areas may be involved in carrying over the target level information in case of level repetition. These areas may also largely participate in the processing of level-changed trials. Here we hypothesized that RH areas underly the inhibitory mechanism performed on the irrelevant level, as one of the components of the level switching process. In an experiment using a within-subject design, hierarchical stimuli were briefly presented either to the right or to the left visual field. 32 adults were instructed to identify the target at the global or local level. We assessed a possible RH dominance for the non-target level inhibition by varying the attentional demands through the manipulation of level repetitions (two or gour repeated-level trials before the switch). The behavioral data confirmed a LH specialization only for the local level processing of letter-based stimuli, and detrimental effect of increased level repetitions before a switch. Further, data provides evidence for a RH advantage in inhibiting the non-target level. Taken together, the data supports the notion of the existence of multiple mechanisms underlying level-switch effects. PMID:24723903

Salt-responsive polyzwitterionic materials for surface regeneration between switchable fouling and antifouling properties.

PubMed

Chen, Hong; Yang, Jintao; Xiao, Shengwei; Hu, Rundong; Bhaway, Sarang M; Vogt, Bryan D; Zhang, Mingzhen; Chen, Qiang; Ma, Jie; Chang, Yung; Li, Lingyan; Zheng, Jie

2016-08-01

Development of smart regenerative surface is a highly challenging but important task for many scientific and industrial applications. Specifically, very limited research efforts were made for surface regeneration between bio-adhesion and antifouling properties, because bioadhesion and antifouling are the two highly desirable but completely opposite properties of materials. Herein, we developed salt-responsive polymer brushes of poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3-yl) propane-1-sulfonate) (polyVBIPS), which can be switched reversibly and repeatedly between protein capture/release and surface wettability in a controllable manner. PolyVBIPS brush has demonstrated its switching ability to resist both protein adsorption from 100% blood plasma/serum and bacterial attachment in multiple cycles. PolyVBIPS brush also exhibits reversible surface wettability from ∼40° to 25° between in PBS and in 1M NaCl solutions in multiple cycles. Overall, the salt-responsive behaviors of polyVBIPS brushes can be interpreted by the "anti-polyelectrolyte effect", i.e. polyVBIPS brushes adopt a collapsed chain conformation at low ionic strengths to achieve surface adhesive, but an extended chain conformation at high ionic strength to realize antifouling properties. We expect that polyVBIPS will provide a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, and regenerative properties. Unlike many materials with "one-time switching" capability for surface regeneration, we developed a new regenerative surface of zwitterionic polymer brush, which exhibits a reversible salt-induced switching property between a biomolecule-adhesive state and a biomolecule repellent state in complex media for multiple cycles. PolyVBIPS is easily synthesized and can be straightforward coated on the surface, which provides a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, regenerative properties. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dynamics and Stability of Capillary Surfaces: Liquid Switches at Small Scales

NASA Technical Reports Server (NTRS)

Steen, Paul H.; Bhandar, Anand; Vogel, Michael J.; Hirsa, Amir H.

2004-01-01

The dynamics and stability of systems of interfaces is central to a range of technologies related to the Human Exploration and Development of Space (HEDS). Our premise is that dramatic shape changes can be manipulated to advantage with minimal input, if the system is near instability. The primary objective is to develop the science base to allow novel approaches to liquid management in low-gravity based on this premise. HEDS requires efficient, reliable and lightweight technologies. Our poster will highlight our progress toward this goal using the capillary switch as an example. A capillary surface is a liquid/liquid or liquid/gas interface whose shape is determined by surface tension. For typical liquids (e.g., water) against gas on earth, capillary surfaces occur on the millimeterscale and smaller where shape deformation due to gravity is unimportant. In low gravity, they can occur on the centimeter scale. Capillary surfaces can be combined to make a switch a system with multiple stable states. A capillary switch can generate motion or effect force. To be practical, the energy barriers of such a switch must be tunable, its switching time (kinetics) short and its triggering mechanism reliable. We illustrate these features with a capillary switch that consists of two droplets, coupled by common pressure. As long as contact lines remained pinned, motions are inviscid, even at sub-millimeter scales, with consequent promise of low-power consumption at the device level. Predictions of theory are compared to experiment on i) a soap-film prototype at centimeter scale and ii) a liquid droplet switch at millimeter-scale.

RISK FOR SWITCH FROM UNIPOLAR TO BIPOLAR DISORDER IN YOUTH WITH ADHD: A LONG TERM PROSPECTIVE CONTROLLED STUDY

PubMed Central

Biederman, Joseph; Petty, Carter R.; Byrne, Deirdre; Wong, Patricia; Wozniak, Janet; Faraone, Stephen V.

2009-01-01

Background To investigate whether ADHD is a risk factor for switches from unipolar to bipolar disorder over time. Methods Data from two large controlled longitudinal family studies of boys and girls with and without ADHD and their siblings were used. Subjects (n=168) were followed prospectively and blindly over an average follow up period of 7 years. Comparisons were made between youth with unipolar major depression who did and did not switch to full or subthreshold BP-I disorder at the follow-up assessment. Subjects were assessed at baseline and follow-up on multiple domains of functioning. Positive family history of parental psychiatric disorders was also compared between groups. Results ADHD was associated with a significantly higher risk for switches from unipolar to bipolar disorder (28% vs 6%; z=2.80, p=0.005). In subjects with ADHD, switches from unipolar to bipolar disorder were predicted by baseline comorbid conduct disorder, school behavior problems, and a positive family history of parental mood disorder. Limitations Psychosis was an exclusionary criterion in the original ascertainment of the studies of ADHD probands, so we were unable to test this as a predictor of switching to BPD. Conclusions ADHD is a risk factor for switches from unipolar to bipolar disorder, and switches could be predicted by the presence of baseline conduct disorder, school behavior problems, and a positive family history of a mood disorder in a parent. These characteristics can aid clinicians in their treatment of youth with MDD. PMID:19324422

Event-Related Potential Responses to Task Switching Are Sensitive to Choice of Spatial Filter

PubMed Central

Wong, Aaron S. W.; Cooper, Patrick S.; Conley, Alexander C.; McKewen, Montana; Fulham, W. Ross; Michie, Patricia T.; Karayanidis, Frini

2018-01-01

Event-related potential (ERP) studies using the task-switching paradigm show that multiple ERP components are modulated by activation of proactive control processes involved in preparing to repeat or switch task and reactive control processes involved in implementation of the current or new task. Our understanding of the functional significance of these ERP components has been hampered by variability in their robustness, as well as their temporal and scalp distribution across studies. The aim of this study is to examine the effect of choice of reference electrode or spatial filter on the number, timing and scalp distribution of ERP elicited during task-switching. We compared four configurations, including the two most common (i.e., average mastoid reference and common average reference) and two novel ones that aim to reduce volume conduction (i.e., reference electrode standardization technique (REST) and surface Laplacian) on mixing cost and switch cost effects in cue-locked and target-locked ERP waveforms in 201 healthy participants. All four spatial filters showed the same well-characterized ERP components that are typically seen in task-switching paradigms: the cue-locked switch positivity and target-locked N2/P3 effect. However, both the number of ERP effects associated with mixing and switch cost, and their temporal and spatial resolution were greater with the surface Laplacian transformation which revealed rapid temporal adjustments that were not identifiable with other spatial filters. We conclude that the surface Laplacian transformation may be more suited to characterize EEG signatures of complex spatiotemporal networks involved in cognitive control. PMID:29568260

Theoretical Insights into the Biophysics of Protein Bi-stability and Evolutionary Switches

PubMed Central

Krobath, Heinrich; Chan, Hue Sun

2016-01-01

Deciphering the effects of nonsynonymous mutations on protein structure is central to many areas of biomedical research and is of fundamental importance to the study of molecular evolution. Much of the investigation of protein evolution has focused on mutations that leave a protein’s folded structure essentially unchanged. However, to evolve novel folds of proteins, mutations that lead to large conformational modifications have to be involved. Unraveling the basic biophysics of such mutations is a challenge to theory, especially when only one or two amino acid substitutions cause a large-scale conformational switch. Among the few such mutational switches identified experimentally, the one between the GA all-α and GB α+β folds is extensively characterized; but all-atom simulations using fully transferrable potentials have not been able to account for this striking switching behavior. Here we introduce an explicit-chain model that combines structure-based native biases for multiple alternative structures with a general physical atomic force field, and apply this construct to twelve mutants spanning the sequence variation between GA and GB. In agreement with experiment, we observe conformational switching from GA to GB upon a single L45Y substitution in the GA98 mutant. In line with the latent evolutionary potential concept, our model shows a gradual sequence-dependent change in fold preference in the mutants before this switch. Our analysis also indicates that a sharp GA/GB switch may arise from the orientation dependence of aromatic π-interactions. These findings provide physical insights toward rationalizing, predicting and designing evolutionary conformational switches. PMID:27253392

The impact on health outcome measures of switching to generic medicines consequent to reference pricing: the case of olanzapine in New Zealand.

PubMed

Lessing, Charon; Ashton, Toni; Davis, Peter B

2015-06-01

New Zealand's Pharmaceutical Management Agency (PHARMAC) manages the list of medicines available for prescribing with government subsidy, within a fixed annual medicines budget. PHARMAC achieves this through a mix of pricing strategies including reference pricing. In 2011, PHARMAC applied generic reference pricing to olanzapine tablets. This study sought to evaluate change in outcome measures of patients switching from originator to generic olanzapine consequent to the introduction of the policy. A retrospective study using national health data collections was conducted. Outcome measures included medicines indicators (change in dosage, concomitant therapy and treatment cessation), health care service indicators (use of emergency departments, hospitals and specialist services), surveillance reports of adverse events, and mortality. Subsequent to the removal of funding for originator brand olanzapine tablets, 99.7% of patients meeting the inclusion criteria switched to using generic olanzapine. Limited case reports of suspected therapeutic loss were received in the study time period. No increase in use of additional oral or injectable antipsychotic medication was observed after switching, nor any increase in other unique, non-antipsychotic prescription items. However, a high incidence of multiple switching between available brands was found. No net impact of switching brands on health service utilisation or mortality was found. The study shows that a switch can be made safely from originator olanzapine to a generic brand, and suggests that switching to generics should generally be viewed more positively. Generic reference pricing achieves considerable savings and, as a pricing policy, could be applied more widely.

Autoinhibition and signaling by the switch II motif in the G-protein chaperone of a radical B12 enzyme.

PubMed

Lofgren, Michael; Koutmos, Markos; Banerjee, Ruma

2013-10-25

MeaB is an accessory GTPase protein involved in the assembly, protection, and reactivation of 5'-deoxyadenosyl cobalamin-dependent methylmalonyl-CoA mutase (MCM). Mutations in the human ortholog of MeaB result in methylmalonic aciduria, an inborn error of metabolism. G-proteins typically utilize conserved switch I and II motifs for signaling to effector proteins via conformational changes elicited by nucleotide binding and hydrolysis. Our recent discovery that MeaB utilizes an unusual switch III region for bidirectional signaling with MCM raised questions about the roles of the switch I and II motifs in MeaB. In this study, we addressed the functions of conserved switch II residues by performing alanine-scanning mutagenesis. Our results demonstrate that the GTPase activity of MeaB is autoinhibited by switch II and that this loop is important for coupling nucleotide-sensitive conformational changes in switch III to elicit the multiple chaperone functions of MeaB. Furthermore, we report the structure of MeaB·GDP crystallized in the presence of AlFx(-) to form the putative transition state analog, GDP·AlF4(-). The resulting crystal structure and its comparison with related G-proteins support the conclusion that the catalytic site of MeaB is incomplete in the absence of the GTPase-activating protein MCM and therefore unable to stabilize the transition state analog. Favoring an inactive conformation in the absence of the client MCM protein might represent a strategy for suppressing the intrinsic GTPase activity of MeaB in which the switch II loop plays an important role.

Analysis of an optically controlled photonic switch.

PubMed

Attard, A E

1999-05-20

The principle that the coupling of light between two fiber waveguides can be controlled by the resonant interference of a third waveguide has been developed [Attard, Appl. Opt. 37, 2296-2302 (1998)]. Here significant details concerning the operation of a photonic switch are obtained, and a more complete analysis is presented. Multiple-resonant conditions are identified for slab and fiber control waveguides at large indices of refraction. Thus a selection of materials with an appropriate refractive index and a Kerr coefficient is rendered more easily. Furthermore it is shown that the light used to control the index of refraction in the control waveguide does not enter the output of the photonic switch but remains confined to the control waveguide, for either a slab or a multimode fiber control waveguide. Spatial fluctuations of the control light beam in the control waveguide do not affect the operation of the photonic switch. Tolerances have been determined for the spacing between the control waveguide and the photonic coupler and also for the index of refraction of the control waveguide.

Pathogen host switching in commercial trade with management recommendations.

PubMed

Picco, Angela M; Karam, Abraham P; Collins, James P

2010-06-01

Global wildlife trade exacerbates the spread of nonindigenous species. Pathogens also move with hosts through trade and often are released into naïve populations with unpredictable outcomes. Amphibians are moved commercially for pets, food, bait, and biomedicine, and are an excellent model for studying how wildlife trade relates to pathogen pollution. Ranaviruses are amphibian pathogens associated with annual population die-offs; multiple strains of tiger salamander ranaviruses move through the bait trade in the western United States. Ranaviruses infect amphibians, reptiles, and fish and are of additional concern because they can switch hosts. Tiger salamanders are used as live bait for freshwater fishing and are a potential source for ranaviruses switching hosts from amphibians to fish. We experimentally injected largemouth bass with a bait trade tiger salamander ranavirus. Largemouth bass became infected but exhibited no signs of disease or mortality. Amphibian bait ranaviruses have the potential to switch hosts to infect fish, but fish may act as dead-end hosts or nonsymptomatic carriers, potentially spreading infection as a result of trade.

Better Bet-Hedging with coupled positive and negative feedback loops

NASA Astrophysics Data System (ADS)

Narula, Jatin; Igoshin, Oleg

2011-03-01

Bacteria use the phenotypic heterogeneity associated with bistable switches to distribute the risk of activating stress response strategies like sporulation and persistence. However bistable switches offer little control over the timing of phenotype switching and first passage times (FPT) for individual cells are found to be exponentially distributed. We show that a genetic circuit consisting of interlinked positive and negative feedback loops allows cells to control the timing of phenotypic switching. Using a mathematical model we find that in this system a stable high expression state and stable low expression limit cycle coexist and the FPT distribution for stochastic transitions between them shows multiple peaks at regular intervals. A multimodal FPT distribution allows cells to detect the persistence of stress and control the rate of phenotype transition of the population. We further show that extracellular signals from cell-cell communication that change the strength of the feedback loops can modulate the FPT distribution and allow cells even greater control in a bet-hedging strategy.

A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae.

PubMed

Atack, John M; Srikhanta, Yogitha N; Fox, Kate L; Jurcisek, Joseph A; Brockman, Kenneth L; Clark, Tyson A; Boitano, Matthew; Power, Peter M; Jen, Freda E-C; McEwan, Alastair G; Grimmond, Sean M; Smith, Arnold L; Barenkamp, Stephen J; Korlach, Jonas; Bakaletz, Lauren O; Jennings, Michael P

2015-07-28

Non-typeable Haemophilus influenzae contains an N(6)-adenine DNA-methyltransferase (ModA) that is subject to phase-variable expression (random ON/OFF switching). Five modA alleles, modA2, modA4, modA5, modA9 and modA10, account for over two-thirds of clinical otitis media isolates surveyed. Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles. Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4). Analyses of a modA2 strain in the chinchilla model of otitis media show a clear selection for ON switching of modA2 in the middle ear. Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

Fast simulation of packet loss rates in a shared buffer communications switch

NASA Technical Reports Server (NTRS)

Chang, Cheng-Shang; Heidelberger, Philip; Shahabuddin, Perwez

1993-01-01

This paper describes an efficient technique for estimating, via simulation, the probability of buffer overflows in a queueing model that arises in the analysis of ATM (Asynchronous Transfer Mode) communication switches. There are multiple streams of (autocorrelated) traffic feeding the switch that has a buffer of finite capacity. Each stream is designated as either being of high or low priority. When the queue length reaches a certain threshold, only high priority packets are admitted to the switch's buffer. The problem is to estimate the loss rate of high priority packets. An asymptotically optimal importance sampling approach is developed for this rare event simulation problem. In this approach, the importance sampling is done in two distinct phases. In the first phase, an importance sampling change of measure is used to bring the queue length up to the threshold at which low priority packets get rejected. In the second phase, a different importance sampling change of measure is used to move the queue length from the threshold to the buffer capacity.

Theoretical implications of quantitative properties of interval timing and probability estimation in mouse and rat.

PubMed

Kheifets, Aaron; Freestone, David; Gallistel, C R

2017-07-01

In three experiments with mice ( Mus musculus ) and rats (Rattus norvigicus), we used a switch paradigm to measure quantitative properties of the interval-timing mechanism. We found that: 1) Rodents adjusted the precision of their timed switches in response to changes in the interval between the short and long feed latencies (the temporal goalposts). 2) The variability in the timing of the switch response was reduced or unchanged in the face of large trial-to-trial random variability in the short and long feed latencies. 3) The adjustment in the distribution of switch latencies in response to changes in the relative frequency of short and long trials was sensitive to the asymmetry in the Kullback-Leibler divergence. The three results suggest that durations are represented with adjustable precision, that they are timed by multiple timers, and that there is a trial-by-trial (episodic) record of feed latencies in memory. © 2017 Society for the Experimental Analysis of Behavior.